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Association of spontaneous abortion with all cause and cause specific premature mortality: prospective cohort study

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  • Peer review
  • Yi-Xin Wang , postdoctoral fellow 1 ,
  • Lidia Mínguez-Alarcón , lecturer 2 3 ,
  • Audrey J Gaskins , assistant professor 4 ,
  • Stacey A Missmer , professor 5 6 ,
  • Janet W Rich-Edwards , associate professor 6 7 ,
  • JoAnn E Manson , professor 2 6 7 ,
  • An Pan , professor 8 ,
  • Jorge E Chavarro , associate professor 1 2 6
  • 1 Department of Nutrition, Harvard T H Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA
  • 2 Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  • 3 Department of Environmental Health, Harvard T H Chan School of Public Health, Boston, MA, USA
  • 4 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
  • 5 Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
  • 6 Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA
  • 7 Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  • 8 Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
  • Correspondence to: J E Chavarro jchavarr{at}hsph.harvard.edu
  • Accepted 10 February 2021

Objective To investigate the association of spontaneous abortion with the risk of all cause and cause specific premature mortality (death before the age of 70).

Design Prospective cohort study.

Setting The Nurses’ Health Study II (1993-2017), United States.

Participants 101 681 ever gravid female nurses participating in the Nurses’ Health Study II.

Main outcomes measures Lifetime occurrence of spontaneous abortion in pregnancies lasting less than 6 months, determined by biennial questionnaires. Hazard ratios and 95% confidence intervals for all cause and cause specific premature death according to the occurrence of spontaneous abortion, estimated with time dependent Cox proportional hazards models.

Results During 24 years of follow-up, 2936 premature deaths were recorded, including 1346 deaths from cancer and 269 from cardiovascular disease. Crude all cause mortality rates were comparable for women with and without a history of spontaneous abortion (1.24 per 1000 person years in both groups) but were higher for women experiencing three or more spontaneous abortions (1.47 per 1000 person years) and for women reporting their first spontaneous abortion before the age of 24 (1.69 per 1000 person years). The corresponding age adjusted hazard ratios for all cause premature death during follow-up were 1.02 (95% confidence interval 0.94 to 1.11), 1.39 (1.03 to 1.86), and 1.27 (1.11 to 1.46), respectively. After adjusting for confounding factors and updated dietary and lifestyle factors, the occurrence of spontaneous abortion was associated with a hazard ratio of 1.19 (95% confidence interval 1.08 to 1.30) for premature mortality during follow-up. The association was stronger for recurrent spontaneous abortions (hazard ratio 1.59, 95% confidence interval 1.17 to 2.15 for three or more spontaneous abortions; 1.23, 1.00 to 1.50 for two; and 1.16, 1.05 to 1.28 for one compared with none), and for spontaneous abortions occurring early in a woman’s reproductive life (1.32, 1.14 to 1.53 for age ≤23; 1.16, 1.01 to 1.33 for ages 24-29; and 1.12, 0.98 to 1.28 for age ≥30 compared with none). When cause specific mortality was evaluated, the association of spontaneous abortion with premature death was strongest for deaths from cardiovascular disease (1.48, 1.09 to 1.99). Spontaneous abortion was not related to premature death from cancer (1.08, 0.94 to 1.24).

Conclusions Spontaneous abortion was associated with an increased risk of premature mortality, particularly death from cardiovascular disease.

Introduction

Reducing a third of premature deaths from non-communicable diseases by 2030 is a United Nation’s sustainable development goal. 1 Identifying risk factors for death from non-communicable disease to highlight priorities for intervention is needed urgently. Although traditional risk factors that affect both men and women (eg, tobacco use, overweight and obesity, and physical inactivity) explain most of the deaths from non-communicable diseases globally, 2 increasing evidence suggests that reproductive factors unique to women are associated with a greater risk of death from non-communicable diseases. Even if reproductive events do not increase the risk of death from non-communicable diseases, they could be useful as an early stress test of underlying risk factors that cause adverse reproductive outcomes and death from non-communicable diseases. 3 4

Spontaneous abortion is one of the most common adverse outcomes of pregnancy, with an estimated prevalence of 12-24% in clinically recognized pregnancies. 5 6 Substantial evidence indicates that women with a history of spontaneous abortion have a greater risk of non-communicable diseases, including hypertension, 7 cardiovascular diseases, 7 8 9 10 11 and type 2 diabetes. 7 12 13 Evidence relating spontaneous abortion to mortality, however, is scant and inconsistent. 14 15 16 Major weaknesses of previous studies included retrospective assessment of spontaneous abortion in the long distant past, and lack of detailed data on various relevant confounders (eg, pre-pregnancy body mass index, history of other pregnancy complications) and mediating lifestyle factors (body mass index, quality of diet, smoking status, and physical activity). Also, whether the association is influenced by the number of spontaneous abortions or age at first spontaneous abortion is unclear. To overcome these limitations, we investigated the associations of spontaneous abortion with all cause and cause specific premature death among participants of the Nurses’ Health Study II. The Nurses’ Health Study II is an ongoing prospective cohort study of women of reproductive age (aged 25-42 at baseline), with continuous follow-up spanning three decades and periodic update of reproductive characteristics and lifestyle and health related factors. 17

Study population

The Nurses’ Health Study II is an ongoing prospective cohort established in 1989 by recruiting 116 429 female nurses of reproductive age (25-42 years) living in one of 14 states in the United States. 17 Participants are followed by biennial questionnaires, which collect information on reproductive history, personal characteristics, lifestyle factors, and the occurrence of diseases. 17 Participants were eligible for inclusion in the current analysis if they had a pregnancy history at recruitment or reported a pregnancy during follow-up up to 2009 (n=101 852). We excluded participants who had missing data on date of birth (n=17), refused to report their history of spontaneous abortion (n=15), or who had died before 1993, the baseline year for this analysis (n=139). The total number of women included in our current analysis was 101 681.

Determination of reproductive history

In the 1993 questionnaire, participants reported their lifetime history of pregnancies, and spontaneous and induced abortions, in pregnancies lasting less than six months. Participants also reported age at these events in the age categories: <18, 18-20, 21-23, 24-26, 27-29, 30-34, and ≥35. In each subsequent biennial questionnaire up to 2009, participants reported any new pregnancies, or spontaneous and induced abortions, that occurred during the past two years. In 2009, when most participants had reached menopause, women also reported the outcome and year of all of their pregnancies, including those ending in spontaneous or induced abortion. Self-report of pregnancy loss, including stillbirth and spontaneous abortion, has been validated in other studies; the sensitivity of reporting a loss when one actually occurred was estimated as 75%. 18 19 Among women who completed the 2009 questionnaire in this cohort, the proportion of women who reported spontaneous abortion in the biennial questionnaires that were also identified as such in 2009 was 83.7% (15 558 of 18 594). Similarly, the proportion of women without a history of spontaneous abortion in the biennial questionnaires that were also confirmed as such in 2009 was 94.4% (45 953 of 48 671). To reduce recall bias, we only used spontaneous abortions reported in the biennial questionnaires to determine the occurrence of spontaneous abortions.

Determination of deaths

Deaths were identified by searching the National Death Index or state vital statistics records, or by reporting from close relatives or postal authorities. Deaths that occurred at ages younger than 70 were defined as premature. 20 21 Causes of death were established by autopsy reports, physician review of medical records, or death certificates, according to the International Classification of Diseases eighth revision (codes for cardiovascular disease and cancer were 390-458 and 140-207, respectively) (supplementary table S1). The validity of this method for determining the number of deaths has been assessed in a similar group of nurses from the Nurses' Health Study. 22 Briefly, all participants known to be alive from the Massachusetts death records were correctly confirmed by the National Death Index (n=224); of 346 participants known to be dead from the state death records, 96.5% of the true deaths were correctly identified by the National Death Index.

Assessment of covariates

A physician’s diagnosis of gestational diabetes mellitus and hypertensive disorders of pregnancy were self-reported on the baseline questionnaire and updated every two years up to 2001. 23 24 Race or ethnicity, height, and body weight at age 18 were collected at baseline. Current body weight was collected at baseline and in the follow-up questionnaires. We calculated body mass index before pregnancy and during each follow-up cycle. Marriage status and parental history of myocardial infarction and stroke before the age of 60 were recorded at baseline and updated about every four years. Lifestyle factors, reproductive characteristics, and health related conditions (eg, smoking, menopausal status, use of oral contraceptives, use of aspirin, and pregnancy complications) were collected at baseline and updated every two years. Data on physical activity were recorded every four to six years from 1991. Usual dietary intake, including alcohol consumption, was assessed with a semi-quantitative food frequency questionnaire every four years from 1991. 17 Participants’ overall quality of their diet was evaluated by calculating the Alternative Healthy Eating Index, 2010 version. 25 The reliability of self-reported gestational diabetes mellitus, hypertensive disorders of pregnancy, smoking habit, body weight, physical activity, and dietary intake has been validated in subgroups of participants from this cohort or similar nurses from the Nurses' Health Study. 26 27 28

Data analysis

Women contributed person time from the date of return of the 1993 questionnaire or follow-up questionnaires when participants reported a pregnancy until death or the end of follow-up (30 June 2017), whichever occurred first. Occurrence of spontaneous abortion was updated every two years from 1993 to 2009, and ever gravid participants without spontaneous abortion were regarded as the reference group. Participants were considered exposed to spontaneous abortion from the age of the first report of a spontaneous abortion.

Time dependent multivariable adjusted Cox proportional hazards models were constructed to estimate hazard ratios and 95% confidence intervals to explore the associations between spontaneous abortion, overall and according to the number of spontaneous abortions and age at first spontaneous abortion, and the risk of all cause and cause specific premature death, while simultaneously adjusting for time varying confounders and risk factors. To control as finely as possible for confounding by age, calendar time, and possible interactions between these two timescales, the models were jointly stratified by age in months (continuous) at the start of follow-up and the calendar year for the current questionnaire cycle. 29 Multivariable adjusted models included terms for race or ethnicity (white or other) and pre-pregnancy body mass index (<25, 25-29.9, or ≥30), and time varying gravidity (1, 2, 3, or ≥4), nulliparity (no or yes), marriage status (never v ever), history of gestational diabetes (no or yes), hypertensive disorders of pregnancy (no or yes), menopausal status (premenopausal, postmenopausal, or unsure or biologically uncertain), use of hormone treatment (never, past, or current), daily use of aspirin (no or yes), and parental history of myocardial infarction or stroke (no or yes). In a secondary multivariable model, we further adjusted for time varying lifestyle factors, including current body mass index (<23, 23-24.9, 25-29.9, or ≥30), smoking status (never, former, current 1-34 cigarettes/day, or current ≥35 cigarettes/day), physical activity (0, 0.1-1.0, 1.1-2.4, 2.5-5.9, or ≥6 hours/week), and Alternative Healthy Eating Index 2010 diet quality score (five categories). For the covariates with missing values (all <5%), an indicator for missing data was created.

We then tested for effect modification by gravidity, parity, pre-pregnancy body mass index, history of gestational diabetes mellitus and hypertensive disorders of pregnancy, parental history of cardiovascular disease, updated body mass index, quality score for diet, physical activity, and smoking status. Interaction on the multiplicative scale was assessed by conducting likelihood ratio tests and on the additive scale by calculating the relative excess risk caused by interaction. 25

Several sensitivity analyses were conducted. First, we included never gravid women as a separate category to evaluate whether completing a pregnancy, rather than spontaneously losing a pregnancy, was responsible for the associations seen. Second, we jointly classified participants according to their history of spontaneous and induced abortion to explore whether the interruption of pregnancy, rather than the spontaneous loss of a pregnancy, was responsible for any observed relations. Third, we excluded women who were diagnosed with cancer (n=2788), type 2 diabetes (n=395), or cardiovascular disease (n=83) before 1993. Fourth, the comparison group was restricted to women whose pregnancies ended in a live birth only, by excluding women with other pregnancy outcomes (induced abortion, stillbirth, tubal or ectopic pregnancy) from the comparison group. Fifth, we excluded women who died as a result of complications of pregnancy, childbirth, and the puerperium. Sixth, we excluded women who did not return any follow-up questionnaires after 1993 (n=976). All data were analyzed with SAS 9.4 for UNIX (SAS Institute).

Patient and public involvement

This research was done without patient involvement. Patients and the public were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. Patients and the public were not invited to contribute to the writing or editing of this document for readability or accuracy.

Among 101 681 gravid women, 25.6% (n=26 102) had at least one pregnancy ending in spontaneous abortion. Table 1 shows participants’ age standardized characteristics in 1993 according to lifetime history of spontaneous abortion. Women who experienced spontaneous abortion were more likely than women who had not had a spontaneous abortion to use aspirin (2235 of 26 102 (8.56%) v 5195 of 75 579 (6.87%)), and to have a higher mean gravidity (3.34 (standard deviation 1.71) v 2.30 (1.22)) and higher prevalence of a parental history of myocardial infarction or stroke at baseline (7144 of 26 102 (27.37%) v 19 674 of 75 579 (26.03%)).

Age standardized baseline (1993) characteristics, according to occurrence of spontaneous abortion at baseline or during follow-up in 101 681 women (Nurses’ Health Study II, 1993-2017)*

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During 2 367 839 person years of follow-up, we reported 2936 premature deaths, including 1346 deaths from cancer and 269 from cardiovascular disease (supplementary table S1). Crude all cause mortality rates were comparable for women with and without a history of spontaneous abortion (1.24 per 1000 person years in both groups, fig 1 ), but were higher for women experiencing three or more spontaneous abortions (1.47 per 1000 person years, table 2 ) and for women reporting their first spontaneous abortion before the age of 24 (1.69 per 1000 person years, table 3 ). The corresponding age adjusted hazard ratios for all cause premature death during follow-up were 1.02 (95% confidence interval 0.94 to 1.11), 1.39 (1.03 to 1.86), and 1.27 (1.11 to 1.46), respectively. Differences in the risk of premature death were more evident after adjustment for gravidity ( fig 1 , table 2 , and table 3 ) and were stronger after further adjustment for potential confounding factors and post-pregnancy dietary and lifestyle factors, particularly in analyses evaluating the relation between the number of spontaneous abortions ( table 2 ) and age at first spontaneous abortion ( table 3 ).

Fig 1

Adjusted hazard ratios and 95% confidence intervals for the risk of all cause and cause specific premature death (before age 70) according to the overall occurrence of spontaneous abortion in 101 681 women (Nurses’ Health Study II, 1993-2017). In the age adjusted model, age in months (continuous) at the start of follow-up and calendar year of the current questionnaire cycle were included as stratification variables. Multivariable model 1 was further adjusted for time varying gravidity (1, 2, 3, or ≥4). Multivariable model 2 was further adjusted for white race or ethnicity (no or yes) and pre-pregnancy body mass index (<25, 25-29.9, or ≥30), and time varying nulliparity (no or yes), marriage status (never v ever or currently married), history of gestational diabetes (no or yes), hypertensive disorders of pregnancy (no or yes), menopausal status (premenopausal, postmenopausal, or unsure or biologically uncertain), use of hormone treatment (never, past, or current), daily use of aspirin (no or yes), and parental history of myocardial infarction or stroke (no or yes). Multivariable model 3 was further adjusted for time varying current body mass index (<23, 23-24.9, 25-29.9, or ≥30), smoking status (never, former, current 1-34 cigarettes/day, or current ≥35 cigarettes/day), physical activity (0, 0.1-1.0, 1.1-2.4, 2.5-5.9, or ≥6 hours/week), and Alternative Healthy Eating Index 2010 dietary score (five categories). NA=not available

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Adjusted hazard ratios for risk of all cause and cause specific premature mortality (before age 70), according to number of spontaneous abortions in 101 681 women (Nurses’ Health Study II, 1993-2017)

Adjusted hazard ratios for risk of all cause and cause specific premature mortality (before age 70), according to age at first spontaneous abortion in 101 681 women (Nurses’ Health Study II, 1993-2017)

In the fully adjusted models, women who experienced a spontaneous abortion were 19% (8-30%) more likely to die prematurely than women who did not have a spontaneous abortion ( fig 1 ). The multivariable adjusted hazard ratios for all cause premature death according to the number of spontaneous abortions were 1.59 (95% confidence interval 1.17 to 2.15) for three or more spontaneous abortions, 1.23 (1.00 to 1.50) for two spontaneous abortions, and 1.16 (1.05 to 1.28) for one spontaneous abortion relative to none ( table 2 ). The multivariable adjusted hazard ratios for all cause premature mortality according to age at first spontaneous abortion were 1.32 (1.14 to 1.53) for women aged 23 or younger, 1.16 (1.01 to 1.33) for ages 24-29, and 1.12 (0.98 to 1.28) for age 30 or older relative to none ( table 3 ). We found no evidence of effect modification of the relation between spontaneous abortion and premature death by reproductive characteristics, lifestyle factors, or body mass index (supplementary table S2).

In cause specific mortality analyses, spontaneous abortion was not related to death from cancer (hazard ratio 1.08, 95% confidence interval 0.94 to 1.24) but was associated with a greater risk of premature death from cardiovascular disease (1.48, 1.09 to 1.99) and of all other causes of death combined (1.25, 1.09 to 1.44) ( fig 1 ). These relations were also stronger in women who had a greater number of spontaneous abortions and those who first experienced a spontaneous abortion early in their reproductive life ( table 2 and table 3 ). In analyses where less common causes of death were disaggregated, spontaneous abortion was associated with a greater risk of death attributed to diseases of the gastrointestinal system (1.97, 1.09 to 3.56) but not related to all other causes of death ( table 4 ).

Adjusted hazard ratios for cause specific premature mortality (before age 70) for less common causes of death, according to overall occurrence of spontaneous abortion in 101 681 women (Nurses’ Health Study II, 1993-2017)

We then conducted a series of sensitivity analyses to evaluate the robustness of the findings and the possibility that the associations seen were not caused by spontaneous abortion itself. First, we performed an analysis where nulligravid women were included as a separate group to examine whether completing pregnancy was beneficial for mortality from cardiovascular disease rather than spontaneous abortion being detrimental. We found that nulligravidity was not related to death from cardiovascular disease in this analysis. Compared with gravid women who had never had a spontaneous abortion, the multivariable adjusted hazard ratio for premature death from cardiovascular disease was 1.47 (95% confidence interval 1.08 to 1.99) for gravid women with a history of spontaneous abortion and 1.21 (0.76 to 1.93) for nulligravid women. Second, to examine whether the termination of a pregnancy rather than spontaneous loss of a pregnancy was responsible for the association with death from cardiovascular disease, we conducted an analysis where induced abortion was classified as a separate comparison group. This analysis showed no relation between induced abortion and mortality from cardiovascular disease. Compared with gravid women who had never had a spontaneous or induced abortion, the multivariable adjusted hazard ratio for premature death from cardiovascular disease was 1.59 (95% confidence interval 1.15 to 2.20) for women who ever had a spontaneous abortion but no induced abortions, 1.06 (0.70 to 1.62) for women who had ever had an induced abortion but no spontaneous abortions, and 1.01 (0.51 to 2.00) for women who had both spontaneous and induced abortions. The results of associations between spontaneous abortion and premature death were also substantially unchanged when we excluded women who received a diagnosis of cancer, type 2 diabetes, or cardiovascular disease before 1993, when the comparison group was restricted to women whose pregnancies ended in a live birth only, when we excluded deaths caused by complications of pregnancy, childbirth, and the puerperium, and when we excluded women who never returned follow-up questionnaires (supplementary table S3).

Principal findings

The results from this large longitudinal study, with a 24 year follow-up, indicated that spontaneous abortion was associated with a greater risk of all cause premature death, particularly for recurrent spontaneous abortions and spontaneous abortions occurring early in a woman’s reproductive life. These associations were primarily because of an increased risk of death from cardiovascular disease, were independent of several shared risk factors (eg, body mass index, smoking, diet, and physical activity), and persisted in a series of sensitivity analyses aimed at isolating the role of spontaneous pregnancy losses from other factors. These findings highlight the growing literature showing that specific reproductive events and risk of chronic disease are linked over a woman’s life course; a better understanding of their associations might lead to insights to prevent adverse reproductive outcomes and premature death.

Underlying mechanisms of the associations seen

The association between spontaneous abortion and cardiovascular disease might reflect shared mechanistic pathways that contribute to spontaneous abortion and to the development of cardiovascular disease and ultimately premature death. For instance, insulin resistance, chronic kidney disease, and immune disorders have been linked to both spontaneous abortion and the development of clinical risk factors for cardiovascular disease. 30 31 32 Likewise, endothelial dysfunction was related to spontaneous abortion by causing defects of the placenta, 33 and was also implicated in the pathogenesis of cardiovascular, microvascular, and homeostatic dysfunction. 34 Some genetic or epigenetic features might also predispose women to both spontaneous abortion and cardiovascular disease, which is supported by the finding that parents of women with recurrent spontaneous abortions have a higher incidence of coronary artery disease. 35 Also, that spontaneous abortion could trigger a cascade that, in turn, leads to premature death, potentially by interactions with established risk factors for cardiovascular disease, has been hypothesized. 36 In support of this hypothesis, Wagner and colleagues found that women with a history of recurrent pregnancy loss showed a proinflammatory state, manifested as increased levels of high sensitivity C reactive protein, that has been strongly associated with future risk of cardiovascular disease. 37 Further research is needed to understand the underlying mechanisms linking spontaneous abortion to premature death from cardiovascular disease.

Comparison with other studies

Previous epidemiological studies have reported an association between a history of spontaneous abortion and a greater risk of cardiovascular disease, 7 8 9 10 11 38 39 40 41 chronic hypertension, 7 and type 2 diabetes. 7 12 13 So far, however, few studies have assessed the association of spontaneous abortion with death. In a Danish register based study (n=1 001 266), Coleman and colleagues reported that women who had registered a spontaneous abortion exhibited an odds ratio for mortality of 3.06 (95% confidence interval 2.19 to 4.28) compared with women without a history of abortion. 14 In contrast, in a Japanese cohort of 54 652 women aged 40-79, Yamada and colleagues found that women with a history of self-reported pregnancy loss (stillbirth, spontaneous and induced abortions combined) had a lower risk of death from cardiovascular disease. 15 In a Chinese cohort of 267 400 female textile workers, ranging in age at enrolment from 30 to over 60, self-reported spontaneous abortion was not related to death from cardiovascular disease. 16 The major methodological weakness of these previous studies is that they determined the occurrence of spontaneous abortions by retrospective recall at one time point in the long distant past or by hospital register databases, which could result in misclassification because most spontaneous abortions do not result in hospital admission. Also, lack of detailed data on various relevant confounders (eg, gravidity, pre-pregnancy body mass index) and mediating lifestyle factors could lead to residual and unmeasured confounding.

We noticed an increasing trend of a higher risk of premature death with a greater number of spontaneous abortions. The Danish register based study also reported a growing trend of higher mortality rates with an increasing number of spontaneous abortions. 14 In the Japanese cohort, Yamada and colleagues reported a twofold higher risk of death from ischemic stroke in a young subgroup of participants (aged 40-59) who experienced two or more pregnancy losses than those with no history of pregnancy loss. 15 Recurrent spontaneous abortion is a major stressful event in a woman’s life and has been associated with adverse mental health problems, such as depression and anxiety after the loss, 42 which are increasingly known as potential risk factors for all cause mortality and mortality related to cardiovascular disease. 43 The association between spontaneous abortion and all cause premature mortality was also stronger in women who experienced their first spontaneous abortion early in their reproductive life, suggesting that spontaneous abortion at an older age is more likely an indication of age related changes, such as chromosomal abnormalities and decreased ovarian function, 44 45 rather than an early sign of underlying physiopathology resulting in a greater risk of premature death.

Strengths and limitations

The strengths of our study include its prospective study design, large sample size, extensive follow-up period across most of the women’s reproductive lifespan, and the availability of various reproductive characteristics, and lifestyle and health related factors that allowed us to control for confounding and examine effect modification.

Our study had several limitations. First, misclassification of the occurrence of spontaneous abortions cannot be entirely ruled out, even though self-reported spontaneous abortion has been found to be reliable in this study and in other cohorts. 18 19 Given our prospective design, however, misclassification should be non-differential with respect to mortality, which would tend to bias effect estimates toward the null. Second, observational studies such as ours can only demonstrate an association, not causality. Whether experiencing the spontaneous loss of a pregnancy merely unmasks pre-existing risks or instead triggers or accelerates the development of premature death is not known. We found that induced abortion had no association with death from cardiovascular disease, however, suggesting that spontaneous abortion is more likely to be a marker than a cause of premature death. Because randomizing women to experience spontaneous loss of a pregnancy is not possible (or ethical, if it were possible), data from high quality observational studies with extended follow-up are, and are likely to remain, the best possible evidence to look at the association between spontaneous abortion and the risk of premature death. Third, although analyses where induced abortions were considered in a separate comparison group were supportive of our hypothesis, this specific analysis should be interpreted with caution as we are unsure of the validity of self-reports of induced abortions in the United States at the time the data were collected, which might have been influenced by cultural views of induced abortion. Fourth, because most of our cohort was non-Hispanic white women and all participants shared a profession and similar educational qualifications, our findings might not be applicable to other racial or ethnic groups and populations with lower educational attainment. Last, we had only a few cases for many of the causes of death, which limited our power to generate accurate estimates for causes of death other than from all cancers and from all cardiovascular disease combined.

Conclusions

We found that spontaneous abortion, particularly recurrent spontaneous abortions and spontaneous abortions occurring early in a woman’s reproductive life, was associated with an increased risk of premature death. The greater risk of all cause premature mortality associated with spontaneous abortion was mainly a result of a higher risk of death from cardiovascular disease. Our results suggest that spontaneous abortion could be an early marker of future health risk in women, including premature death. More research is needed to establish how spontaneous abortion is related to women’s long term health and the mechanisms underlying these relations.

What is already known on this topic

Spontaneous abortion is one of the most common adverse outcomes of pregnancy, with an estimated prevalence of 12-24%

Whether spontaneous abortion is associated with a long term risk of premature death (before the age of 70) is unclear

What this study adds

Spontaneous abortion was associated with a greater risk of premature death, particularly from cardiovascular disease

The association was particularly strong for recurrent spontaneous abortions and spontaneous abortions occurring early in a woman’s reproductive life

Spontaneous abortion could be an early marker of future health risk in women, including an increased risk of premature death

Acknowledgments

We thank the participants and staff of the Nurses’ Health Study II for their valuable contributions, and the following state cancer registries for their help: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington, and Wyoming. The authors assume full responsibility for the analyses and interpretation of these data.

Contributors: Y-XW analyzed and drafted the manuscript. Y-XW and JEC were involved in the study conception and design. LM-A checked the accuracy of the data analysis. Y-XW, LM-A, AJG, SAM, JWR-E, JEM, AP, and JEC participated in the interpretation of the results and critical revision of the manuscript. JEC is the study guarantor and accepts full responsibility for the work and conduct of the study, had access to the data, and controlled the decision to publish. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: This study was supported by grants U01-HL145386, U01-CA176726, R01-HL034594, and R01-HL088521 from the National Institutes of Health. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the US National Institutes of Health for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and the Harvard T H Chan School of Public Health. The completion of the self-administered questionnaire was considered to imply informed consent. Protocol No: 2009-P-002375.

Data sharing: Data described in the manuscript, code book, and analytic code will not be made publicly available. Further information, including the procedures for obtaining and accessing data from the Nurses’ Health Studies II, is described at www.nurseshealthstudy.org/researchers (email: [email protected] ).

The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: Study participants are periodically updated on findings from the study through multiple channels, including a yearly newsletter, the study website, and social media feeds.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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spontaneous abortion case study

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Spontaneous Abortion

(miscarriage; pregnancy loss).

, MD, UCLA Health

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spontaneous abortion case study

Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin , and ultrasonography. Treatment may be expectant management or with medication or procedural uterine evacuation.

Approximately 10 to 15% of confirmed pregnancies spontaneously abort, and over 80% of spontaneous abortions occur in the first trimester ( 1 General references Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more ).

Fetal death and early delivery are classified as follows ( 2 General references Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more , 3 General references Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more ):

Spontaneous abortion: Pregnancy loss before 20 weeks gestation

Fetal death ( stillbirth Stillbirth Stillbirth is fetal death (fetal demise) at ≥ 20 weeks gestation (> 28 weeks in some definitions). Management is delivery and postpartum care. Maternal and fetal testing is done to determine... read more ): Fetal death at ≥ 20 weeks

Preterm delivery Preterm Labor Labor (contractions resulting in cervical change) that begins before 37 weeks gestation is considered preterm. Risk factors include prelabor rupture of membranes, uterine abnormalities, infection... read more : Delivery of a live fetus between 20 weeks and 36 weeks/6 days

The American College of Obstetricians and Gynecologists defines a first-trimester pregnancy loss as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 6/7 weeks of gestation ( 3 General references Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more ).

Terminology for abortion varies based on several factors. Definitions specify the stage of development, embryonic (≤ 10 weeks of gestation) or fetal (≥ 11 weeks). For spontaneous abortion, descriptions are based on the location of the fetus and other products of conception and whether there is cervical dilation (see table ).

spontaneous abortion case study

General references

1. Magnus MC, Wilcox AJ, Morken NH, et al : Role of maternal age and pregnancy history in risk of miscarriage: Prospective register based study. BMJ 364:l869, 2019. doi: 10.1136/bmj.l869

2. First- and Second-Trimester Pregnancy Loss . In: Cunningham F, Leveno KJ, Dashe JS, Hoffman BL, Spong CY, Casey BM, eds. Williams Obstetrics , 26e. McGraw Hill; 2022. Accessed August 28, 2023.

3. American College of Obstetricians and Gynecologists (ACOG) : ACOG Practice Bulletin No. 200 Summary: Early Pregnancy Loss. Obstet Gynecol 132(5):1311-1313, 2018. doi:10.1097/AOG.0000000000002900

Etiology of Spontaneous Abortion

Early spontaneous abortion is often caused by a chromosomal abnormality Overview of Chromosomal Abnormalities . Maternal reproductive tract abnormalities (eg, bicornuate uterus, fibroids, adhesions) may also cause pregnancy loss through 20 weeks gestation. Isolated spontaneous abortions may result from certain viral infections—most notably cytomegalovirus, herpesvirus, parvovirus, and rubella virus. Other causes include immunologic abnormalities and major physical trauma. Most often, the cause is unknown.

Risk factors for spontaneous abortion include

Extremes of maternal age

History of spontaneous abortion

Cigarette smoking

Use of certain substances (eg, cocaine Social and Illicit Drugs During Pregnancy , alcohol) Social and Illicit Drugs During Pregnancy

A poorly controlled chronic disease (eg, diabetes Diabetes Mellitus in Pregnancy Pregnancy makes glycemic control more difficult in preexisting type 1 (insulin-dependent) and type 2 (non–insulin-dependent) diabetes but does not appear to exacerbate diabetic retinopathy,... read more , hypertension Hypertension in Pregnancy Recommendations regarding classification, diagnosis, and management of hypertensive disorders (including preeclampsia) are available from the American College of Obstetricians and Gynecologists... read more , overt thyroid disorders Thyroid Disorders in Pregnancy Thyroid disorders may predate or develop during pregnancy. Pregnancy does not change the symptoms of hypothyroidism and hyperthyroidism. Fetal effects vary with the disorder and the medications... read more ) in the mother

In a national database study, the risks of miscarriage across maternal age groups were as follows: < 20 years (17%); 20 to 24 (11%); 25 to 29 (10%); 30 to 34 (11%); 35 to 39 (17%); 40 to 44 (33%); > 45 (57%) ( 1 Etiology reference Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more ).

Subclinical thyroid disorders, a retroverted uterus, and minor trauma have not been shown to cause spontaneous abortions.

Etiology reference

Symptoms and signs of spontaneous abortion.

Symptoms of spontaneous abortion include crampy pelvic pain Pelvic Pain During Early Pregnancy Pelvic pain is common during early pregnancy and may accompany serious or minor disorders. Some conditions causing pelvic pain also cause vaginal bleeding. In some of these disorders (eg, ruptured... read more , uterine bleeding, and eventually expulsion of tissue.

Bleeding in early pregnancy Vaginal Bleeding During Early Pregnancy Vaginal bleeding occurs in approximately 20% of confirmed pregnancies during the first 20 weeks of gestation; about half of these cases end in spontaneous abortion ( 1). Vaginal bleeding is... read more is common; in one study of over 4500 women, bleeding occurred in approximately 25% of first-trimester pregnancies, and 12% of pregnancies with bleeding resulted in pregnancy loss ( 1 Symptoms and signs reference Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more ).

Late spontaneous abortion may begin with a gush of fluid when the membranes rupture. Hemorrhage is rarely massive. A dilated cervix indicates that abortion is inevitable.

If products of conception remain in the uterus after spontaneous abortion, uterine bleeding may occur, sometimes after a delay of hours to days. Infection may also develop, causing fever, pain, and sometimes sepsis (called septic abortion Septic Abortion Septic abortion is serious uterine infection during or shortly before or after a spontaneous or an induced abortion. Septic abortion is a gynecologic emergency. Septic abortions usually result... read more ).

Symptoms and signs reference

1. Hasan R, Baird DD, Herring AH, et al : Patterns and predictors of vaginal bleeding in the first trimester of pregnancy. Ann Epidemiol 20(7):524-531, 2010. doi:10.1016/j.annepidem.2010.02.006

Diagnosis of Spontaneous Abortion

Transvaginal ultrasonography

Quantitative beta subunit of human chorionic gonadotropin (beta-hCG)

Pelvic examination

Pregnancy is diagnosed with a urine or serum beta-hCG test. Transvaginal ultrasonography is the main method used to evaluate for spontaneous abortion. If ultrasonography is not available, hCG results may be informative. There is no single hCG level that is diagnostic of spontaneous abortion; serial beta-hCG levels that decrease across several measurements are consistent with a failed pregnancy.

Transvaginal ultrasonography is performed to confirm intrauterine pregnancy and check for fetal cardiac activity, which is usually detectable after 5.5 to 6 weeks gestation. However, gestational age is often somewhat uncertain, and serial ultrasonography is often required. If cardiac activity is absent and had been detected previously during the current pregnancy, fetal demise is diagnosed.

In early pregnancy, for patients with suspected spontaneous abortion, transvaginal ultrasound findings diagnostic of pregnancy failure are one or more of the following ( 1 Diagnosis reference Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more ):

Crown-rump length ≥ 7 mm and no heartbeat

Mean sac diameter ≥ 25 mm and no embryo

Absence of an embryo with a heartbeat, after a previous scan in current pregnancy: ≥ 2 weeks earlier that showed a gestational sac without a yolk sac OR ≥ 11 days earlier in the current pregnancy that showed a gestational sac with a yolk sac

There are many ultrasound findings that raise suspicion for but are not diagnostic of pregnancy failure, including characteristics of the gestational or yolk sac, absence of embryo or heartbeat, and crown-rump length. If these findings are present, serial evaluation is required to confirm whether a pregnancy is viable.

Traditionally, the status of the abortion process is classified as follows:

Threatened abortion: Patients have uterine bleeding and it is too early to assess whether the fetus is alive and viable and the cervix is closed. Potentially, the pregnancy may continue without complications.

Inevitable abortion: The cervix is dilated. If the cervix is dilated, the volume of bleeding should be evaluated because it is sometimes significant.

Incomplete abortion: The products of conception are partially expelled.

Complete abortion: The products of conception have passed and the cervix is closed (see table ).

Missed abortion: Death of an embryo or a fetus is confirmed, but there is no bleeding or cervical dilation and the products of conception have not been expelled.

An anembryonic pregnancy (formerly blight ovum) refers to a nonviable pregnancy with a gestational sac, but with no yolk sac or embryo visualized on transvaginal ultrasonography.

For recurrent pregnancy loss Recurrent Pregnancy Loss Recurrent pregnancy loss is ≥ 2 to 3 spontaneous abortions. Determining the cause may require extensive evaluation of both parents. Some causes can be treated. Causes of recurrent pregnancy... read more , typically testing is done to determine the cause of abortion.

Differential diagnosis

Bleeding Vaginal Bleeding During Early Pregnancy Vaginal bleeding occurs in approximately 20% of confirmed pregnancies during the first 20 weeks of gestation; about half of these cases end in spontaneous abortion ( 1). Vaginal bleeding is... read more is common in early pregnancy (for differential diagnosis, see table ).

Pelvic pain Pelvic Pain During Early Pregnancy Pelvic pain is common during early pregnancy and may accompany serious or minor disorders. Some conditions causing pelvic pain also cause vaginal bleeding. In some of these disorders (eg, ruptured... read more or pressure is also a common pregnancy symptom (see table for differential diagnosis).

Diagnosis reference

1. Doubilet PM, Benson CB, Bourne T, et al : Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med 369(15):1443-1451, 2013. doi:10.1056/NEJMra1302417

Treatment of Spontaneous Abortion

For threatened abortion, observation

For inevitable, incomplete, or missed abortions, observation or surgical or medical uterine evacuation

If the mother is Rh-negative, Rho(D) immune globulin

Pain medication as needed

Emotional support

For threatened abortion, treatment is observation, but clinicians may periodically evaluate the woman's symptoms or do ultrasonography to check fetal status. No evidence suggests that bed rest decreases risk of subsequent completed abortion.

For inevitable, incomplete, or missed abortions, treatment is waiting for spontaneous passage of products of conception, management with medications, or uterine evacuation.

In the first trimester , expectant management is an option, but this approach is not recommended during the second trimester due to limited safety studies and risk of hemorrhage ( 1 Treatment references Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more ). Expectant management has an 80% success rate for complete expulsion within 8 weeks, with symptomatic women having better outcomes than asymptomatic women. Bleeding and cramping may occur, and patients should be counseled about when to return to the healthcare facility if symptoms are severe or to confirm passage of gestational tissue. Ultrasound and reported symptoms are used to confirm passage of gestational tissue; in a patient with a previous ultrasound that showed a gestational sac, a follow-up ultrasound with no gestational sac is the most common criterion for complete expulsion. For patients who cannot return for ultrasound confirmation, triaging via telemedicine and/or home urine pregnancy tests may be useful. If complete expulsion is not achieved within a reasonable time, medical management or surgery may be necessary.

Until 10 to 12 weeks gestation, medical management may be used if spontaneous expulsion does not occur or if a patient prefers use of medications to allow a more predictable process. A common medication regimen is 800 mcg of misoprostol vaginally; a repeat dose may be necessary. Administering 200 mg of mifepristone orally 24 hours before the misoprostol can significantly improve treatment success, if mifepristone is available ( 1 Treatment references Spontaneous abortion is pregnancy loss before 20 weeks gestation. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment... read more ).

Spontaneous abortions that are not completely expelled with expectant management or medications require surgical uterine evacuation. Also, some women may prefer surgical evacuation due to more immediate completion and less need for follow-up care. Traditionally, uterine evacuation was performed with sharp curettage alone. However, suction curettage Instrumental evacuation In the United States, about half of pregnancies are unintended. About 40% of unintended pregnancies end in induced abortion; 90% of procedures are done during the 1st trimester. In the United... read more is now favored due to superior outcomes and can be completed in an office setting with local anesthesia and/or sedation in first trimester loss patients.

Urgent surgical evacuation may be needed in cases of hemorrhage, hemodynamic instability, or infection.

If complete abortion seem likely based on symptoms and/or ultrasound, further management with medications or uterine evacuation is typically not required. Uterine evacuation may be needed if bleeding occurs and/or if other signs indicate that products of conception may be retained.

Pain medications should be given, as appropriate. Rho(D) immune globulin Prevention Hemolytic disease of the fetus and neonate is hemolytic anemia in the fetus (or neonate, as erythroblastosis neonatorum) caused by transplacental transmission of maternal antibodies to fetal... read more is given if the pregnant patient is Rh-negative.

After a spontaneous abortion, parents may feel grief or guilt. They should be given emotional support and, in most cases of spontaneous abortions, reassured that their actions were not the cause. Formal counseling or support groups may be made available if appropriate.

Treatment references

1. American College of Obstetricians and Gynecologists (ACOG) : ACOG Practice Bulletin No. 200: Early pregnancy loss. Obstet Gynecol 132(5):e197–e207, 2018. doi:10.1097/AOG.0000000000002899

2. Zhang J, Gilles JM, Barnhart K, et al : A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 353(8):761-769, 2005. doi:10.1056/NEJMoa044064

3. Schreiber CA, Creinin MD, Atrio J, et al : Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med 378(23):2161-2170, 2018. doi:10.1056/NEJMoa1715726

Spontaneous abortion is pregnancy loss before 20 weeks gestation; it occurs in approximately 10 to 15% of confirmed pregnancies.

Spontaneous abortion is often caused by chromosomal abnormalities or maternal reproductive tract abnormalities (eg, bicornuate uterus, fibroids), but etiology in an individual case is usually not confirmed.

Confirm spontaneous abortion and determine pregnancy status with quantitative beta-hCG, ultrasonography, and pelvic examination; a dilated cervix means that abortion is inevitable.

Treat with expectant management (observe for passage of products of conception) or surgical or medication (with misoprostol or sometimes mifepristone ) uterine evacuation.

Often, uterine evacuation is not needed for complete abortions.

Provide emotional support to the parents.

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Data are stratified by gestational age groups (6-8, 9-13, and 14-19 weeks), maternal age group, number of antenatal visits, race and ethnicity, and Vaccine Safety Datalink site. The dashed beige lines indicate time during pregnancy but outside the surveillance period; the amount of time represented varies by pregnancy and is not to scale with the figure. The solid blue lines represent pregnancy time during the surveillance period. LMP indicates last menstrual period.

Generalized estimating equation models included gestational age group, surveillance period, maternal age group, number of antenatal visits, site, and race and ethnicity factors and accounted for unique pregnancies that included multiple pregnancy periods. mRNA indicates messenger RNA.

eTable. Secondary Analyses, Adjusted Odds Ratios and 95% Confidence Intervals Among Pregnant People Eligible for a COVID-19 Booster Dose, by 28-Day and 42-Day Exposure Windows and by Manufacturer

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Kharbanda EO , Haapala J , Lipkind HS, et al. COVID-19 Booster Vaccination in Early Pregnancy and Surveillance for Spontaneous Abortion. JAMA Netw Open. 2023;6(5):e2314350. doi:10.1001/jamanetworkopen.2023.14350

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COVID-19 Booster Vaccination in Early Pregnancy and Surveillance for Spontaneous Abortion

  • 1 HealthPartners Institute, Minneapolis, Minnesota
  • 2 Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, New York
  • 3 Kaiser Permanente Center for Health Research, Portland, Oregon
  • 4 Institute for Health Research, Kaiser Permanente Colorado, Denver
  • 5 Marshfield Clinic Research Institute, Marshfield, Wisconsin
  • 6 Kaiser Permanente Southern California, Pasadena
  • 7 Denver Health, Denver, Colorado
  • 8 Kaiser Permanente Vaccine Study Center, Oakland, California
  • 9 Kaiser Permanente Washington Health Research Institute, Seattle, Washington
  • 10 Centers for Disease Control and Prevention, Atlanta, Georgia

Question   Is COVID-19 booster vaccination in early pregnancy associated with an increased risk of spontaneous abortion?

Findings   In this case-control surveillance study of more than 100 000 pregnancies at 6 to 19 weeks’ gestation from 8 health systems in the Vaccine Safety Datalink, the odds of having received a COVID-19 booster vaccination in either a 28- or 42-day exposure window before spontaneous abortion were not increased compared with ongoing pregnancies.

Meaning   These findings support the safety of COVID-19 booster vaccination in early pregnancy.

Importance   Adherence to COVID-19 booster vaccine recommendations has lagged in pregnant and nonpregnant adult populations. One barrier to booster vaccination is uncertainty regarding the safety of booster doses among pregnant people.

Objective   To evaluate whether there is an association between COVID-19 booster vaccination during pregnancy and spontaneous abortion.

Design, Setting, and Participants   This observational, case-control, surveillance study evaluated people aged 16 to 49 years with pregnancies at 6 to 19 weeks’ gestation at 8 health systems in the Vaccine Safety Datalink from November 1, 2021, to June 12, 2022. Spontaneous abortion cases and ongoing pregnancy controls were evaluated during consecutive surveillance periods, defined by calendar time.

Exposure   Primary exposure was receipt of a third messenger RNA (mRNA) COVID-19 vaccine dose within 28 days before spontaneous abortion or index date (midpoint of surveillance period in ongoing pregnancy controls). Secondary exposures were third mRNA vaccine doses in a 42-day window or any COVID-19 booster in 28- and 42-day windows.

Main Outcomes and Measures   Spontaneous abortion cases and ongoing pregnancy controls were identified from electronic health data using a validated algorithm. Cases were assigned to a single surveillance period based on pregnancy outcome date. Eligible ongoing pregnancy time was assigned to 1 or more surveillance periods as an ongoing pregnancy-period control. Generalized estimating equations were used to estimate adjusted odds ratios (AOR) with gestational age, maternal age, antenatal visits, race and ethnicity, site, and surveillance period as covariates and robust variance estimates to account for inclusion of multiple pregnancy periods per unique pregnancy.

Results   Among 112 718 unique pregnancies included in the study, the mean (SD) maternal age was 30.6 (5.5) years. Pregnant individuals were Asian, non-Hispanic (15.1%); Black, non-Hispanic (7.5%); Hispanic (35.6%); White, non-Hispanic (31.2%); and of other or unknown (10.6%); and 100% were female. Across eight 28-day surveillance periods, among 270 853 ongoing pregnancy-period controls, 11 095 (4.1%) had received a third mRNA COVID-19 vaccine in a 28-day window; among 14 226 cases, 553 (3.9%) had received a third mRNA COVID-19 vaccine within 28 days of the spontaneous abortion. Receipt of a third mRNA COVID-19 vaccine was not associated with spontaneous abortion in a 28-day window (AOR, 0.94; 95% CI, 0.86-1.03). Results were consistent when using a 42-day window (AOR, 0.97; 95% CI, 0.90-1.05) and for any COVID-19 booster in a 28-day (AOR, 0.94; 95% CI, 0.86-1.02) or 42-day (AOR, 0.96; 95% CI, 0.89-1.04) exposure window.

Conclusions and Relevance   In this case-control surveillance study, COVID-19 booster vaccination in pregnancy was not associated with spontaneous abortion. These findings support the safety of recommendations for COVID-19 booster vaccination, including in pregnant populations.

As of March 2023, more than 682 million SARS-CoV-2 infections and more than 6.8 million COVID-19 deaths have been reported worldwide. 1 Although COVID-19 in otherwise healthy young adults is often mild or asymptomatic, infections during pregnancy are associated with increased risk of morbidity and adverse birth outcomes. 2 , 3 Vaccination has been shown to reduce the risks of severe disease during pregnancy and to provide additional protection from complications in newborns. 4 - 9

Because of waning immunity and the emergence of more contagious variants, starting in September 2021, booster doses of the messenger RNA (mRNA) vaccines were made available for populations in the United States who had completed the primary vaccine series and were at increased risk for severe illness due to COVID-19, including pregnant people. 10 Subsequently, all adolescents and adults were encouraged to receive a COVID-19 vaccine booster after primary vaccination. 11

Adherence to COVID-19 booster vaccine recommendations has lagged in pregnant and nonpregnant adult populations. 12 , 13 One barrier to booster vaccination is the uncertainty regarding the effectiveness and duration of protection of additional vaccine doses. Others may question whether a booster is needed given a prior history of SARS-CoV-2 infection. An additional concern among pregnant people is regarding the safety of booster doses. Previous studies 5 , 14 - 17 have demonstrated that receipt of 1 or 2 mRNA COVID-19 vaccine doses in pregnancy, as part of the primary vaccine series, was not associated with adverse pregnancy or birth outcomes, including spontaneous abortion, preterm birth, small-for-gestational-age birth, and infant neonatal care admissions. The aim of the current study was to evaluate potential associations between COVID-19 booster vaccination in early pregnancy and spontaneous abortion through adaptation of previously described COVID-19 vaccination in pregnancy safety surveillance. 15

The Vaccine Safety Datalink (VSD) is a collaborative effort between the Centers for Disease Control and Prevention’s (CDC’s) Immunization Safety Office and several large US integrated health care systems. The aim of the VSD is to monitor the safety of vaccines routinely administered in the United Sates. 18 In this observational, case-control, surveillance study conducted from November 1, 2021, to June 12, 2022, we used administrative and electronic health record (EHR) data from 8 sites participating in the VSD to evaluate potential associations between receipt of COVID-19 booster vaccine doses before 20 weeks’ gestation and spontaneous abortion. Primary analyses focused on receipt of a third mRNA COVID-19 vaccine dose in a 28-day exposure window. Secondary analyses evaluated receipt of a booster dose in 28-day or 42-day exposure windows in the full population and limited to the subset who had completed the primary vaccine series. This surveillance was approved by the institutional review boards of all participating sites and the CDC with a waiver of informed consent because this was a minimal risk, observational study and was conducted consistent with federal law and CDC policy. The analytic approach followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline for case-control designs. External researchers can request deidentified data from the VSD for conducting secondary analyses, as described on the VSD website. 19

Data for this case-control surveillance study came from 8 VSD sites (Kaiser Permanente: Washington, Northwest, Northern California, Southern California, and Colorado; Denver Health; HealthPartners; and Marshfield Clinic). People in the VSD population aged 16 to 49 years with a pregnancy 6 to 19 weeks’ gestation between November 1, 2021, and June 12, 2022, were identified using a validated algorithm applied to automated electronic health data. 20 The algorithm uses International Statistical Classification of Diseases, Tenth Revision, Clinical Modification ( ICD-10-CM ) and Current Procedural Terminology ( CPT ) codes from inpatient, outpatient, and emergency department visits, supplemented with clinical data, with updates on a weekly basis, to identify ongoing and completed pregnancies. Ectopic pregnancies, gestational trophoblastic disease, and pregnancies ending in therapeutic abortion were excluded. Pregnancies resulting from assisted reproduction, and thus at increased risk for having a medically attended spontaneous abortion, were also excluded. Exclusions were identified through diagnostic ( ICD-10-CM ) or procedure ( CPT ) codes.

Surveillance was conducted from November 2021 through the middle of June 2022. Data presented are from the final data extraction on August 3, 2022. For the primary analyses, evaluating a 28-day vaccine exposure window, eight 28-day surveillance periods were included. For secondary analyses, evaluating a 42-day exposure window, five 42-day surveillance periods were included. Midpoints of the surveillance periods were assigned as the index date for ongoing pregnancies. This index date was then used to assign a gestational age for an ongoing pregnancy period and to evaluate for receipt of a COVID-19 booster vaccination in the prior 28 or 42 days ( Figure 1 ). 21

Spontaneous abortion cases and ongoing pregnancy controls were identified using a validated algorithm, applied to automated electronic health data. In a previous validation, of 105 spontaneous abortions identified by the algorithm, agreement on pregnancy outcome was 95% and agreement on date of pregnancy outcome was 94%. 20 Consistent with prior work, 15 gestational age for both spontaneous abortions and ongoing pregnancies was based on the algorithm’s hierarchical approach to clinical data (last menstrual period and estimated delivery date), gestational age–specific ICD-10-CM codes (eg, Z3A.11 for 11 weeks’ gestation), or trimester-specific ICD-10-CM codes (eg, O13.2 for gestational hypertension without significant proteinuria, second trimester). Spontaneous abortion cases without gestational age available from these sources were assigned to the earliest gestational age category (6-8 weeks). Ongoing pregnancies with unknown gestational age were excluded.

Spontaneous abortions occurring between 6 and 19 weeks’ gestation were included as cases and assigned to a single surveillance period based on the pregnancy outcome date. 15 In the primary analyses, during each 28-day surveillance period, eligible ongoing pregnancies between 6 and 19 weeks’ gestation were included as ongoing pregnancy-period controls and assigned an index date equal to the midpoint (day 14) of the 28-day surveillance period. For secondary analyses, using a 42-day surveillance period, the index date was assigned at the midpoint (day 21) of the surveillance period. In both primary and secondary analyses, ongoing pregnancies could be included in more than 1 surveillance period, contributing data as 2 or more ongoing pregnancy-period controls; pregnancies ending in a spontaneous abortion case in 1 surveillance period could contribute data as an ongoing pregnancy-period control in 1 or more surveillance periods before the spontaneous abortion.

As previously described, most vaccines administered in the VSD pregnant population have been the mRNA COVID-19 vaccines, mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech). 14 , 22 A previous case-control surveillance study 15 of spontaneous abortion after receipt of the COVID-19 primary vaccine series in pregnancy used a 28-day exposure window, consistent with the presumed timing of the inflammatory response after COVID-19 vaccination. As such, primary analyses for the evaluation of booster vaccination in early pregnancy evaluated a third mRNA vaccine (mRNA-1273 or BNT162b2) dose occurring in a 28-day exposure window before the date for the spontaneous abortion (or index date in ongoing pregnancy controls).

In secondary analyses, we evaluated any COVID-19 vaccine booster (including a second dose of Ad26.COV.2.S [Janssen] or a second or third dose of an mRNA COVID-19 vaccine after Ad26.COV.2.S or a fourth or fifth mRNA COVID-19 vaccine dose) in a 28-day exposure window. In addition, we evaluated a third mRNA vaccine dose or any COVID-19 vaccine booster in a 42-day exposure window before spontaneous abortion (or index date in ongoing pregnancy controls). Secondary analyses also evaluated associations between COVID-19 booster vaccination and spontaneous abortion among those who had completed the primary vaccine series and thus were booster eligible.

COVID-19 vaccines administered from the start of the COVID-19 vaccine program (December 15, 2020) through June 12, 2022, in the eligible study population were identified from standardized VSD files. The VSD vaccine files include EHR data as well as medical and pharmacy claims and are supplemented through bidirectional communication with regional or state immunization information systems with standardized data quality checks and deduplication of vaccines from multiple sources. 23 Vaccines were then classified as first, second, third, or subsequent doses. To reduce the potential for vaccine data from different sources (eg, EHR, state immunization registry, and claims) to be counted as distinct doses, we required at least 14 days between dose 1 and dose 2 and at least 28 days between dose 2 and dose 3 or subsequent doses. The median (IQR) time between the second and third mRNA COVID-19 vaccine dose was 252 (220-289) days.

Covariates associated with likelihood of vaccination and risks for spontaneous abortion outcomes were included in models. Maternal age was categorized into the following groups: 16 to 24, 25 to 34, 35 to 39, and 40 to 49 years. Race and ethnicity were based on self-report as documented in the EHR and categorized as Asian, non-Hispanic; Black, non-Hispanic; Hispanic; White, non-Hispanic; or other or unknown (including Hawaiian or other Pacific Islander, Native American or Aleutian, and multiple races). Antenatal health care visits before the spontaneous abortion (or index date for ongoing pregnancy controls) came from EHR data and were classified as 1 or fewer or 2 or more. Gestational week of the spontaneous abortion or index date for ongoing pregnancy-period controls was categorized as 6 to 8, 9 to 13, or 14 to 19 weeks. The VSD site and surveillance period were also included as covariates.

In primary analyses, we calculated the odds of receiving a third mRNA COVID-19 vaccine in the 28 days before spontaneous abortion for cases compared with the odds of receiving a third mRNA COVID-19 vaccine in the 28 days before an index date for ongoing pregnancy-period controls. Generalized estimating equations with binomial distribution and logit link with robust variance estimates were used to account for unique pregnancies that contributed data in 2 or more surveillance periods and included covariates listed as main factors. Subgroup analyses by manufacturer (Moderna for mRNA-1273 and BioNTech-Pfizer for BNT162b2) were also conducted.

Using this same approach, we calculated adjusted odds ratios (AORs) and 95% CIs for receipt of any COVID-19 booster vaccine in the 28 days before spontaneous abortion or index date in ongoing pregnancy periods. In addition, we evaluated receipt of a third mRNA COVID-19 vaccine or any COVID-19 vaccine booster in the 42 days before spontaneous abortion or index date in ongoing pregnancy periods in secondary analyses. This same approach was applied in secondary analyses for the subset who were booster eligible, having completed the primary COVID-19 vaccine series. All analyses were performed using SAS/STAT software, version 9.4 (SAS Institute Inc).

A total of 112 718 unique pregnancies (mean [SD] maternal age, 30.6 [5.5] years; 100% women; 15.1% Asian, non-Hispanic; 7.5% Black, non-Hispanic; 35.6% Hispanic; 31.2% White, non-Hispanic; and 10.6% other or unknown race or ethnicity) were included in the study, with 14 226 pregnancies (12.6%) ending in a spontaneous abortion. The primary analyses included a total of 285 079 pregnancy periods (14 226 spontaneous abortion cases and 270 853 ongoing pregnancy-period controls), with 11 648 (4.1%) having received a third mRNA vaccine in a 28-day exposure window. Across both cases and controls, receipt of a third mRNA vaccine dose in a 28-day window varied by race and ethnicity (2775 [6.5%] in Asian, non-Hispanic people, 495 [2.3%] in Black, non-Hispanic people, 3276 [3.2%] in Hispanic people, and 4323 [4.9%] in White, non-Hispanic pregnant people) ( Table 1 ).

Of 270 853 ongoing pregnancy-period controls, 11 095 (4.1%) received a third mRNA COVID-19 vaccine dose within 28 days of their index date, whereas 553 of 14 226 cases (3.9%) ending in spontaneous abortion received a third mRNA COVID-19 vaccine dose within 28 days of the spontaneous abortion. Although third mRNA vaccine doses were noted in every surveillance period, most were during the first four 28-day surveillance periods ( Table 2 ).

In primary analyses, receipt of a third mRNA COVID-19 vaccine was not associated with spontaneous abortion (AOR, 0.94; 95% CI, 0.86-1.03) ( Table 3 ). Results were consistent when stratified by vaccine manufacturer (mRNA-1273: AOR, 0.93; 95% CI, 0.81-1.07; and BNT162b2: AOR, 0.95; 95% CI, 0.84-1.07) ( Figure 2 ).

Among 270 853 ongoing pregnancy-period controls, 11 952 (4.4%) received any COVID-19 booster dose within 28 days of their index date, whereas 592 (4.2%) of 14 226 cases received any COVID-19 vaccine booster dose in a 28-day window before the spontaneous abortion. In these analyses, among 12 544 booster doses administered to cases and controls, 11 701 (93.3%) were third doses, 698 (5.6%) were second doses, 135 (1.1%) were fourth doses, and 10 (0.1%) were fifth doses. Receipt of any COVID-19 booster vaccination within a 28-day window was not associated with spontaneous abortion (AOR, 0.94; 95% CI, 0.86-1.02) ( Table 3 ), with results consistent when stratified by vaccine manufacturer (mRNA-1273: AOR, 0.94; 95% CI, 0.82-1.07; and BNT1262b2: AOR, 0.93; 95% CI, 0.83-1.05) ( Figure 2 ).

Secondary analyses included 103 156 unique pregnancies across five 42-day surveillance periods from November 1, 2021, to May 29, 2022; 89 830 (87.1%) remained ongoing pregnancies and 13 326 (12.9%) ended in a spontaneous abortion. Secondary analyses using a 42-day surveillance period included a total of 182 025 pregnancy periods (13 326 cases and 168 699 ongoing pregnancy-period controls), with 11 669 (6.4%) having received a third mRNA vaccine and 12 494 (6.9%) having received any COVID-19 vaccine booster in a 42-day exposure window. Receipt of a third mRNA COVID-19 vaccine (AOR, 0.97; 95% CI, 0.90-1.05) or any COVID-19 vaccine booster (AOR, 0.96; 95% CI, 0.89-1.04) was not associated with spontaneous abortion ( Table 3 ). Results were consistent when stratified by vaccine manufacturer ( Figure 2 ). In secondary analyses limited to those who were booster eligible, there was no association between COVID-19 booster vaccination and spontaneous abortion, consistent with results for the full cohort (eTable in Supplement 1 ).

In this large case-control surveillance study of more than 100 000 unique pregnancies and analyses that included 285 079 pregnancy periods, receipt of a COVID-19 booster vaccine in early pregnancy was not associated with spontaneous abortion. Our primary analyses focused on the receipt of a third mRNA COVID-19 vaccine in a 28-day exposure window because this was the most common type of booster vaccination in our population. Our findings were consistent in secondary analyses that evaluated receipt of any COVID-19 booster, the 42-day exposure window, and associations in the subset who had completed the primary vaccine series.

The need to monitor the safety of booster vaccination in early pregnancy is clear, given the potential for repeat vaccine doses to be associated with local and systemic symptoms. 24 Furthermore, concerns regarding reactogenicity of booster vaccination may be contributing to vaccine hesitancy. 24 However, data to date have not demonstrated that COVID-19 booster vaccination is associated with an increase in acute reactions in pregnant or other adult populations. A prospective study 24 of more than 17 000 adults receiving a COVID-19 booster vaccine, including 2009 who were pregnant at the time of vaccination, found that the rates of self-reported local and systemic reactions after COVID-19 booster vaccination were similar to those following a second COVID-19 vaccine dose. As of March 24, 2022, the Vaccine Adverse Event Reporting System had received 323 reports of adverse events in pregnant people after a COVID-19 booster vaccine. However, the overall safety profile was similar to that after the initial COVID-19 vaccine series. 25 In addition, v-Safe, a voluntary after-vaccination health checker, found that individuals 18 years or older reported fewer injection site or systemic reactions after a first booster dose than after dose 1 or dose 2 of the primary series. 26 Similarly, our surveillance study of third mRNA vaccine doses and spontaneous abortion found an AOR of 0.94 (95% CI, 0.86-1.03), consistent with our findings following the first or second mRNA vaccine dose (AOR, 1.02; 95% CI, 0.96-1.08).

This study has several strengths, including the use of a large and diverse population-based sample, the availability of comprehensive data on COVID-19 vaccine exposures, 23 and the ability to monitor associations between vaccine exposures in early pregnancy and spontaneous abortion with data and analyses updated on a monthly basis. 27 However, several limitations to these analyses should be noted. First, spontaneous abortion cases were identified and assigned a gestational age based on automated electronic health data by using a validated algorithm. The algorithm shows substantial agreement with manual record review for distinguishing pregnancies ending in live birth from pregnancies ending in spontaneous abortion. However, for pregnancies ending in spontaneous abortion, the agreement between the algorithm assigned and record review gestational age might be lower. 20 Errors in algorithm-derived gestational age assignment could result in misclassification of vaccine exposure status, biasing results to the null, especially when applying a 28-day exposure window. It was reassuring that results were consistent in secondary analyses using a 42-day exposure window.

Second, all included spontaneous abortion cases were medically attended and estimated to have reached at least 6 weeks’ gestation. These requirements are consistent with definitions applied in prior maternal vaccine safety surveillance studies 15 , 28 , 29 and with American College of Obstetricians and Gynecologists case definitions. 30 Furthermore, multiple-gestation pregnancies with a single fetal demise could not be excluded. Alternate approaches would be needed (eg, prospective design and active participant enrollment) to analyze all cases of early pregnancy loss.

Third, although we included available covariates, including maternal age group and number of antenatal visits, as main factors in the analyses, we did not have data on other important confounders, such as maternal educational level, prior history of spontaneous abortion, maternal body mass index, or recent COVID-19 infection. Residual confounding is a potential limitation of observational studies of maternal vaccination. 27

Fourth, our primary analyses focused on a third mRNA vaccine dose (after 2 prior mRNA vaccines) because this was the most common booster vaccine type used in VSD during the surveillance period. We did not have sufficient mRNA COVID-19 vaccine doses administered in pregnant people after prior receipt of the Janssen vaccine or second doses of the Janssen vaccine to specifically evaluate these exposures, but they were included in the secondary analyses of any COVID-19 vaccine booster. Furthermore, these analyses predated availability of the bivalent COVID-19 booster vaccine.

In summary, compared with ongoing pregnancies, the odds of having received a COVID-19 booster vaccination in a 28- or 42-day exposure window before spontaneous abortion were not increased. These findings support the safety of recommendations for COVID-19 booster vaccination, including in pregnant populations. As of September 1, 2022, bivalent COVID-19 booster vaccines have been approved and recommended for use in the United States. 31 Studies of bivalent booster vaccine exposures in early pregnancy are ongoing and will be important.

Accepted for Publication: April 5, 2023.

Published: May 19, 2023. doi:10.1001/jamanetworkopen.2023.14350

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Kharbanda EO et al. JAMA Network Open .

Corresponding Author: Elyse O. Kharbanda, MD, MPH, HealthPartners Institute, Mail Stop 21112R, Minneapolis, MN 55440-1524 ( [email protected] ).

Author Contributions: Drs Kharbanda and Vazquez-Benitez had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kharbanda, Lipkind, DeSilva, Daley, Weintraub, Vazquez-Benitez.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kharbanda, Haapala, Vazquez-Benitez.

Critical revision of the manuscript for important intellectual content: Kharbanda, Lipkind, DeSilva, Zhu, Vesco, Daley, Donahue, Getahun, Hambidge, Irving, Klein, Nelson, Weintraub, Williams, Vazquez-Benitez.

Statistical analysis: Haapala, Nelson, Vazquez-Benitez.

Obtained funding: Kharbanda, Irving, Nelson.

Administrative, technical, or material support: Zhu, Daley, Donahue, Hambidge, Weintraub, Williams.

Supervision: Lipkind, Hambidge, Klein, Weintraub.

Conflict of Interest Disclosures: Dr Lipkind reported receiving personal fees from Pfizer outside the submitted work. Dr Vesco reported receiving grants from Pfizer outside the submitted work. Dr Klein reported receiving grants from Pfizer, Merck, GlaxoSmithKline, and Sanofi Pasteur outside the submitted work. Dr Nelson reported receiving personal fees from Elsevier outside the submitted work. Dr Vazquez-Benitez reported receiving grants from AbbVie and Sanofi Pasteur outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by contract 200-2012-53526 from the Centers for Disease Control and Prevention.

Role of the Funder/Support: The CDC participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Mention of a product or company name is for identification purposes only and does not constitute endorsement by the Centers for Disease Control and Prevention.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: Leslie Kuckler, MPH, HealthPartners Institute; Erika Kiniry, MPH, and Rachel Burganowski, MS, Kaiser Washington; Kristin Goddard, MPH, and Pat Ross, BA, Kaiser Northern California; Hannah Berger, MPH, Kayla Hanson, MPH, Sai Sudha Medabalimi, M Pharm, and Erica Scotty, MS, Marshfield Clinic; JoAnn Shoup, PhD, Kaiser Colorado; and Brad Crane, MS, Kaiser Permanente Northwest assisted with data collection. These individuals were all compensated through CDC contracts for their work on the study.

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Spontaneous abortion and ectopic pregnancy: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data.

Author information, affiliations.

  • Eckert LO 2
  • Babarinsa I 3
  • Harrison MS 5

ORCIDs linked to this article

  • Fay E | 0000-0001-5582-2835
  • Subelj M | 0000-0001-7858-557X
  • Kochhar S | 0000-0002-1150-5691
  • Kawai AT | 0000-0002-2923-2169
  • Kharbanda EO | 0000-0003-1806-6502

Vaccine , 01 Dec 2017 , 35(48 Pt A): 6563-6574 https://doi.org/10.1016/j.vaccine.2017.01.047   PMID: 29150062  PMCID: PMC5714431

Abstract 

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Elsevier Full-Text Article

Spontaneous abortion and ectopic pregnancy: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data

Caroline e. rouse.

a Brigham and Women’s Hospital, Boston, MA, USA

Linda O. Eckert

b University of Washington, Seattle, WA, USA

Isaac Babarinsa

c Sidra Medical and Research Center/Weill Cornell Medicine-Qatar/Women’s Hospital, Doha, Qatar

Manish Gupta

d Barts Health NHS Trust, London, UK

Margo S. Harrison

e Columbia University Medical Center, New York, NY, USA

Alison Tse Kawai

f Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA

Elyse O. Kharbanda

g HealthPartners Institute, Minneapolis, MN, USA

Merita Kucuku

h Department of Vaccines Control, National Agency for Medicines & Medical Devices, Albania

i Sanofi Pasteur, Swiftwater, PA, USA

Tamala Mallett Moore

Maja subelj.

j National Institute of Public Health, Ljubljana, Slovenia

Sonali Kochhar

k Global Healthcare Consulting, India

m Erasmus University Medical Center, Rotterdam, The Netherlands

Fernanda Tavares-Da-Silva

l GlaxoSmithKline Biologicals, Wavre, Belgium

  • Associated Data
  • 1. Preamble

1.1. Need for developing case definitions and guidelines for data collection, analysis, and presentation for spontaneous abortion and ectopic pregnancy as adverse events following immunization during pregnancy

Vaccine-preventable infectious diseases are responsible for maternal, morbidity and mortality. Immunization of pregnant women can protect against vaccine-preventable infections, and may have the added benefit of direct fetal protection. Outcomes of spontaneous abortion and ectopic pregnancy following maternal receipt of vaccination have been less studied. There have been few prospective clinical trials evaluating vaccination in pregnancy; most safety data available are derived from registries where outcomes are passively reported.

Spontaneous abortion and ectopic pregnancy are important pregnancy outcomes that should be included in vaccine registries or included as important outcomes in vaccine research. As many organizations define pregnancy loss uniquely we will compare and contrast the existing definitions and provide guidance for use of this adverse event term in studies of maternal immunization.

Definition and diagnosis of spontaneous abortion and ectopic pregnancy

First trimester spontaneous abortion (Less than 14 weeks 0 days gestation)

Many terms have been used to describe the failure of an early pregnancy, including: early pregnancy loss, early pregnancy failure, miscarriage, and spontaneous abortion. Pregnancy failure can be further classified as inevitable, missed, anembryonic, or embryonic demise [1] , [2] . For the purposes of this document, we will use the term “spontaneous abortion” (“SA”) to describe early pregnancy loss. Various national and international organizations have released guidelines for the diagnosis and/or workup of suspected early or first trimester spontaneous abortion, which are presented in the Tables.

Second trimester spontaneous abortion (Between 14 weeks 0 days and 21 weeks 6 days)

The arbitrary division by gestational age between abortion and stillbirth complicates the definition and diagnostic criteria for second trimester abortion. Existing definitions are outlined in the Tables.

Ectopic pregnancy

Ectopic pregnancy is one in which the pregnancy implants in a location other than the uterine endometrium. While most ectopic pregnancies occur in the fallopian tube (up to 97%), pregnancies can also implant in the abdomen, cervix, ovary and cornua of the uterus [3] . Society guidelines agree that the evaluation of a woman with a pregnancy of uncertain location should include an ultrasound examination followed by serum measurement of beta human chorionic gonadotropin (β-HCG) level if no intrauterine pregnancy is identified by ultrasound. If the serum β-HCG is above the discriminatory zone (the serum β-HCG level at which an intrauterine pregnancy should be visible, generally around 1500–2000 mIU/ml) and no intrauterine pregnancy is identified, an ectopic pregnancy is likely [3] , [4] , [5] . It should be noted that these society guidelines are primarily applicable for high resource settings given reliance on ultrasound for diagnosis, whereas the definitions in this document can be applied to all settings.

Induced abortion

While a full case definition for induced abortion is not included in this document, we recommend reporting this as a pregnancy outcome of interest. Induced abortion is the termination of pregnancy through medical or surgical procedures. Guidelines for safe, comprehensive care of women with induced abortion have been published by many groups, including the World Health Organization (WHO), the American Congress of Obstetricians and Gynaecologists (ACOG), the Royal College of Obstetricians and Gynaecologists (RCOG), the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), and the Society of Obstetricians and Gynaecologists of Canada (SOGC) [6] , [7] , [8] , [9] , [10] , [11] .

Epidemiology of spontaneous abortion and ectopic pregnancy

Spontaneous abortion (SA) is a common outcome. Published frequency of SA reported by several authors varies depending on the definition used [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] . In one systematic review study, the cumulative risk of SA for weeks 5 through 20 of gestation ranged from 11 to 22 miscarriages per 100 women (11–22%) [28] . This number varies by age group and study population, with women over 35 years of age experiencing the highest rates of SA [29] , depending on gestational age, with a higher risk of SA earlier in gestation [30] .

Ectopic pregnancy is a serious adverse pregnancy outcome and is one of the most common causes of maternal mortality in early pregnancy [31] . Because, particularly in high resource areas, it can be treated in the outpatient setting (the visits for which are not easily tracked) confirming the incidence of ectopic pregnancy is challenging. Reported rates range generally range from 0.6% to 2.4% [32] , [33] , [34] , [35] , [36] . These rates may be increasing secondary to an increase in the use of assisted reproductive technologies and in pelvic infection [36] . The case mortality rate varies between low and high resource settings. The mortality rate for ectopic pregnancy in the United Kingdom is 3.6/10,000 cases [37] ; this rate is ten times higher in developing countries [38] , which may be in part explained by the difficulty diagnosing and managing ectopics in regions with limited availability of ultrasound and/or quantitative HCG.

Causes and risk factors of spontaneous abortion

The most common and well-documented cause of spontaneous abortion is aneuploidy, or abnormal chromosome number (genetic factors) [39] . Studies have shown that approximately 50% of spontaneous abortions are associated with fetal chromosomal abnormalities [39] . Many studies have shown that maternal age is also a risk factor for SA. A Danish registry study that examined the outcomes of more than 1.2 million pregnancies [29] demonstrated that the risk of spontaneous loss is three times higher in women age 40 or older as compared to the under 25 age group, making age a stronger risk factor than any other known effect [39] . Other risk factors include paternal age, previous pregnancy loss, thyroid abnormalities, pre-gestational diabetes, congenital uterine anomalies, exposure to lead, mercury, organic solvents and ionizing radiation, smoking and alcohol use [39] . A recent UK population based case-control study, found the following factors to be independently associated with SA after adjustment for confounding: high maternal age, previous SA, previous pregnancy termination and infertility, assisted conception, low pre-pregnancy body mass index, regular or high alcohol consumption, feeling stressed (including trend with number of stressful or traumatic events), high paternal age and conception occurring after a change in partner [40] . Additionally, multiparity carries a risk of reproductive failure, so pregnancy order, desired family size, and maternal age should be used in consideration of the etiology of SA [41] . Paternal exposures should also be considered when studying SA because theoretically any exposure of either parent prior to conception (i.e. males during spermatogenesis and females around time of conception and during pregnancy) could increase the risk of spontaneous loss [41] . Importantly, the risk of spontaneous abortion is inversely related to week of gestation; in one study, for example, the risk of SA at 6 completed weeks of gestation was found to be 9.4% while the risk at 10 completed weeks was 0.7% [42] .

Several studies have suggested that certain psychological factors can contribute to the risk for SA, such as affective disorders (depression, dysthymia and mania), and anxiety disorders, including: agoraphobia, generalized anxiety disorder, panic disorder, simple phobia, social phobia and posttraumatic stress disorder [40] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] .

Causes and risk factors of ectopic pregnancy

Prior tubal surgery, in particular tubal ligation, is associated with very high rates of ectopic pregnancy. A large retrospective cohort study showed that while sterilization failure after tubal ligation is rare (0.1 to 0.8% in the first year after the procedure), approximately 1/3 of the resulting pregnancies were ectopic [55] . Use of an intrauterine device (IUD) is similarly associated with very low rates of pregnancy (0.5 per 100 users in 5 years for the levonorgesterel [LNG] device), but high rates of ectopic pregnancy (1 in 2) for those women who did conceive with the LNG-IUD in situ [56] . For women who conceive with the copper containing IUD in site, the ectopic pregnancy rate is 1 in 16 [57] .

A prior history of ectopic pregnancy is another important risk factor for ectopic pregnancy, with recurrence rates ranging from 8 to 15%, depending on the modality used to treat the previous ectopic [58] . Women with a history of diethylstilbestrol exposure in utero also have an increased risk of ectopic pregnancy, with rates 9 times higher than baseline [59] . Pelvic infection, including that resulting from gonorrhea or chlamydia, is a major contributor to ectopic pregnancy risk. The rate of ectopic pregnancy in a woman with a history of one chlamydial infection was found to be 0.13%; this rate increased to 0.49% after two chlamydial infections, and rose to 1.4% after three or more infections [60] . Multiple reports have found an increase in ectopic pregnancy risk with assisted reproductive technology, with rates ranging from 2.2% to 4.5% [61] , [62] , [63] .

Spontaneous abortion following immunization

Data from clinical trials and observational studies support the safety of inactivated vaccines or toxoids (e.g., tetanus, pertussis or influenza) for maternal immunization in many parts of the world.

Influenza vaccines:

Inactivated influenza vaccines (IIV) are recommended for use in pregnant women regardless of trimester due to the increased risk of infection and complications during pregnancy [64] , [65] , [66] . Systematic reviews for inactivated influenza virus vaccines did not find an association with SA and IIV, although the majority of maternal immunization studies are focused on the vaccines containing the influenza A (H1N1) pandemic antigen and limited data exists during the first trimester [67] , [68] , [69] , [70] . Preliminary results of 2010–11 and 2011–12 seasons’ data show an increased risk of SA following IIV among pregnant women in the 1–28 day risk window who had received a pH1N1-containing vaccine the prior influenza season, adjusted odds ratio (aOR) 2.0 (95% CI 1.1–3.6) [71] . However these findings are inconsistent with prior research on IIV safety in pregnancy. Safety studies continue, and follow-up studies are planned in more recent influenza seasons.

Tetanus-containing vaccines:

Fewer data exist regarding spontaneous abortion risk following administration of tetanus-toxoid containing vaccines (e.g., TT, Td, TdaP). In countries where maternal and neonatal tetanus remains a public health concern, the WHO recommends that in the absence of a reliable vaccination history or completion of the childhood vaccination series, pregnant women receive tetanus vaccination [72] . Additionally, In the past half-decade, TdaP has been introduced for routine use in pregnant women in a number of countries (e.g., Argentina, Israel, New Zealand, the United Kingdom, and the United States) to protect newborn infants against pertussis [73] . Because the recommended vaccination timing for TdaP is third trimester (to optimize maternal antibody response and transfer of antibodies to the infant) [66] , [73] , it is anticipated that the majority of pregnant women receiving the vaccine will do so after the period of risk for a spontaneous abortion (i.e., after 22 weeks gestation). However, the existing data do not support an increased risk for spontaneous abortion following TdaP vaccination during pregnancy. One small cohort study in the United States conducted prior to routine vaccination during pregnancy reported a lower rate of spontaneous or elective abortions among 138 women receiving TdaP during pregnancy, as compared to 552 pregnant women who did not receive the vaccine (2.9% vs. 8.9%) [74] . The remaining data on spontaneous abortion risk following pertussis-containing vaccines comes from passive surveillance, including an analysis of the Vaccine Adverse Event Reporting System (VAERS) in the United States [75] . The VAERS analysis included more than 3 years of data following the recommendation to routinely vaccinate pregnant women with TdaP and found no evidence for any increase in the number of spontaneous abortion reports.

Several vaccines are not recommended for administration in pregnancy, including but not limited to those outlined below, are often inadvertently administered to women of reproductive age, and therefore unintentional exposures during pregnancy may occur. Most live vaccines are contraindicated or not recommended for use during pregnancy because of the theoretical risk of transmission of the virus to the fetus through the placenta [65] .

Human papillomavirus vaccines:

Vaccines against human papillomavirus (HPV) are not recommended for use during pregnancy, but because they are often administered to women of reproductive age, they may be inadvertently administered during early pregnancy. Overall, the data collected as part of pregnancy registries, epidemiological studies and unintended exposures during clinical trials on HPV vaccines are mostly reassuring with respect to pregnancy outcomes data, including spontaneous abortion [76] , [77] , [78] , [79] , however specific studies of these vaccines in pregnant women were not conducted and the available safety data are insufficient to draw definite conclusions.

Meningococcal vaccines:

Evidence on the safety of administration of meningococcal vaccination during pregnancy is scarce. Information on spontaneous abortion risk following immunization with quadrivalent meningococcal conjugate vaccines (MCV4) is derived from passive surveillance, including a VAERS analysis that did not find any safety concerns [80] . As of June 2015, over 220 million individuals between the ages 1 and 29 years have received a new monovalent meningococcal A conjugate vaccine in 15 countries of the African belt, as part of mass immunization campaign that includes pregnant women [81] , [82] . An observational cohort study conducted in Ghana did not observe any difference in risk of spontaneous abortion among 1730 immunized pregnant women (0.9%), as compared to 919 concurrent unvaccinated controls (0.7%) or 3551 historical unvaccinated controls (1.0%) [83] . To date, no data are available on the safety of monovalent meningococcal B vaccines, currently licensed for use in Europe and the United States, when administered during pregnancy.

Rubella and varicella vaccines:

Rubella and varicella are of specific interest because of the potential sequelae of wild-type infection in susceptible pregnant women, which could hypothetically cause congenital rubella syndrome and congenital varicella syndrome. Much of the research on safety of measles, rubella (MR) and varicella vaccines has examined congenital anomalies outcomes. Data on spontaneous abortion risk following MR vaccines are derived from adverse events registries and exposure-based registries, including a VAERS analysis of MMR (measles, mumps, rubella) vaccine and surveillance for cases during mass MR vaccination campaigns in several countries in Central and South America. Although limited, these data do not indicate any concerns related to spontaneous abortion risk [84] , [85] , [86] , [87] . An exposure based registry of pregnant women inadvertently receiving varicella vaccine also found no evidence for a safety signal for spontaneous abortion [88] .

Oral polio virus vaccine:

Oral polio virus vaccine, which contains live attenuated poliovirus types 1, 2, and 3, has been used to protect pregnant women and neonates against poliomyelitis since its introduction in the early 1960s. While immunization of adults with poliovirus vaccine is not routinely recommended if the series is completed during childhood, immunization of pregnant women at high risk of endemic or epidemic exposure is recommended by WHO and several national immunization technical advisory groups [65] . Limited data on spontaneous abortion following polio virus vaccination exist. In Israel, one study examined rates of spontaneous abortion during a mass oral polio virus vaccination program that was prompted by a polio epidemic in 1988. During the epidemic, over 90% of the population, including pregnant women, was administered oral polio virus vaccine, and the number of spontaneous abortions was similar both before (October through December 1987) and during the vaccination campaign (October through December 1988) [89] .

Ectopic pregnancy following immunization

Data from clinical trials and observational studies on ectopic pregnancy following immunization are scarce.

1.2. Methods for the development of the case definitions and guidelines for data collection, analysis, and presentation for spontaneous abortion and ectopic pregnancy as adverse events following immunization during pregnancy

Following the process described in the overview paper [90] as well as on the Brighton Collaboration Website http://www.brightoncollaboration.org/internet/en/index/process.html , the Brighton Collaboration Abortion Working Group was formed in 2015 and included members of clinical, academic, public health, research and industry background. The composition of the working and reference group as well as results of the web-based survey completed by the reference group with subsequent discussions in the working group can be viewed at: http://www.brightoncollaboration.org/internet/en/index/working_groups.html .

To guide the decision-making for the case definition and guidelines, a literature search was performed using Medline, Embase and the Cochrane Libraries, including the terms abortion, miscarriage, spontaneous abortion, induced abortion, elective abortion, ectopic pregnancy, pregnancy loss, blighted ovum, anembryonic pregnancy, vaccine, immunization, maternal, pregnancy, vaccine, safety and vaccination . Exhaustive search strategies were implemented using appropriate key words, accepted MeSH words, and combinations thereof. All abstracts were screened for possible reports of abortion following immunization. Searches were restricted to references in English, and involving only human subjects. Multiple general medical, pediatric, obstetrics and infectious disease text books were also searched. For vaccines without published data, reviewed package inserts were reviewed (specifically for HPV9). Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (CDC ACIP) presentations available on the web for relevant studies were also reviewed.

The search and screening resulted in the identification of articles with potentially relevant material for further evaluation. This literature provided several different general definitions for abortion, its epidemiology, numerous descriptions for abortion causes and/or risk factors and the diagnostic criteria put forth. Most publications addressing abortion following immunization were case reports of single cases or case series describing various pregnancy outcomes, for which terminology was very inconsistent and very few used case definitions. There was no publication identified addressing ectopic pregnancy as an outcome following immunization.

1.3. Rationale for selected decisions about the case definition of spontaneous abortion and the case definition of ectopic pregnancy as adverse events following immunization during pregnancy

Related term(s)

As previously mentioned, for the purposes of this document, we will be using exclusively the terms “spontaneous abortion” and “ectopic pregnancy.” There are many terms in use to describe pregnancy loss, including pregnancy failure, miscarriage, and spontaneous abortion, which can be further classified into threatened, inevitable, and missed abortion, anembryonic pregnancy, or embryonic demise.

Formulating a case definition that reflects diagnostic certainty: weighing specificity versus sensitivity

It needs to be re-emphasized that the grading of definition levels is entirely about diagnostic certainty, not clinical severity of an event. Detailed information about the severity of the event should always be recorded, as specified by the data collection guidelines.

The number of symptoms and/or signs that will be documented for each case may vary considerably. The case definition has been formulated such that the Level 1 definition is highly specific for the condition. As maximum specificity normally implies a loss of sensitivity, two additional diagnostic levels have been included in the definition, offering a stepwise increase of sensitivity from Level One down to Level Three, while retaining an acceptable level of specificity at all levels. In this way it is hoped that all possible cases of spontaneous abortion/ectopic pregnancy can be captured.

Rationale for individual criteria or decision made related to the case definition

There is a need to consider data sources and availability of existing data when defining pregnancy outcomes in research. The interpretation of data is difficult when definitions of commonly used terms differ in the literature. Flexibility and alignment with existing definitions where studies/surveillance are performed are necessary to ensure comparability and interpretation of data. Sometimes these data are not made available. As previously discussed, spontaneous abortion and ectopic pregnancy are relatively common pregnancy outcomes. Given that vaccination is also a common practice in pregnancy, there is a need for development of precise definitions of pregnancy outcomes. Careful studies are required in which appropriate controls are chosen and where the background rates of the pregnancy outcomes of concern are known. Furthermore, while recording of these common outcomes is important, it is clear that it must be done so using precise, predefined criteria in order to avoid any unmerited concern about an association of between spontaneous abortion or ectopic pregnancy and vaccination.

Determination of the gestational age at onset of the event

A proposed algorithm for estimating gestational age for studies in various community settings is presented in a related manuscript [91] . We propose utilizing this algorithm when reporting cases of spontaneous abortion/ectopic pregnancy following vaccine administration.

Gestational age cut-offs for spontaneous abortion

There is recognition that the gestational age used to define first and, in particular, second trimester spontaneous abortion varies between and even within countries (see Table 1 ). However, we have chosen the cut-offs presented in this document in a pragmatic manner for the purposes of classification of pregnancy outcomes. Specifically, we have chosen to define a spontaneous abortion as a pregnancy loss that occurs up to 21 weeks 6 days, with outcomes after that gestational age pertaining to the stillbirth or preterm birth categories. This then represents a “harmonized” suggested cut-off with no bearing over legal or reporting requirement issues. We strongly emphasize that this gestational age cut-off should be used for research and data collection purposes only, and is not intended to inform or impact clinical care.

Conventional definitions for spontaneous abortion.

Timing post immunization in pregnancy

The time interval from immunization to onset of spontaneous abortion or ectopic pregnancy is not part of the definition, but it is recommended to be used in the data analysis to examine factors such as temporal clusters as well as determining whether the outcome of interest occurred before or after the vaccine exposure. Where feasible, details of this interval should be assessed and reported as described in the data collection guidelines (see guideline 34, Section 3.2 ).

1.4. Guidelines for data collection, analysis and presentation

As mentioned in the overview paper [90] , the case definition is accompanied by guidelines that are structured according to the steps of conducting a clinical trial, i.e. data collection, analysis and presentation. Neither case definition nor guidelines are intended to guide or establish criteria for management of ill infants, children, or adults, but were instead developed to improve data comparability.

1.5. Periodic review

Similar to all Brighton Collaboration case definitions and guidelines, review of the definition with its guidelines is planned on a regular basis (i.e. every three to five years) or more often if needed.

2. Case definitions of spontaneous abortion and ectopic pregnancy 3

For all levels of diagnostic certainty, the definitions of spontaneous abortion and ectopic pregnancy must include:

Current society guidelines for diagnosing spontaneous abortion.

  • – Determination of fetal gestational age through maternal information OR through fetal information [91] .

2.1. Spontaneous abortion and ectopic pregnancy ascertainment of levels of certainty

The ultimate level of certainty for the diagnosis of spontaneous abortion should incorporate the level of certainty for gestational age, such that even if the level of certainty about the diagnosis of spontaneous abortion is a Level 1, if the pregnancy dating is poor (Level 3), the diagnosis of spontaneous abortion becomes less certain, which the level should reflect, and should be reported as the same level as the pregnancy dating in this case, Level 3.

Gestational age assessment: Should be determined using the Brighton Preterm Birth Gestational Age algorithm [91] .

2.2. First trimester spontaneous abortion

2.2.1. documentation of all aspects is required for level of ascertainment.

Level 1 (Highest level, gold standard diagnosis, maximum sensitivity and specificity)

Crown-rump length >7 mm and no visible heartbeat on transvaginal ultrasound

Crown-rump length >15 mm and no visible heartbeat on transvaginal ultrasound

Ultrasound examination demonstrating mean gestational sac diameter >25 mm and no visible embryo or yolk sac

Second transvaginal ultrasound >7 days later (or 14 days later if transabdominal) confirming diagnosis of non-viable pregnancy

Absence of embryo with heartbeat >2 weeks after a transabdonimal scan that showed a gestational sac without a yolk sac

Absence of embryo with heartbeat >11 days after a transvaginal scan that showed a gestational sac with a yolk sac

Gestational age within pre-defined range for selected abortion definition as assessed by maternal and/or fetal parameters (Level 1–2) (using the Brighton Preterm Birth Gestational Age algorithm).

Positive urine or blood pregnancy test that becomes negative after 7 days

Products of conception found on histopathological evaluation of pregnancy tissue

Ultrasound examination demonstrating an empty uterine cavity in a woman who had clear evidence of intrauterine pregnancy on previous ultrasound examination

Vaginal bleeding, external cervical or open or closed with visible expulsion of pregnancy tissue/products of conception

Level 2 (Missing at least one confirmatory diagnostic parameter, remains sensitive and specific)

Does not qualify as a level 1

Crown-rump length > 7 mm and no visible heartbeat, confirmed on transvaginal ultrasound

Crown-rump length > 15 mm and no visible heartbeat, confirmed on transvaginal ultrasound

Mean gestational sac diameter is 25 mm or more and no visible embryo

Gestational age within pre-defined range for selected abortion definition as assessed by maternal and/or fetal parameters (Level 1–2) (using Brighton Preterm Birth Gestational Age algorithm).

Level 3 . (Less sensitive, with specificity)

Does not qualify as a level 1 or level 2

Gestational age within pre-defined range for selected abortion definition as assessed by maternal and/or fetal parameters (Level 3) (using Brighton Preterm Birth Gestational Age algorithm).

Level 4 (Reported spontaneous abortion with insufficient evidence to meet the case definition)

Does not qualify as a level 1, 2 or 3

Maternal self-report or documentation in medical record without sufficient ultrasound or laboratory evidence to confirm

2.3. Second trimester spontaneous abortion

2.3.1. documentation of all aspects is required for level of ascertainment.

The ultimate level of certainty for the diagnosis of spontaneous abortion should incorporate the level of certainty for gestational age, such that even if the level of certainty about the diagnosis of abortion is a Level 1, if the pregnancy dating is poor (Level 2), the diagnosis of abortion becomes less certain, which the level should reflect, and should be reported as the same level as the pregnancy dating in this case, Level 2.

Gestational age assessment: Should be determined using the Brighton Preterm Birth Gestational Age algorithm.

Level 1 (Highest level, gold standard diagnosis, maximum sensitive and specificity)

Gestational age within pre-defined range for selected abortion definition as assessed by maternal and/or fetal-neonatal parameters (Level 1–2) (using Brighton Preterm Birth Gestational Age algorithm).

No visible heartbeat on ultrasound

Visible expulsion of pregnancy tissues/products of conception on examination of the cervix

Products of conception found on histopathological evaluation of uterine contents

Level 2 (Missing at least one important parameter; remains sensitive, specific)

No level 3 definition for second trimester

Level 4 (Reported abortion with insufficient evidence to meet the case definition)

Does not qualify as a level 1 or 2

2.4. Ectopic pregnancy

2.4.1. documentation of all aspects is required for level of ascertainment.

Gestational age within pre-defined range for selected ectopic pregnancy definition as assessed by maternal and/or fetal-neonatal parameters (Level 1–2) (using Brighton Preterm Birth Gestational Age algorithm).

B-HCG serum blood test >2000 mlU/ml

TVUS showing no intrauterine pregnancy

TVUS showing extrauterine pregnancy

No products of conception found on endometrial curettage after D&C procedure

Level 3 (Less sensitive, with specificity)

Gestational age within pre-defined range for selected ectopic pregnancy definition as assessed by maternal and/or fetal-neonatal parameters (Level 2–3) (using Brighton Preterm Birth Gestational Age algorithm).

Positive urine pregnancy test

Level 4 (Reported ectopic pregnancy with insufficient evidence to meet the case definition)

  • 3. Guidelines for data collection, analysis and presentation of spontaneous abortion/ectopic pregnancy

It was the consensus of the Brighton Collaboration spontaneous abortion/ectopic pregnancy Working Group to recommend the following guidelines to enable meaningful and standardized collection, analysis, and presentation of information about these events. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographical region, and whether the source of information is a prospective clinical trial, a post-marketing surveillance or epidemiological study, or an individual report of abortion. Also, as explained in more detail in the overview paper in this volume, these guidelines have been developed by this working group for guidance only, and are not to be considered a mandatory requirement for data collection, analysis, or presentation.

3.1. Data collection

These guidelines represent a desirable standard for the collection of available pregnancy outcome data following immunization to allow comparability. The guidelines are not intended to guide the primary reporting of these events to a surveillance system. Investigators developing a data collection tool based on these data collection guidelines also need to refer to the criteria in the case definition, which are not repeated in these guidelines.

Guidelines 1–46 below have been developed to address data elements for the collection of adverse event information as specified in general drug safety guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [97] , and the form for reporting of drug adverse events by the Council for International Organizations of Medical Sciences [98] . These data elements include an identifiable reporter and patient, one or more prior immunizations, and a detailed description of the adverse event, in this case, of abortion following immunization. The additional guidelines have been developed as guidance for the collection of additional information to allow for a more comprehensive understanding of spontaneous abortion/ectopic pregnancy following immunization.

3.1.1. Source of information/reporter

For all cases and/or all study participants, as appropriate, the following information should be recorded:

Date of report.

Name and contact information of person 4 reporting the event as specified by country specific data protection law.

Relationship of the reporter to the vaccine recipient [e.g.,immunizer (clinician, nurse) attending physician, family member [indicate relationship, self [vaccine recipient], other.

3.1.2. Vaccinee/control

3.1.2.1. demographics.

For all cases and/or all study participants (i.e. pregnant women), as appropriate, the following information should be recorded:

Case study participant identifiers (first name initial followed by last name initial) or code (or in accordance with country- specific data protection laws).

Date of birth, age of patient.

Gestational age.

Country of residence.

Occupation(s).

3.1.2.2. Clinical and immunization history

Past medical history, including hospitalizations, underlying diseases/disorders, pre-immunization signs and symptoms including identification of indicators for, or the absence of, a history of allergy to vaccines, vaccine components or medications; food allergy; allergic rhinitis; eczema; asthma.

Any medication history (other than treatment for the event described) prior to, during, and after immunization including prescription and non-prescription medication as well as medication or treatment with long half-life or long term effect (e.g. immunoglobulins, blood transfusion and immune-suppressants) or substance abuse (e.g. narcotics or other recreational drug, alcohol or smoking).

Immunization history (i.e. previous immunizations and any adverse event following immunization (AEFI), in particular occurrence of the same event after a previous immunization.

Clinical confirmation of pregnancy prior to maternal immunization.

3.1.3. Details of the immunization

Date and time of immunization(s).

Description of all vaccine (s), including name of vaccines, manufacturer, lot number, expiration date, multi or mono dose vial, volume (e.g. 0.25 Ml, 0.5 mL, etc.), dose number if part of series of immunizations against the same disease(s), description of the adjuvants and any diluents, and the manufacturer, lot number, and expiration date of any diluents used.

The anatomical sites (including left or right side) of all immunizations (e.g. vaccine A in proximal left lateral thigh, vaccine B in left deltoid).

Route and method of administration (e.g. intramuscular, intradermal, subcutaneous, and needle-free (including type and size), other injection devices).

Needle length and gauge.

If the immunization is part of:

  • • Routine immunization program
  • • Preventive mass immunization campaign
  • • Mass immunization campaign for outbreak response
  • • Domestic travel from non-endemic to endemic area
  • • International travel
  • • Occupational risk

3.1.4. The adverse event

For all cases at any level of diagnostic certainty and for reported events with insufficient evidence, the criteria fulfilled to meet the case definition should be recorded.

Specifically document (if available):

(If data not available because of regulatory guidelines, please specify data cannot be disclosed.)

Clinical description of signs and symptoms of spontaneous abortion or ectopic pregnancy, and if there was medical confirmation of the event (i.e. patient seen by physician).

Date/time of onset, 5 first observation 6 and diagnosis 7 ; as well as end of episode 8 and final outcome. 9

Concurrent signs, symptoms, exposures and diseases.

Pregnancy details:

  • • Pregnancy details: date of last normal menstrual period, ultrasound examinations, antenatal care visits, pregnancy-related illnesses and complications.
  • • Results of ultrasound examinations, antenatal care visits, laboratory examinations, other clinical tests, surgical and/ or pathological findings and diagnosis preferable to perform at reliable and accredited laboratories. If more than one measurement of particular parameters is taken and recorded, the value corresponding to the largest deviation from the expected normal value or range of parameter should be reported.
  • • Spontaneous abortion or ectopic pregnancy details: specifically document (if available) mode of treatment (e.g. dilation and curettage, etc) and complications, if any (e.g. hemorrhage, infection, ruptured ectopic pregnancy, etc.).

Measurement/testing

  • • Values and units of routinely measured parameters (e.g. temperature, blood pressure) – in particular those indicating the severity of the event;
  • • Method of measurement (e.g. type of thermometer, oral or other route duration of measurement, etc.);
  • • Results of laboratory examinations, surgical and/or pathological findings and diagnoses if present.

Treatment given for the event, especially specify what and dosing, if applicable.

Outcome 8 at last observation (e.g. for an event that meets the case definition of spontaneous abortion, it results in death of the embryo/fetus but not necessarily the mother). Add descriptions if maternal death occurred. Also, for multiple gestation, if concomitant twin death occurred. For example:

  • • Recovery to pre- immunization health status
  • • Spontaneous resolution
  • • Ongoing treatment/recovering
  • • Persistence of the event/unresolved
  • • Significant complications of treatment/sequelae
  • • Maternal death and description of any other outcome

Objective clinical evidence supporting classification of the event as “serious” 10 (i.e. results in death of the embryo/fetus, hospitalisation of the mother).

Exposures other than the immunization before and after immunization (e.g. trauma, induced, environmental) considered potentially relevant to the reported event.

3.1.5. Miscellaneous/general

The duration of follow-up reported during the surveillance period should be predefined likewise. It should aim to continue to resolution of the event (i.e. the outcome of the pregnancy is captured).

Methods of data collection should be consistent within and between study groups, if applicable.

Follow-up of cases should attempt to verify and complete the information collected as outlined in data collection guidelines 1–27.

Guidance should be provided to optimize the quality and completeness of information.

Reports of pregnancy outcomes should be collected throughout the study period regardless of the time elapsed between immunization and the adverse event. If this is not feasible due to the study design, the study periods during which safety data are being collected should be clearly defined.

The safety monitoring should take into account:

  • • Biologic characteristics of the vaccines (e.g., live attenuated versus inactivated component vaccines).
  • • The vaccine preventable-disease.
  • • Non clinical and clinical data obtained previously and
  • • Characteristics of the target population (e.g., nutrition, underlying disease like immunocompromised illness).

Methods of data collection should be consistent within and between study groups or surveillance systems, if applicable.

3.2. Data analysis

The following guidelines represent a desirable standard for analysis of data on spontaneous abortion and ectopic pregnancy to allow for comparability of data, and are recommended as an addition to data analyzed for the specific study question and setting.

Reported events should be classified in one of the following five categories including the three levels of diagnostic certainty. Events that meet the case definition should be classified according to the levels of diagnostic certainty as specified in the case definition. Events that do not meet the case definition should be classified in the additional categories for analysis.

Event classification in 5 categories 11

Event meets case definition

Level 1: Criteria as specified in the case definition

Level 2: Criteria as specified in the case definition

Level 3: Criteria as specified in the case definition

Event does not meet case definition

Additional categories for analysis

Reported event with insufficient evidence to meet the case definition 12

Not a case of spontaneous abortion/ectopic pregnancy 13

The interval between immunization and reported abortion could be defined as the date/time of immunization (last vaccination) to the date/time of onset 4 of the event, consistent with the definition. It is important to note that timing of fetal demise may differ by days to weeks from the time when a spontaneous abortion or ectopic pregnancy is clinically recognized. If few cases are reported, the concrete time course could be analyzed for each; for a large number of cases, data can be analyzed in the following increments for identification of temporal clusters:

Subjects with spontaneous abortion or ectopic pregnancy by interval to presentation

If more than one measurement of a particular criterion is taken and recorded, the value corresponding to the greatest magnitude of the adverse experience could be used as the basis for analysis. Analysis may also include other characteristics like qualitative patterns of criteria defining the event.

The distribution of data (as numerator and denominator data) could be analyzed in predefined increments (e.g. measured values, times), where applicable. Increments specified above should be used. When only a small number of cases is presented, the respective values or time course can be presented individually.

Data on spontaneous abortion/ectopic pregnancy obtained from subjects receiving a vaccine should be compared with those obtained from an appropriately selected and documented control group(s) to assess background rates in non-exposed populations, and should be analyzed by study arm and dose where possible, e.g. in prospective clinical trials. It should be emphasized that because risk of spontaneous abortion/ectopic pregnancy is time-dependent (i.e. inversely related to week of gestation [42] , choosing appropriate control groups is paramount. For example, if a group receiving vaccination is compared to a group receiving a placebo but the women in the vaccine arm receive the vaccine at 6 weeks gestation and the control women receive the placebo at 8 weeks, the rate of SA after the vaccination will be higher, reflecting differences in background risk.

3.3. Data presentation

These guidelines represent a desirable standard for the presentation and publication of data on abortion following immunization to allow for comparability of data, and are recommended as an addition to data presented for the specific study question and setting. Additionally, it is recommended to refer to existing general guidelines for the presentation and publication of randomized controlled trials, systematic reviews, and meta-analyses of observational studies in epidemiology (e.g. statements of Consolidated Standards of Reporting Trials (CONSORT) [99] , of Improving the quality of reports of meta-analyses of randomized controlled trials (QUORUM) [100] , and of Meta-analysis Of Observational Studies in Epidemiology (MOOSE) [101] , respectively).

All reported events should be presented according to the categories listed in guideline 36.

Data on possible abortion events should be presented in accordance with data collection guidelines 1–35 and data analysis guidelines 36–40.

Data should be presented with numerator and denominator (n/N) (and not only in percentages), if available.

Although immunization safety surveillance systems denominator data are usually not readily available, attempts should be made to identify approximate denominators. The source of the denominator data should be reported and calculations of estimates be described (e.g. manufacturer data like total doses distributed, reporting through Ministry of Health, coverage/population based data, etc.).

The incidence of cases in the study population should be presented and clearly identified as such in the text.

If the distribution of data is skewed, median and inter-quartile range are usually the more appropriate statistical descriptors than a mean. However, the mean and standard deviation should also be provided.

Any publication of data on pregnancy outcomes should include a detailed description of the methods used for data collection and analysis as possible. It is essential to specify:

  • • The study design;
  • • The method, frequency and duration of monitoring for pregnancy outcomes;
  • • The trial profile, indicating participant flow during a study including drop-outs and withdrawals to indicate the size and nature of the respective groups under investigation;
  • • The type of surveillance (e.g. passive or active surveillance);
  • • The characteristics of the surveillance system (e.g. population served, mode of report solicitation);
  • • The search strategy in surveillance databases;
  • • Comparison group(s), if used for analysis;
  • • The instrument of data collection (e.g. standardized questionnaire, diary card, report form);
  • • Whether the day of immunization was considered “day one” or “day zero” in the analysis;
  • • Whether the date of onset 4 ) and/or the date of first observation 5 and/or the date of diagnosis 6 was used for analysis; and
  • • Use of this case definition, in the abstract or methods section of a publication 14 .

The findings, opinions and assertions contained in this consensus document are those of the individual scientific professional members of the working group. They do not necessarily represent the official positions of each participant’s organization. Specifically, the findings and conclusions in this paper are those of the authors and do not necessarily represent the views of their respective institutions.

  • Acknowledgements

The authors are grateful for the support and helpful comments provided by the Brighton Collaboration Steering Committee and Reference Group, as well as other experts consulted as part of the process. The authors are also grateful to Jan Bonhoeffer, Jorgen Bauwens of the Brighton Collaboration Secretariat and Sonali Kochhar of Global Healthcare Consulting for final revisions of the final document. We would also to acknowledge the contributions made by Karalee Scheaffer, Information Scientist SciInteL, Pasteur, Swiftwater PA, for contributions made to the literature review. Finally, we would like to thank the members of the WHO/CIOMS Working Group on Vaccine Pharmacovigilance ( http://www.cioms.ch/frame_current_programme.htm ) for the review of, constructive comments on, and endorsement of this document.

3 The case definition should be applied when there is no clear alternative diagnosis for the reported event to account for the combination of symptoms.

4 If the reporting center is different from the vaccinating center, appropriate and timely communication of the adverse event should occur.

5 The date and/or time of onset is defined as the time post immunization, when the first sign or symptom indicative for abortion occurred. This may only be possible to determine in retrospect.

6 The date and/or time of first observation of the first sign or symptom indicative for abortion can be used if date/time of onset is not known.

7 The date of diagnosis of an episode is the day post immunization when the event met the case definition at any level.

8 The end of an episode is defined as the time the event no longer meets the case definition at the lowest level of the definition.

9 Example: recovery to pre-immunization health status, spontaneous resolution, therapeutic intervention, persistence of the event, sequelae, death.

10 An AEFI is defined as serious by international standards if it meets one or more of the following criteria: 1) it results in death, 2) is life-threatening, 3) it requires inpatient hospitalisation or results in prolongation of existing hospitalisation, 4) results in persistent or significant disability/incapacity, 5) is a congenital anomaly/birth defect, 6) is a medically important event or reaction. For abortion, the event meets the definition of serious (i.e. it results in death of the embryo/fetus).

11 To determine the appropriate category, the user should first establish, whether a reported event meets the criteria for the lowest applicable level of diagnostic certainty, e.g. Level three. If the lowest applicable level of diagnostic certainty of the definition is met, and there is evidence that the criteria of the next higher level of diagnostic certainty are met, the event should be classified in the next category. This approach should be continued until the highest level of diagnostic certainty for a given event could be determined. major criteria can be used to satisfy the requirement of minor criteria. If the lowest level of the case definition is not met, it should be ruled out that any of the higher levels of diagnostic certainty are met and the event should be classified in additional categories four or five.

12 If the evidence available for an event is insufficient because information is missing, such an event should be categorised as “reported abortion with insufficient evidence to meet the case definition”.

13 An event does not meet the case definition if investigation reveals a negative finding of a necessary criterion (necessary condition) for diagnosis. Such an event should be rejected and classified as “Not a case of abortion”.

14 Use of this document should preferably be referenced by referring to the respective link on the Brighton Collaboration website ( http://www.brightoncollaboration.org ).

Appendix A Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.vaccine.2017.01.047 .

  • Appendix A. Supplementary material
  • 2. Case definitions of spontaneous abortion and ectopic pregnancy3

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The body mass index and the risk of ectopic pregnancy: a 5-year retrospective case-control study

  • Jin-Shuang Ji 1 ,
  • Ling Liu 2 ,
  • Huan Huang 1 ,
  • Hong-Wei Chen 1 ,
  • Li Xiao 1 , 2 ,
  • Xiang-Yi Lu 1 ,
  • Yang-Yang Ni 1 ,
  • Wen-Juan Jia 1 &
  • Lei Huang 1 , 2  

BMC Pregnancy and Childbirth volume  24 , Article number:  143 ( 2024 ) Cite this article

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Acknowledging the associated risk factors may have a positive impact on reducing the incidence of ectopic pregnancy (EP). In recent years, body mass index (BMI) has been mentioned in research. However, few studies are available and controversial on the relationship between EP and BMI.

We retrospectively studied the EP women as a case group and the deliveries as a control group in the central hospital of Wuhan during 2017 ~ 2021. χ 2 test of variables associated with ectopic pregnancy was performed to find differences. Univariate and multivariate binary logistic regression analysis was conducted to analyze the association of the variables of age, parity, history of induced abortion, history of ectopic pregnancy, history of spontaneous abortion, history of appendectomy surgery and BMI (< 18.5 kg/m 2 , 18.5 ~ 24.9 kg/m 2 , 25 kg/m 2  ~ 29.9 kg/m 2 , ≥ 30 kg /m 2 ) with EP.

They were 659 EP and 1460 deliveries. The variables of age, parity, history of induced abortion, history of ectopic pregnancy and BMI were different significantly( P  < 0.05). Multivariate analysis showed that the variables of age > 35 years old [(OR (Odds Ratio), 5.415; 95%CI (Confidence Interval), 4.006 ~ 7.320, P  < 0.001], history of ectopic pregnancy (OR, 3.944; 95%CI, 2.405 ~ 6.467; P  < 0.001), history of induced abortion(OR, 3.365; 95%CI, 2.724 ~ 4.158, P  < 0.001) and low BMI (< 18.5 kg/m 2 ) (OR, 1.929; 95%CI, 1.416 ~ 2.628, P  < 0.001])increased the risk of EP.

The history of ectopic pregnancy, history of induced abortion and age > 35 years old were the risk factors with EP. In addition to these traditional factors, we found low BMI (< 18.5 kg/m 2 ) with women may increase the risk to EP.

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Introduction

Ectopic pregnancy (EP) refers to a pregnancy that occurs outside the uterine cavity, and the incidence rate accounts for about 1%~2% of all pregnancies [ 1 , 2 ]. More than 90% of EP are tubal pregnancy accounting for the first maternal mortality rate in first-trimester pregnancy [ 3 , 4 ]. Nowadays, the incidence of ectopic pregnancy is still on the rise worldwide [ 5 , 6 , 7 ]. We have known that the risk factors for EP, including the history of ectopic pregnancy, the history of tubal surgery, the history of induced abortion, the history of spontaneous abortion, chlamydial infection and pelvic inflammatory disease, the history of infertility, the history of smoking, age > 35 years old [ 8 , 9 , 10 , 11 , 12 ]. With the growth of economic level and the improvement of people’s living standard, risk factors for ectopic pregnancy are also in change.

In recent years, due to aesthetic aberrations, more and more women pursued the ideal body or were underweight [ 13 , 14 ]. And in clinical workflow, we observed patients with ectopic pregnancies were lean. Whether there is some association between body mass index (BMI) and ectopic pregnancy. In a prospective study, it suggested that low BMI was associated with EP after receiving assisted reproductive technology (ART) [ 15 ]. Another study suggested that obese women were at higher risk of ectopic pregnancy [ 16 ]. However, BMI may not be associated with ectopic pregnancy in other studies [ 11 , 17 ]. At present, there are different opinions on the relationship between BMI and EP. The findings of these studies are conflicting, and the studies on BMI did not control other related risk factors. So, there is some bias. There are few studies on the direct relationship between BMI and EP, and further research is needed to confirm their relationship.

This study was retrospective case-control research in the central hospital of Wuhan during 2017 ~ 2021. We included BMI in the study of risk factors. We performed univariate and multivariate binary logistic regression analysis to find relationship between BMI and EP. We found a new risk factor for ectopic pregnancy. It alerts and advocates women to have a healthy body mass index to protect fertility.

Study population

We retrospectively studied the case of ectopic pregnancy (EP) as a case group in the central hospital of Wuhan during 2017 ~ 2021. And pregnant women who gave birth and filed in this hospital during the same period were randomly selected as the control group (according to the order of registration, 10 records were randomly selected from each page). Prepregnancy height (m), weight (kg) and other mask data were provided by the medical information department of the hospital and filing system. This study had been approved by the institutional ethics committees of the central hospital of Wuhan.

Diagnosis of ectopic pregnancy: confirmed by laparoscopic surgery and pathological diagnosis. A retrospective cohort study was conducted in the central hospital of Wuhan between January 2017 and December 2021. Inclusion criteria: Women aged 18–45 years, Cases with height and weight information. Exclusion criteria: The history of assisted reproductive technology (ART), those with metabolic diseases such as hypertension, diabetes, heart disease, polycystic ovary syndrome (PCOS), hyperthyroidism and hypothyroidism, and malignant tumors, because of missing data. According to the inclusion and exclusion criteria, the case group and control group were obtained. The flowchart of the study was in (Fig.  1 ).

Study variables

Sociodemographic characteristics, including age, occupation and region. For comparability between ectopic pregnancy and delivery, we included the previously known risk factors of EP, these variables were age, parity, history of induced abortion, history of ectopic pregnancy, history of spontaneous abortion, history of appendectomy surgery and BMI. According to the World Health Organization (WHO) of classification standard of BMI in 2021, it is divided into low BMI (< 18.5 kg/m 2 ), normal BMI (18.5 ~ 24.9 kg/m 2 ), overweight (25 ~ 29.9 kg/m 2 ), obesity (≥ 30 kg /m 2 ). BMI is defined as the body weight divided by the square of height.

Study outcomes

The primary outcomes of this study were age > 35 years old, history of induced abortion, history of ectopic pregnancy, low BMI (< 18.5 kg/m 2 ).

Statistical analysis

Categorical variables were expressed as frequencies and percentages, and χ 2 test was used to assess the difference of variables. Binomial logistic regression was for univariate and multivariate analyses.

IBM SPSS Statistics (R26.0.0.0) software was used for data analysis and GraphPad prism (R9.3.1) software for graphing. All comparisons were two-tailed. When P value < 0.05, the results were considered statistically significant.

figure 1

The flowchart of the study

Sociodemographic characteristics of women

The sociodemographic characteristics of age, region and occupation in the 2119 women were in Table  1 . The results showed that there were 659 EP in the case group and 1460 deliveries in the control group. There were significant differences in age and occupation between groups ( P  < 0.001). The median age of EP patients were 31(27 ~ 36) years old. In these women, 949 (46.2%) women were employees, and 272 (42.2%) patients with EP were employees. region distribution showed no significant differences between groups ( P  = 0.418).

Analysis for the clinical characteristics of ectopic pregnancy

We included risk factors associated with ectopic pregnancy, then performed chi-square test to compare these variables. The results showed that history of spontaneous abortion and history of appendectomy surgery was not statistically significant( P  > 0.05). However, the variables of age, parity, history of induced abortion, History of ectopic pregnancy and BMI were different significantly( P  < 0.001). 498(75.6%) patients with EP were normal BMI. 89(13.5%) EP was low BMI. 59(9.0%) patients with EP were overweight. 13(2.0%) EP was obesity. In summary, the majority of patients (75.6%) of EP was normal BMI, secondly 13.5% patients with EP were low BMI (Table  2 ).

Univariate and multivariate analysis of risk factors of ectopic pregnancy

We performed univariate and multivariate binomial logistic regression analysis to find risk factors of EP. univariate analysis showed that the variables of age, parity, history of induced abortion, history of ectopic pregnancy and BMI were risk factors of EP ( P  < 0.001). The history of spontaneous abortion was the risk factor with EP and but not statistically significant ( P  = 0.176). the history of appendectomy surgery was the protective factor with EP and but not statistically significant ( P  = 0.569).

Multivariate analysis revealed that the variables of age, history of induced abortion, history of ectopic pregnancy and BMI were risk factors for EP( P  < 0.001). according to the value of Odds Ratio from large to small size was age > 35 years old [OR, 5.415; 95%CI, 4.006 ~ 7.320, P  < 0.001], history of ectopic pregnancy [OR, 3.944; 95%CI, 2.405 ~ 6.467; P  < 0.001], history of induced abortion[(OR, 3.365; 95%CI, 2.724 ~ 4.158, P  < 0.001], low BMI (< 18.5 kg/m 2 ) [(OR, 1.929; 95%CI, 1.416 ~ 2.628, P  < 0.001].And yet, Overweight (25 kg/m 2  ~ 29.9 kg/m 2 ) was the risk factor of EP but no statistically significant ( P  = 0.331), obesity(≥ 30 kg/m 2 ) was the protective factor with EP insignificantly ( P  = 0.803) (Fig.  2 ).

figure 2

Forest plot of univariate and multivariate of binomial logical regression analysis of EP

In this study, we directly included risk factors associated with ectopic pregnancy as well as body mass index to conduct univariate and multivariate analysis. This is a relatively systematic study of risk factors for ectopic pregnancy, a new variable of body mass index was also included. We found the history of ectopic pregnancy, history of induced abortion, age > 35 years old and low BMI (< 18.5 kg/m 2 ) were the risk factors with EP. And low BMI (< 18.5 kg/m 2 ) was 1.929 times higher risk to EP compared with normal BMI (18.5 kg/m 2  ~ 24.9 kg/m 2 ). Our findings hope that it may improve awareness of these factors, and further research common to these conditions.

Theoretically, any condition that prevents or retards migration of the fertilized ovum to the uterus could predispose a woman to ectopic gestation (current intrauterine device use, the history of infertility, the history of pelvic inflammatory disease, and prior tubal surgery) [ 18 ]. As the economy develops, more and more women choose the contraceptive method of IUD. The risk of ectopic pregnancy in different types of intrauterine device may be different, and the concentration of drugs in IUDs may have some mechanism of action with fallopian tube function. In addition, IUDs are foreign to the uterine cavity and may cause the endometrium to be out of sync with fallopian tube function [ 19 , 20 ]. Pelvic inflammatory disease (PID) changes the inner environment of the pelvic uterus, affecting the transport environment of fallopian tubes, thereby increasing the risk of ectopic pregnancy. The two most common pathogens, Neisseria gonorrhoea and chlamydia trachomatis, have been shown to be mainly associated with ectopic pregnancy [ 21 , 22 , 23 ]. Whether the inflammation caused by appendicitis also affects the function of fallopian tubes, there is currently no evidence of higher levels. However, some retrospective studies have shown that the history of appendectomy is associated with increasing risk of ectopic pregnancy [ 24 ]. In contrast to our study, we found that women with previous history of appendectomy were not at increased risk of ectopic pregnancy, either through univariate analysis or and multivariate analysis. So, the problem is whether abdominal surgery or inflammation of the appendix caused the ectopic pregnancy. Similarly, the history of two or three cesarean deliveries is associated with increased risk for subsequent ectopic pregnancy in relation to women who had one prior cesarean delivery [ 25 ]. We hypothesize that multiple prior cesareans may increase pelvic adhesion leading to tubal hypoplasia. However, there is no experimental evidence.

With age, some risk factors associated with ectopic pregnancy may accumulate. Epidemiological surveys showed a worldwide phenomenon of postponement of the age of childbearing to the 30s, fertility rates were also declining [ 26 ]. With the improvement of economic and educational level, the divorce rate and multiple sexual partners among these women are likely to increase [ 27 ]. This may lead to pelvic inflammatory disease and tubal disease, and ectopic pregnancy. In a Chinese study, the proportion of EP among those ≥ 35 years old was reversed from a downward trend (2011–2016 annual percentage change (APC) − 4.13) to an upward trend (2016–2020 APC 4.04) [ 28 ]. Some study showed that age > 35 years increased the risk of ectopic pregnancy [ 29 , 30 ]. In agreement with our data, ectopic pregnancy was more likely to occur over the age of 35, the value of odds ratio was 5.415 and the largest in this study, there was a major impact effect on ectopic pregnancy.

There has been a great deal of research showing that an increased risk of repeat EP in patients with history of ectopic pregnancies. In a large French case-control study, women with one ectopic pregnancy had the higher risk of repeated ectopic pregnancy (OR = 12.5), especially for women with two or more ectopic pregnancies [ 9 ]. In a recent study, women with the history of ectopic pregnancy had the 2.72 times higher risk of ectopic pregnancy recurrence (Adjusted odds ratio [AOR] = 2.72, 95% confidence interval [CI]: 1.83–4.05) [ 19 ]. In our study, multivariate analysis showed that the risk of ectopic pregnancy was 3.944 times higher in women with the history of ectopic pregnancy. Women with previous history of ectopic pregnancy may affect fallopian tube function after conservative or surgical treatment, such as oviduct blockage, oviduct water accumulation, oviduct inflammation, etc.

Induced abortion remains noticeable in China [ 31 ]. In a recent cross-sectional study, of all abortions, 65.2% were repeat induced abortions [ 32 ]. The history of induced abortion was associated with an increased risk of ectopic pregnancy [OR, 1.5; 95%CI, 1.0 ~ 2.0], particularly in the case of women who have had several induced abortions [ 33 ]. In a prospective study by Skjeldestad, Induced abortion did not increase the risk of ectopic pregnancy [ 34 ]. In our study, the history of induced abortion was significantly associated with ectopic pregnancy(OR, 3.365; 95%CI, 2.724 ~ 4.158). But the relationship between history of spontaneous abortion and ectopic pregnancy was no statistically significant. We assumed that one or more abortions increased the chance of uterine manipulation, leading to an enhanced risk of uterine infection. The possibility of pelvic inflammatory disease and tubal disease cannot be excluded.

In this study, we considered the inclusion of body mass index to explore the risk factors for ectopic pregnancy. However, the relationship between BMI and EP is rarely studied. Pan pointed out that obese women have a higher risk of EP [ 16 ], and it was suggested that low BMI was associated with EP after receiving ART in this prospective study [ 15 ]. In these studies, the relationship between BMI and EP was not directly investigated, and other factors associated with EP were not controlled. Therefore, there was difference. In our study, by including risk factors associated with EP, multivariate analysis showed that body mass index was associated with EP after adjustment and appeared in low BMI (< 18.5 kg/m 2 ). There were few reports in the literature on the mechanism. We consider that leptin levels in women with low body mass index are alternately regulated with insulin growth factor-1 [ 35 , 36 ], and that leptin is critically linked to reproductive function [ 37 ]. However, a unique hormonal regulation exists during embryonic development, maturation, and egg transport through the fallopian oviduct [ 38 ]. This suggests that it may affect embryonic development and fallopian tube function by impacting hormonal regulation.

This study is a retrospective study, which effect is less than randomized controlled studies. Subsequent multicenter trial and large-sample research is required. The BMI is a new risk factor compared to other factors, which is a highlight of our research. We are better able to regulate weight relative to other physiological factors to guide the clinical.

The history of ectopic pregnancy, history of induced abortion and age > 35 years old were the risk factors with EP. In addition to the traditional risk factors, we found an association between body mass index and the risk of ectopic pregnancy. Women with a low BMI (< 18.5 kg/m 2 ) had a slightly higher risk of ectopic pregnancy than women with normal BMI. We hope future studies focus on these risk factors and advocate a healthy body mass index to protect female fertility by improving body mass index.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Ectopic pregnancy

Body mass index

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Acknowledgements

I would like to express my gratitude to Prof. Xiong Li and Prof. Jin-Ming Fang for their great support and help on my project. They gave me so much constructive help for statistical analysis.

This work was supported by Project Health Commission of Hubei Province (WJ2021D006) , Project Health Commission of Wuhan City (WX20A05) and Electrophysiological Foundation of Chinese Association of Plastics and Aesthetics [2022]02015.

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Jin-Shuang Ji, Huan Huang, Hong-Wei Chen, Li Xiao, Xiang-Yi Lu, Yang-Yang Ni, Wen-Juan Jia & Lei Huang

The Diagnosis and Therapy Center of Pelvic Floor Rehabilitation and Electrophysiology, Tongji Medical College, The Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, 430014, Hubei, China

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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jin-Shuang Ji, Ling Liu, Huan Huang, Hong-Wei Chen, Li Xiao, Xiang-Yi Lu, Yang-Yang Ni, Wen-Juan Jia, Lei Huang. The first draft of the manuscript was written by Jin-Shuang Ji and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Research has been performed in accordance with the Declaration of Helsinki. The study was approved by the Ethics Committee of The Central Hospital of Wuhan, Affiliated Hospital of Huazhong University of Science and Technology (No. 2022WHZXKYL034). As this study is a retrospective study, it will not adversely affect the health of patients, nor will it involve the privacy and personal identity information of patients. The Ethics Committee of The Central Hospital of Wuhan, Affiliated with Hospital of Huazhong University of Science and Technology has waived the requirement of informed consent of patients.

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Ji, JS., Liu, L., Huang, H. et al. The body mass index and the risk of ectopic pregnancy: a 5-year retrospective case-control study. BMC Pregnancy Childbirth 24 , 143 (2024). https://doi.org/10.1186/s12884-024-06319-z

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DOI : https://doi.org/10.1186/s12884-024-06319-z

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  • Ectopic pregnancy (EP)
  • Risk factors
  • Low body mass index (BMI)
  • Retrospective case-control study

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spontaneous abortion case study

February 15, 2024

Medication Abortion Using Telehealth Is As Safe As In-Person Care, Study Finds

Researchers find that medication abortion provided at home with a Zoom or text link to a medical provider is extremely safe and effective

By Joanna Thompson

A person looks at an Abortion Pill (RU-486) for unintended pregnancy from Mifepristone displayed on a smartphone

Olivier Douliery/AFP via Getty Images

The combination of mifepristone and misoprostol, the two-drug regimen that is usually prescribed to terminate a pregnancy, is extremely safe and effective — even when the medication abortion is provided over a remote telehealth connection, a new study shows. In a survey of more than 6,000 remote medication abortions between April 2021 and January 2022, only 0.25 percent of patients experienced adverse outcomes such as excessive bleeding or infection. Less than 2.5 percent experienced a continued pregnancy. Published on February 15 in Nature Medicine, the study research is the largest study of at-home telehealth abortion to date.

“The study finds that providing telehealth care is just as safe and effective as providing abortion care in person,” says Ushma Upadhyay, a quantitative public health scientist at the University of California, San Francisco, and the paper’s lead author. In addition to synchronous abortion care, in which a patient communicated with a health professional over the phone or a video chat, Upadhyay’s team evaluated asynchronous care, in which the patient and provider did not interact in real time. The researchers found that both approaches had equally successful outcomes.

“Providing the option of asynchronous care really helps improve access,” says Kelly Cleland, executive director of the American Society for Emergency Contraception, who was not involved in the study. For example, receiving abortion care via secure text messaging might be the best option for people who live in a rural area with limited Wi-Fi access or who could face threats of violence from intimate partners. The new study supports this as a safe and effective option, Cleland says.

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Medication abortion accounts for more than half of all abortions in the US, according to a 2022 survey from the Guttmacher Institute. It is a vital form of health care for people who live in an area without easy access to an abortion clinic or where abortion is illegal. Most experts predict that the percentage of medication abortions in the U.S. will only increase in coming years, as COVID waves continue to surge and care options becomes increasingly restricted in many parts of the country.

Most medication abortions are administered by first using 200 milligrams of mifepristone—which blocks the release of the hormone progesterone—followed by up to 1,600 micrograms of misoprostol, which causes the uterus to empty. Despite more than 20 years of data attesting to their safety, both drugs and especially mifepristone—have repeatedly been subject to scrutiny and regulatory challenges. This trend has not slowed in the wake of the Supreme Court’s 2022 decision in Dobbs v. Jackson Women’s Health Organization, which overturned Roe v. Wade .

“This is really important and timely evidence,” says Silpa Srinivasulu, a public health researcher at the Reproductive Health Access Network, who was not involved in the research. The new study comes just weeks before the Supreme Court is scheduled to hear a case that could jeopardize mifepristone’s Food and Drug Administration approval and effectively ban its use.

Under current guidelines, mifepristone should be prescribed by a certified health care provider to patients 10 weeks or less into a pregnancy. The agency expanded the drug’s approval in 2021 to include telehealth prescriptions—a provision that helped thousands of Americans stay safe during the height of the COVID pandemic. Soon afterward, however, antiabortion advocates filed a lawsuit that has challenged not only the updated guidelines but also mifepristone’s initial FDA approval in 2000.

Many health care providers have pointed out that the scientific basis of the current lawsuit is flimsy at best and nonexistent at worst. In fact, two key papers cited by the plaintiffs in the suit as evidence of mifepristone’s potential for harm were recently retracted . “These obstacles are politically motivated attacks,” Srinivasulu says. “They’re not grounded in science.”

Health care experts also worry that the case could undermine the FDA’s ability to evaluate other drugs. A decision in favor of a small group of doctors “with an axe to grind against abortion” might call into question the agency’s authority to regulate everything from cancer treatments to Tylenol, Cleland says. “It’s wild.”

But the new research clearly demonstrates that “the FDA followed the science when it expanded how medication abortion can be provided,” Upadhyay says. She hopes that the Supreme Court will do the same in its upcoming decision.

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  • Published: 15 February 2024

Effectiveness and safety of telehealth medication abortion in the USA

  • Ushma D. Upadhyay   ORCID: orcid.org/0000-0002-2731-2157 1 ,
  • Leah R. Koenig 1 , 2 ,
  • Karen Meckstroth 1 ,
  • Jennifer Ko 1 ,
  • Ena Suseth Valladares 3 &
  • M. Antonia Biggs 1  

Nature Medicine ( 2024 ) Cite this article

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  • Adverse effects
  • Epidemiology
  • Health services
  • Outcomes research

Telehealth abortion has become critical to addressing surges in demand in states where abortion remains legal but evidence on its effectiveness and safety is limited. California Home Abortion by Telehealth (CHAT) is a prospective study that follows pregnant people who obtained medication abortion via telehealth from three virtual clinics operating in 20 states and Washington, DC between April 2021 and January 2022. Individuals were screened using a standardized no-test protocol, primarily relying on their medical history to assess medical eligibility. We assessed effectiveness, defined as complete abortion after 200 mg mifepristone and 1,600 μg misoprostol (or lower) without additional intervention; safety was measured by the absence of serious adverse events. We estimated rates using multivariable logistic regression and multiple imputation to account for missing data. Among 6,034 abortions, 97.7% (95% confidence interval (CI) = 97.2–98.1%) were complete without subsequent known intervention or ongoing pregnancy after the initial treatment. Overall, 99.8% (99.6–99.9%) of abortions were not followed by serious adverse events. In total, 0.25% of patients experienced a serious abortion-related adverse event, 0.16% were treated for an ectopic pregnancy and 1.3% abortions were followed by emergency department visits. There were no differences in effectiveness or safety between synchronous and asynchronous models of care. Telehealth medication abortion is effective, safe and comparable to published rates of in-person medication abortion care.

In 2021, the US Food and Drug Administration (FDA) removed the in-person dispensing requirement on mifepristone, the first drug used in a medication abortion. This ruling allowed clinicians to begin offering a ‘no-test’ telehealth model of medication abortion care. Clinicians could now offer entirely remote consultations, using the patient’s self-reported medical history instead of ultrasonography or other tests to screen for medical eligibility.

Moving abortion out of the clinic reduced travel, cost and stigma-related barriers and increased convenience for patients 1 , 2 . While telehealth abortion is usually conducted through synchronous communication, with a real-time scheduled videoconference appointment with the patient, some virtual clinics rely on entirely asynchronous communication, using secure text messaging without a scheduled interaction. Follow-up for both models is usually asynchronous, through secure text messaging.

This expansion of services became critical after the June 2022 Supreme Court Dobbs v. Jackson Women’s Health Organization decision allowed states to ban abortion. In states such as Illinois, Kansas and Colorado, where abortion remained legal but neighboring states banned abortion, clinics experienced large increases in patient volume 3 . Telehealth became vital to meeting increased demand by reducing appointment waiting times and serving patients from states with abortion bans 4 . Some individuals from US states with an abortion ban use methods such as mail forwarding and mailing medications to a friend or Post Office box close to the border in states where abortion is permitted, minimizing the travel required 5 . Additionally, some clinicians have begun to use the legal protections of their state’s “shield laws” to provide medication abortion via telehealth to patients in banned states 6 .

However, access to mifepristone for medication abortion has been under threat, with a federal court ruling to reverse FDA regulatory approvals of mifepristone, including the 2021 decision that allowed telehealth for abortion to continue even after the pandemic. This ruling was issued despite multiple FDA reviews and abundant evidence demonstrating the effectiveness and safety of mifepristone 7 . According to the mifepristone label, 97.4% of 16,794 patients in US clinical trials of in-person medication abortion had a complete abortion and less than 0.5% had a serious adverse event 8 .

While decades of evidence support the effectiveness and safety of mifepristone provided in person, the evidence supporting no-test direct-to-patient telehealth abortion is more limited. Before 2021, US research on the effectiveness and safety of telehealth abortion was limited to clinic-to-clinic 9 , 10 , 11 or direct-to-patient models that required pre-abortion ultrasonography or other tests 12 . To date, only five US studies have examined the outcomes of no-test direct-to-patient telehealth abortion models; four of these had small (fewer than 350) samples of patients receiving such care; thus, they were underpowered to examine outcomes as rare as serious adverse events 13 , 14 , 15 , 16 . The fifth study was a retrospective examination of no-test medication abortion provided either in-person or by telehealth and mail. Among 3,779 medication abortions, 95% were complete without procedural intervention and 0.5% experienced a serious adverse event. Effectiveness and safety were similar whether medications were dispensed in-person or by mail 17 , 18 . However, this study did not report the effectiveness and safety outcomes of asynchronous telehealth abortion.

In this study, we used data from the California Home Abortion by Telehealth (CHAT) study to follow a large sample of patients across the US from three virtual clinics to estimate the effectiveness and safety of medication abortion care provided via telehealth. Clinicians provided telehealth abortion care via either synchronous (video) or asynchronous (secure text messaging) methods. They screened patients using a published, standardized no-test protocol, primarily relying on patient medical history to assess medical eligibility 19 . Patients who had any risk factors for or symptoms of ectopic pregnancy or were potentially beyond the gestational limit of the virtual clinic were referred for pre-abortion ultrasonography. Eligible patients received 200 mg mifepristone and 800 or 1,600 μg buccal or vaginal misoprostol via mail order pharmacy. Outcome data were collected by scheduled follow-up interactions conducted remotely 3–7 days after intake and again 2–4 weeks after medication administration (Fig. 1 ). Our primary aim was to assess the effectiveness and safety of telehealth medication abortion care. Our secondary aim was to compare effectiveness and safety outcomes between synchronous and asynchronous models of telehealth.

figure 1

Timing and content of the electronic medical records and survey data analyzed in the CHAT study.

We received electronic medical records for 6,974 encounters. Among those, 6,154 patients met the eligibility criteria and had abortion medications dispensed to them in 20 states and Washington, DC. We excluded cases where the patient took neither mifepristone nor misoprostol ( n  = 120) leaving 6,034 patients in the analytical sample (Fig. 2 ). Among these, 1,600 patients provided supplementary self-reported data on their outcomes via surveys (Extended Data Table 1 ).

figure 2

Patient flow chart depicting the exclusion criteria.

All patients were pregnant and seeking abortion. Half (50.3%) were 30 years or older and 4.6% were aged under 20 years (Table 1 ). Race, ethnicity or ethnic grouping was unknown for one-third (34.3%) of patients because one of the clinics did not record these data in their medical records for the first half of the study period. Among the subsample with known race, ethnicity or ethnic grouping, nearly two-thirds (62.7%) were white. Most (84.3%) patients had pregnancy durations under 7 weeks (≤49 days). Medical records did not document patient sex or gender.

Overall, 72.3% of patients received asynchronous care. Among patients of the clinic that offered asynchronous care but allowed patients to request a phone or video call, 0.3% requested a call with the provider. Patients who were younger (100.0% for 16–18 years, 79.3% for 18–19 years), Asian, Native Hawaiian or Pacific Islander (82.3%), Middle Eastern or North African (80.0%), living in an urban area (72.7%) and who had pregnancy durations over 56 days (74.8% for 50–56 days, 99.6% for 57–63 days and 100.0% for 64–70 days) were more likely to have received asynchronous care.

Of the sample, 76% (4,613 of 6,034) of cases had any follow-up contact with the virtual clinic or by surveys (Fig. 2 ). Abortion outcomes were known (ascertained using a test or the patient’s history) for 74% (4,454 of 6,034) of the analytical sample. There were few sociodemographic characteristics associated with unknown outcomes. Outcomes were less likely to be known for American Indian or Alaska Native patients (57.1%), Middle Eastern or North African patients (64.0%), patients with a previous birth (70.4%), patients with a pregnancy duration of 57–63 days (66.7%) and 64–70 days (68.4%), and patients receiving asynchronous care (69.6%) (Extended Data Table 2 ). Among patients with unknown outcomes, two requested abortion pill reversal after they took mifepristone but before misoprostol. Both were advised that evidence-based reversal treatment does not exist and referred to urgent in-person care. No further information on their outcomes was available.

Effectiveness

Overall, results from both the complete case analysis and the imputed models found that 97.7% (95% confidence interval (CI) = 97.2–98.1%) of abortions were complete without a subsequent known intervention or ongoing pregnancy after initial treatment (Table 2 and Extended Data Table 3 ). The effectiveness of synchronous and asynchronous telehealth was similar; in the complete case analysis effectiveness was 98.3% (95% CI = 97.5–99.0%) in the synchronous group and 97.4% (95% CI = 96.9–98.0%) in the asynchronous group. In the final imputed analysis, effectiveness was 98.3% (95% CI = 97.7–99.0%) in the synchronous group and 97.4% (95% CI = 96.9–98.0%) in the asynchronous group. Effectiveness also did not differ according to patient age, pregnancy duration, race, ethnicity or ethnic grouping, urbanicity, previous birth, previous abortion or whether the patient had screening ultrasonography.

Among the 2.3% (95% CI = 1.9–2.8%) of patients whose abortion was not initially complete, 0.56% were treated with more than 200 mg mifepristone, more than 1,600 μg misoprostol or other uterotonic medication to complete the abortion, 1.4% were treated with an aspiration or other abortion procedure, 0.16% were treated for an ectopic pregnancy and 0.94% had a confirmed or suspected continuing pregnancy (Table 3 ).

Overall, six (0.16%) patients had ectopic pregnancies; three (0.12%) were suspected ectopic pregnancies treated with methotrexate; one (0.07%) was an ectopic pregnancy treated with an unknown treatment; one (0.12%) was a cesarean scar ectopic pregnancy treated with an unknown treatment; and one (0.09%) was a ruptured ectopic pregnancy treated with a salpingectomy.

Overall, the rate of abortions that were not followed by a serious adverse event was 99.7% (95% CI = 99.5–99.8%) in the complete case analysis and 99.8% (95% CI = 99.6–99.9%) in the final imputed model (Table 2 and Extended Data Table 3 ). Safety was similar between patients who received synchronous and asynchronous care; in the complete case analysis, the safety rate was 99.7% (95% CI = 99.4–100.0%) in the synchronous group and 99.6% (95% CI = 99.4–99.9%) in the asynchronous group. In the final imputed model, safety was 99.8% (95% CI = 99.5–100.0%) among synchronous patients and 99.7% (95% CI = 99.6–99.9%) among asynchronous patients. In the final imputed models, safety was lower among Black or African American patients (99.3%, 95% CI = 98.7–100.0%) than among white patients (99.8%, 95% CI = 97.0–100.0%). No other factors were significantly associated with reduced safety.

Among the 0.25% of patients who experienced a serious adverse event, 0.10% received blood transfusions and 0.02% had abdominal surgery to treat a ruptured ectopic pregnancy; 0.17% of patients had hospital admissions requiring overnight stays. Among the ten (0.17%) hospital admissions, four (0.12%) received inpatient aspiration procedures, two (0.10%) were treated for infection and received an aspiration, one (0.09%) involved a blood transfusion and aspiration, one (0.09%) underwent surgery to treat a ruptured ectopic pregnancy, one (0.08%) was treated with intravenous antibiotics and one (0.09%) had a uterine infection treated with unknown treatment.

Other outcomes

Overall, 1.3% (95% CI = 1.1–1.6%) of abortions were followed by a known emergency department visit, 38.3% of which resulted in no treatment. Emergency department visits were similar between synchronous patients (1.2%, 95% CI = 0.7–1.7%) and asynchronous patients (1.4%, 95% CI = 1.0–1.7%). We identified no cases where, at the subsequent follow-up, it was determined that the abortion occurred beyond 70 days’ gestation.

Sensitivity analyses

The first sensitivity analysis, where we conservatively categorized the 25 patients who were referred to in-person care and were subsequently lost to follow-up as requiring additional intervention to complete the abortion, resulted in effectiveness rates that were not significantly different from the primary analysis; overall 97.1% (95% CI = 96.5–97.6%), with 98.1% (95% CI = 97.3–98.8%) among synchronous patients and 96.7% (95% CI = 96.0–97.3%) among asynchronous patients.

In the second sensitivity analysis modeling effectiveness, we considered patients as having complete abortions regardless of the amount of misoprostol they received, which is consistent with the Medical Abortion Reporting of Efficacy (MARE) guidelines 20 . (Total misoprostol dosages according to pregnancy duration are reported in Extended Data Table 4 .) This also resulted in effectiveness rates that were not significantly different from the primary analysis: 97.9% (95% CI = 97.4–98.3%) overall, 98.4% (95% CI = 97.8–99.0%) among patients who received synchronous care and 97.7% (95% CI = 97.1–98.2%) among patients who received asynchronous care.

The third sensitivity analysis, where we examined effectiveness and safety only among the subsample of patients with supplementary self-reported data on their outcomes via surveys in addition to standard clinical follow-up ( n  = 1,600), resulted in effectiveness rates that were not significantly different from the primary analysis: 96.7% (95% CI = 95.7–97.6%), with 97.1% (95% CI = 95.6–98.6%) among those who received synchronous care and 96.4% (95% CI = 95.2–97.6%) among those who received asynchronous care. This sensitivity analysis resulted in a similar safety rate of 99.3% (95% CI = 98.9–99.7%), and rates of 99.4% (95% CI = 98.7–100.0%) among those who received synchronous care versus 99.3% (95% CI = 98.8–99.8%) of those who received asynchronous care.

In the fourth sensitivity analysis, we conducted delta-adjusted pattern-mixture modeling to examine the potential impact of loss to follow-up on the observed results (Extended Data Table 5 ). Across a range of delta values, we found that the results were largely consistent with the main analysis. Under an extreme scenario in which those with unknown outcomes had ten times the odds of an incomplete abortion or serious adverse event, effectiveness for the entire sample would be 93.3% (95% CI = 92.1–94.5%) and safety would be 98.9% (95% CI = 98.3–99.4%). Under this scenario, effectiveness would be higher in the synchronous group than the asynchronous group, but there would be no differences in safety. Under the opposite and also extreme scenario in which those with unknown outcomes had ten times lower odds of an incomplete abortion, effectiveness would be 98.2% (95% CI = 97.9–98.6%) and safety would be 99.7% (95% CI = 99.6–99.9%), with no significant differences in effectiveness and safety between synchronous and asynchronous groups.

In this large prospective cohort study, telehealth medication abortion provided primarily without tests was effective and safe. The overall 98% effectiveness rate of our primary analysis, and the effectiveness rates from the sensitivity analyses, were similar to previous large US studies of in-person medication abortion care, which found rates of 95–98% 21 , 22 , 23 , 24 . The serious adverse event rate of 0.25% and ectopic pregnancy rate of 0.14% were also similar to previous studies of in-person medication abortion care, which found adverse event rates of 0.2–0.5%, and ectopic pregnancy rates of 0.2% 8 , 23 , 24 , 25 . Both effectiveness and safety rates were similar to the rates for medication abortions with in-person screening tests as published on the FDA label (Fig. 3 ) 8 .

figure 3

The gray bars represent published estimates from the FDA label for in-person dispensing of mifepristone; the blue bars represent the rates found in the CHAT study. Estimates for the CHAT study were calculated using marginal estimates from logistic regression analyses conducted on n  = 6,034 patients. The published estimates of in-person dispensing represent the published rates drawn from the FDA label for mifepristone in 2016. The 95% CIs are represented by the black error bars.

The effectiveness and safety rates found in this study are consistent with, although slightly lower than, those found in studies of no-test telehealth abortion in other countries. A national study in the UK, which included 18,435 telehealth medication abortions, found that 99% were complete without intervention and serious adverse events occurred in 0.02% (refs. 26 , 27 , 28 ). This higher documented effectiveness rate may be explained by the lack of routine follow-up after medication abortion care in the UK; additional interventions that patients may receive may not be systematically reported to the original abortion provider.

The rates in our study are also similar to the effectiveness and safety rates documented from self-managed medication abortion models (defined as using abortion pills to end a pregnancy outside of the formal healthcare system), in the USA 29 and internationally, including in contexts where abortion is legally restricted 30 , 31 .

The effectiveness rates for both synchronous and asynchronous services were very high and similar to in-person care. These findings have important implications for service delivery and health equity. Synchronous models with videoconferencing require strong Internet connectivity. Asynchronous models can be accessed using more types of devices; they may be more private, require shorter waiting times and can be more easily integrated into work or home schedules because no appointment is needed 32 , 33 , 34 . Offering patients a choice between synchronous and asynchronous care is consistent with patient-centered care and may increase access for people historically excluded from healthcare, particularly those living in rural areas or those who live far from an abortion-providing facility 1 , 35 , 36 .

We used a more conservative definition of effectiveness than recommended by the MARE guidelines 20 but used in previous studies 17 , 37 . Our definition included an additional 22 patients who received a second medication abortion (mifepristone plus misoprostol) or more than one additional dose of misoprostol. In the context of telehealth and in the wake of the Dobbs decision, patients living in states that have banned abortions may experience more barriers to procedural treatment for incomplete abortion and thus be more likely to obtain additional medications to complete the abortion. Therefore, our definition of effectiveness may better account for patient experience.

While safety was over 99% among all ethnic groups, Black patients had significantly higher rates of serious adverse events than white patients. This finding is consistent with research showing higher rates of adverse obstetric outcomes among Black patients. Growing consensus finds that these disparities in obstetric health are rooted in implicit biases and structural racism 38 , 39 .

This analysis provides an initial picture of the real-world effectiveness and safety of a rapidly expanding model of abortion care among a large US cohort. However, this analysis has several limitations. One is the lack of clinic-level variation in synchronous and asynchronous models, which may limit generalizability. However, each virtual clinic had multiple providers offering care, thereby increasing variation within each clinic and thus the generalizability of our findings. For example, different providers may use different thresholds or criteria for when to refer patients to in-person care for an ultrasound or exam, which may impact effectiveness rates. This natural variation strengthens the premise that these results could be applied to other providers offering synchronous or asynchronous care. While there was no direct comparison group, we were able to compare our results to widely accepted rates in the published literature using standardized guidelines for measuring medication abortion outcomes.

Additionally, we identified no cases of unexpected pregnancy durations beyond 70 days. This is surprising given that a previous study of no-test medication abortion found a rate of 0.38% 17 . This lack of evidence may be due to underreporting. Although most patients can accurately assess their pregnancy duration 40 , 41 , patients who later learned that they provided a date of last menstrual period that underestimated their pregnancies may have felt that they could be held responsible and thus not reported it to the virtual clinic, particularly if it resulted in an abortion beyond 70 days.

Finally, another limitation is the follow-up rate; at 74% it was similar or higher than other studies on abortion 17 , 31 , 42 , 43 ; attrition may have introduced selection bias given that some groups had lower follow-ups than others. In particular, we observed lower follow-up rates in the asynchronous group than the synchronous group. Telehealth is a less medicalized healthcare model, and asynchronous care even less so; those who opt for it may prefer a more autonomous experience. This differential follow-up may overestimate effectiveness and safety rates for asynchronous patients if those with concerning symptoms seek additional care without informing the virtual clinic. On the other hand, it might underestimate effectiveness rates if patients who have a negative pregnancy test or clear signs of complete abortion do not feel that they must report their outcome back to the virtual clinic. We attempted to limit this potential bias with multiple imputation. We also explored this limitation through a sensitivity analysis simulating higher and lower odds of incomplete abortions and serious adverse events among those lost to follow-up relative to those with known outcomes. This analysis demonstrated that differences in effectiveness between synchronous and asynchronous groups could reach significance under extreme scenarios, but differences in safety remained nonsignificant in all scenarios tested.

These findings provide evidence that telehealth for abortion is effective and safe, with rates similar to in-person care. Additionally, synchronous and asynchronous care are comparably effective and safe. Although telehealth models cannot serve the needs and preferences of everyone, such as those who do not have electronic devices or those who are beyond the first trimester of pregnancy, offering people telehealth options has the potential to expand access to abortion care. These results are reassuring as more clinicians begin to provide telehealth abortion care to patients in US states with a ban, under the legal protections of their state’s shield laws. At the same time, 11 states continue to permit abortion but have prohibitions on no-test telehealth abortion ( https://www.rhites.org/state-based-resources ). This study demonstrates that policies that restrict telehealth abortion owing to concerns or claims about effectiveness or safety need to be revisited and revised to ensure equitable access to this essential healthcare service.

The CHAT study was approved by the University of California, San Francisco institutional review board (no. 20-32951) and registered with ClinicalTrials.gov (registration: NCT04432792 ). We used Strengthening the Reporting of Observational studies in Epidemiology guidelines to design and report the results of this study. All survey respondents provided consent to participate in the research.

Data source and study cohort

The CHAT study followed the patients of three US virtual abortion clinics: Choix (which opened in October 2020); Hey Jane (which opened in January 2021); and Abortion on Demand (which opened in April 2021). These virtual clinics were selected because they were among the first to open in the USA after the FDA temporarily suspended the in-person dispensing requirement during the COVID-19 emergency, and because they operated in states with large populations.

Medication protocols included 200 mg mifepristone orally and 800 µg misoprostol buccally or vaginally for pregnancy durations less than 63 days or 1,600 µg for pregnancy durations of 63 or more days. Care was provided based on a published protocol 19 by nurse practitioners, nurse midwives, physician assistants and physicians who specialize in abortion care. Clinics offered synchronous (video) or asynchronous (secure text messaging) telehealth abortion with mail order pharmacy delivery. One clinic offered only synchronous medication abortion care, one offered only asynchronous care and one offered asynchronous care with an option to have a phone or video call with the provider if preferred. Patients learned about the services through Web searches, social media or referrals.

During the study period, one clinic offered abortion care up to 56 days (8 weeks) of pregnancy, whereas the two other clinics offered it up to 70 days (10 weeks). As per the published protocol, patients were evaluated for medical eligibility based on the reported medical history. Pregnancy duration at intake was primarily based on self-reported date of last menstrual period or by ultrasonography, if available. Some patients had already had ultrasonography before contacting the virtual clinic. Additionally, patients were referred for pre-abortion ultrasonography if they had any risk factors for, or symptoms of, ectopic pregnancy 19 or were potentially beyond the gestational limit of the virtual clinic. Some of these patients returned to the virtual clinic after their eligibility was confirmed by ultrasonography and obtained a telehealth abortion; thus, they were included in the study. Others opted for in-person care and thus were excluded.

Each clinic had two scheduled follow-up interactions. The first confirmed medication administration and assessed symptoms of complete abortion 3–7 days after intake. The second was a low-sensitivity pregnancy test at 2 weeks or a high-sensitivity test at 4 weeks after medication administration. Follow-up interactions were conducted by text messaging, secure messaging or telephone. At each scheduled follow-up, clinicians made up to four attempts to contact patients. Clinicians referred patients to in-person care if any adverse event or incomplete abortion was suspected and outcomes of care were documented whenever possible.

For this analysis, we evaluated data collected from two sources, both imported into REDCap 44 . We obtained anonymized medical record data of consecutive patients receiving care from the participating virtual clinics between April 2021 and January 2022.

Additionally, each virtual clinic invited all patients seen between June 2021 and January 2022 to enroll in three surveys about their abortion experience, including any additional treatments received. After providing electronic informed consent, participants completed a baseline survey on the date of the intake, which included sociodemographic characteristics and medical history. Participants completed a second survey 3–7 days after the intake, to assess medication administration, additional medical care and any adverse events, and a final survey 4 weeks after the intake to assess additional medical care and adverse events (Fig. 1 ). The survey sample was powered to assess the acceptability of telehealth (published separately 2 ); thus, we aimed to collect complete sets of surveys from 1,600 participants. Survey participants received a US$50 electronic debit card on completion of all three surveys.

The primary outcomes were effectiveness and safety based on standard definitions in previous studies 17 , 24 , 37 , 45 . We generally followed the MARE guidelines for reporting outcomes 20 . We defined effectiveness as the proportion of medication abortions that were complete after initial treatment with 200 mg mifepristone and 1,600 µg or less of misoprostol without known subsequent intervention. Abortions were not considered complete if (1) the patient had an aspiration, dilation and evacuation, other procedure or surgical intervention to complete the abortion; (2) the patient received more than 200 mg mifepristone, more than 1,600 µg misoprostol, or a uterotonic medication to complete the abortion; (3) the patient received treatment for suspected or confirmed ectopic pregnancy; or (4) the patient had a continuing pregnancy confirmed by ultrasonography or suspected at last contact. While MARE guidelines define effectiveness as successful expulsion of pregnancy without the need for procedural intervention, we chose a more conservative definition, recognizing that patients may view the need to have what constitutes a second medication abortion treatment as a failure of the medication abortion protocol.

We defined safety using standardized definitions from the Procedural Abortion Incident Reporting and Surveillance Framework 45 and Standardizing Abortion Research Outcomes protocol 46 as the proportion of abortions that were not followed by a known abortion-related serious adverse event. Serious adverse events included: blood transfusion; abdominal surgery (including salpingectomy, laparotomy and laparoscopy to treat an ectopic pregnancy); hospital admission requiring overnight stay; or death.

Effectiveness and safety outcomes were determined from all information collected in the medical records and surveys. Abortion completion was determined based on the virtual clinic’s designation, either using a test (urine pregnancy test, ultrasonography or serum human chorionic gonadotrophin) or using the patient’s medical history (using a checklist reflecting symptoms of complete abortion) without further contact related to the abortion for at least 6 weeks after the intake visit. Patients without outcomes noted in the medical records were determined to have complete abortions if they completed a survey at least 28 days after screening and did not report an intervention or ongoing pregnancy.

Secondary outcomes included the number of cases where, at the subsequent follow-up, it was determined that at intake the patient had been beyond 70 days’ gestation. We also evaluated rates of suspected or confirmed ectopic pregnancy and emergency department visits.

We examined the categorical covariates reflecting participant age at abortion intake in years (16–17 years, 18–19 years, 20–24 years, 25–29 years, 30–34 years and 35 years or older), and pregnancy duration in days at abortion intake (less than 35 days, 35–49 days, 50–56 days, 57–63 days, 64–70 days or unknown). We also included a measure of race, ethnicity or ethnic grouping indicated by participants on an intake form or in the surveys (American Indian or Alaska Native, Asian, Native Hawaiian or Pacific Islander, Black or African American, Middle Eastern or North African, White, Multiracial or Unknown). We included binary covariates for urbanicity (suburban or rural versus urban), whether the patient had a previous abortion, whether the patient had a previous birth and whether the patient had confirmatory pre-abortion ultrasonography.

The key exposure was a binary measure reflecting whether the patient received care synchronously (video) or asynchronously (secure text messaging).

Statistical analysis

The study was powered to detect differences in the rarest primary outcome, that is, serious adverse events. We aimed to have outcome data from 4,202 patients. The study was designed to detect a difference of 0.4% or more in the rate of serious adverse events compared to 0.5%, the rate for in-person medication abortions as published in the FDA label 8 , with 90% power and a two-sided alpha of 0.05. With a final sample size of 4,454, the study had more than 90% power to detect a difference of 2% or more in the effectiveness rate compared to the 3% rate for in-person medication abortions as published on the FDA label 8 .

We described the characteristics of the overall sample and the subsample of patients who completed the surveys. We examined the extent of loss to follow-up and whether loss to follow-up differed between those who obtained synchronous and asynchronous care. We then conducted multiple imputation by chained equations to account for missing covariate and outcome data with 100 replications for primary regression analyses, assuming that missing data were related to observed patient and abortion characteristics. Multiple imputation by chained equations iteratively impute missing data using predictive models based on other variables in the dataset, and accounts for statistical uncertainty in the imputations 47 . Imputation models included patient age, urbanicity, whether the patient obtained screening ultrasonography, whether the patient obtained synchronous or asynchronous telehealth care, whether the patient participated in CHAT surveys, virtual clinics, and whether the patient used an abortion fund to pay for any portion of their abortion.

We developed logistic regression models for all effectiveness and safety outcomes. We used multivariable models for outcomes n  > 15, adjusting for a binary measure of whether the patient received screening via synchronous or asynchronous methods. These models were also adjusted for baseline patient and abortion characteristics, including patient age, race, ethnicity or ethnic grouping, and pregnancy duration. We included binary measures reflecting whether the patient had a previous abortion or birth, and whether the patient had pre-abortion ultrasonography 21 . For rare outcomes ( n  < 15), we used unadjusted logistic regression models.

We calculated marginal estimates, the corresponding 95% CIs and P values from the logistic regression results to estimate the predicted probability of each effectiveness and safety outcome. Primary estimates came from logistic regression analyses performed on imputed data. P values correspond to a Wald test in the logistic regressions, comparing each group to the reference group. We then compared results with published estimates of effectiveness and safety. All statistical tests were two-tailed with significance set at 0.05. All analyses were conducted using Stata v.17.0 (StataCorp LLC).

We conducted several sensitivity analyses to assess the robustness of our findings. First, we replicated the effectiveness analysis, assuming that patients who were referred to in-person care after taking the medications and were then lost to follow-up required further intervention to complete the abortion. Second, we replicated the effectiveness analysis by categorizing all patients who received any additional misoprostol as completed abortions. This is consistent with the MARE guidelines and previous studies 26 , 48 , which classified patients who received more than 1,600 μg of misoprostol (more than two doses) as successful abortions. Third, we examined both effectiveness and safety outcomes only among the subsample of patients who completed the surveys to evaluate whether the main findings held true among this sample with supplementary self-reported data on their outcomes. Finally, to test how robust our results were to the follow-up rates, we used delta-adjusted pattern-mixture model imputation 49 to simulate the outcomes under different assumptions regarding patients with missing outcome data, hypothesizing results if they had lower or higher odds of incomplete abortion or serious adverse events than those with outcome data.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

The datasets analyzed during this study are not publicly available because the patients who underwent an abortion did not consent to sharing their data beyond the primary researchers and because the legal status of abortion care is continually changing. The de-identified, individual-level data used to reach the study conclusions are available to qualified investigators from the corresponding author. Requesters must include a description of their research project, the qualifications of the research team, whether the analysis has institutional review board approval and how the results will be disseminated. Requesters must also sign a data use agreement to (1) use the data only for research purposes, (2) not attempt to re-identify the data or contact the study participants, (3) secure the data using appropriate computer technology and (4) destroy the data after the analyses are completed. Responses can be expected within 1 month of a request.

Code availability

Data analyses were carried out using Stata v.17.0 (StataCorp LLC) as specified in the Methods . The code is available on GitHub ( https://github.com/Upadhyay-Lab ).

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Acknowledgements

We thank M. Cervantes, L. Shin, K. Song, A. Becker and L. Peters for their contributions to data collection and management and other input on the CHAT study. We also thank C. Adam, M. Adam, K. Baron, S. Bussmann, L. Coplon, L. Dubey, L. DuBois, K. Freedman, G. Izarra, J. Phifer and A. Wagner for their support with data acquisition. We thank E. Wells and F. Coeytaux for their early input on study design, and E. Raymond for thoughtful guidance on classifying adverse events. We thank W. J. Boscardin for his input on pattern-mixture modeling. The CHAT study was supported by the BaSe Family Fund, the Erik E. and Edith H. Bergstrom Foundation, the Isabel Allende Foundation, Jess Jacobs, the Kahle/Austin Foundation, the Lisa and Douglas Goldman Fund, Preston-Werner Ventures (all to U.D.U.) and a Resource Allocation Program Award from the University of California, San Francisco National Center of Excellence in Women’s Health (to M.A.B.). L.R.K. was funded in part by a training grant from the National Institute of Child Health and Human Development of the National Institutes of Health under award no. F31HD111277 for the duration of the study. The funders had no role in study design, data collection and analysis, the writing of the manuscript or the decision to submit the manuscript for publication.

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Ushma D. Upadhyay, Leah R. Koenig, Karen Meckstroth, Jennifer Ko & M. Antonia Biggs

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA

Leah R. Koenig

California Latinas for Reproductive Justice, Los Angeles, CA, USA

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Contributions

U.D.U. obtained the funding for the study. U.D.U., L.R.K., E.S.V. and K.M. conceptualized and designed the study. L.R.K. conducted the data analysis. U.D.U. supervised the data analysis. J.K. provided management and administration for the study. U.D.U., L.R.K. and M.A.B. drafted the manuscript. All authors interpreted the data, reviewed the manuscript drafts, provided substantive input on its content and approved the final version of the manuscript. U.D.U. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Ushma D. Upadhyay .

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K.M. reports receiving personal fees from Danco Laboratories, a distributor of mifepristone, for staffing a US Food and Drug Administration-mandated expert hotline. The other authors declare no competing interests.

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Upadhyay, U.D., Koenig, L.R., Meckstroth, K. et al. Effectiveness and safety of telehealth medication abortion in the USA. Nat Med (2024). https://doi.org/10.1038/s41591-024-02834-w

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DOI : https://doi.org/10.1038/s41591-024-02834-w

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Reproductive rights in America

Research at the heart of a federal case against the abortion pill has been retracted.

Selena Simmons-Duffin

Selena Simmons-Duffin

spontaneous abortion case study

The Supreme Court will hear the case against the abortion pill mifepristone on March 26. It's part of a two-drug regimen with misoprostol for abortions in the first 10 weeks of pregnancy. Anna Moneymaker/Getty Images hide caption

The Supreme Court will hear the case against the abortion pill mifepristone on March 26. It's part of a two-drug regimen with misoprostol for abortions in the first 10 weeks of pregnancy.

A scientific paper that raised concerns about the safety of the abortion pill mifepristone was retracted by its publisher this week. The study was cited three times by a federal judge who ruled against mifepristone last spring. That case, which could limit access to mifepristone throughout the country, will soon be heard in the Supreme Court.

The now retracted study used Medicaid claims data to track E.R. visits by patients in the month after having an abortion. The study found a much higher rate of complications than similar studies that have examined abortion safety.

Sage, the publisher of the journal, retracted the study on Monday along with two other papers, explaining in a statement that "expert reviewers found that the studies demonstrate a lack of scientific rigor that invalidates or renders unreliable the authors' conclusions."

It also noted that most of the authors on the paper worked for the Charlotte Lozier Institute, the research arm of anti-abortion lobbying group Susan B. Anthony Pro-Life America, and that one of the original peer reviewers had also worked for the Lozier Institute.

The Sage journal, Health Services Research and Managerial Epidemiology , published all three research articles, which are still available online along with the retraction notice. In an email to NPR, a spokesperson for Sage wrote that the process leading to the retractions "was thorough, fair, and careful."

The lead author on the paper, James Studnicki, fiercely defends his work. "Sage is targeting us because we have been successful for a long period of time," he says on a video posted online this week . He asserts that the retraction has "nothing to do with real science and has everything to do with a political assassination of science."

He says that because the study's findings have been cited in legal cases like the one challenging the abortion pill, "we have become visible – people are quoting us. And for that reason, we are dangerous, and for that reason, they want to cancel our work," Studnicki says in the video.

In an email to NPR, a spokesperson for the Charlotte Lozier Institute said that they "will be taking appropriate legal action."

Role in abortion pill legal case

Anti-abortion rights groups, including a group of doctors, sued the federal Food and Drug Administration in 2022 over the approval of mifepristone, which is part of a two-drug regimen used in most medication abortions. The pill has been on the market for over 20 years, and is used in more than half abortions nationally. The FDA stands by its research that finds adverse events from mifepristone are extremely rare.

Judge Matthew Kacsmaryk, the district court judge who initially ruled on the case, pointed to the now-retracted study to support the idea that the anti-abortion rights physicians suing the FDA had the right to do so. "The associations' members have standing because they allege adverse events from chemical abortion drugs can overwhelm the medical system and place 'enormous pressure and stress' on doctors during emergencies and complications," he wrote in his decision, citing Studnicki. He ruled that mifepristone should be pulled from the market nationwide, although his decision never took effect.

spontaneous abortion case study

Matthew Kacsmaryk at his confirmation hearing for the federal bench in 2017. AP hide caption

Matthew Kacsmaryk at his confirmation hearing for the federal bench in 2017.

Kacsmaryk is a Trump appointee who was a vocal abortion opponent before becoming a federal judge.

"I don't think he would view the retraction as delegitimizing the research," says Mary Ziegler , a law professor and expert on the legal history of abortion at U.C. Davis. "There's been so much polarization about what the reality of abortion is on the right that I'm not sure how much a retraction would affect his reasoning."

Ziegler also doubts the retractions will alter much in the Supreme Court case, given its conservative majority. "We've already seen, when it comes to abortion, that the court has a propensity to look at the views of experts that support the results it wants," she says. The decision that overturned Roe v. Wade is an example, she says. "The majority [opinion] relied pretty much exclusively on scholars with some ties to pro-life activism and didn't really cite anybody else even or really even acknowledge that there was a majority scholarly position or even that there was meaningful disagreement on the subject."

In the mifepristone case, "there's a lot of supposition and speculation" in the argument about who has standing to sue, she explains. "There's a probability that people will take mifepristone and then there's a probability that they'll get complications and then there's a probability that they'll get treatment in the E.R. and then there's a probability that they'll encounter physicians with certain objections to mifepristone. So the question is, if this [retraction] knocks out one leg of the stool, does that somehow affect how the court is going to view standing? I imagine not."

It's impossible to know who will win the Supreme Court case, but Ziegler thinks that this retraction probably won't sway the outcome either way. "If the court is skeptical of standing because of all these aforementioned weaknesses, this is just more fuel to that fire," she says. "It's not as if this were an airtight case for standing and this was a potentially game-changing development."

Oral arguments for the case, Alliance for Hippocratic Medicine v. FDA , are scheduled for March 26 at the Supreme Court. A decision is expected by summer. Mifepristone remains available while the legal process continues.

  • Abortion policy
  • abortion pill
  • judge matthew kacsmaryk
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Association between previous spontaneous abortion and preeclampsia: a case–control study

Ahmed mohamedain.

1 Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan

Duria A. Rayis

Nadiah alhabardi.

2 Department of Obstetrics and Gynecology, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Kingdom of Saudi Arabia

Associated Data

The datasets generated and/or analysed during the current study are not publicly available (because the manuscript is still under the peer review process) but are available from the corresponding author on reasonable request.

The association between previous spontaneous abortion and preeclampsia is not yet fully understood. The current study was conducted to assess the association between previous spontaneous abortion and preeclampsia among pregnant women in Sudan.

A case–control study (involving 180 women in each study group) was conducted at Saad Abuelela Hospital, Khartoum, Sudan. The cases were pregnant women with preeclampsia, while the control group included healthy pregnant women. The participants’ sociodemographic, obstetric, and clinical characteristics were assessed via a questionnaire.

There was no significant difference in the age, parity, education level, employment status, blood group, body mass index, and hemoglobin level between the patient and control groups. Forty (22.2%) women with preeclampsia and 68 (37.8%) women in the control group had a history of spontaneous abortion ( p  = 0.001).

Multivariate logistic regression analysis (adjusted) revealed that women with a history of spontaneous abortion had a lower risk of preeclampsia than those without a history of spontaneous abortion [adjusted odds ratio (AOR) = 0.44, 95% confidence interval (CI) = 0.26‒0.73]. However, women with a history of preeclampsia had a higher risk of recurrence of preeclampsia (AOR = 1.92, 95% CI = 1.11‒3.32).

The present study revealed that previous spontaneous abortion reduced the risk of preeclampsia by 59.0%.

Introduction

Preeclampsia is a multi-pathway disorder that is characterized by new-onset hypertension and proteinuria in the second half of pregnancy (i.e., after the 20th week of gestation); it is one of the most common pregnancy-related disorders [ 1 ]. Preeclampsia is a global health challenge, affecting 2%–8% of pregnant or parturient women. It can have maternal and perinatal adverse effects and is the leading cause of maternal and perinatal morbidity and mortality [ 2 ]. Despite advances in various sciences to understand the pathophysiology of preeclampsia, its exact cause and etiology remain unclear. Previous research has revealed several sociodemographic, obstetric, clinical, biochemical, and genetic factors associated with preeclampsia [ 3 ]. We previously found that preeclampsia/eclampsia was responsible for 4.2% of the admissions (total admissions = 4689) to a maternity hospital in Kassala in eastern Sudan and that preeclampsia was the main cause of maternal and perinatal morbidity and mortality [ 4 ].

Several studies have reported an association between prior abortion and preeclampsia [ 5 – 16 ]. However, the results of these studies are inconsistent; while some studies have reported an increased risk of preeclampsia in women with a history of abortions [ 5 – 8 ], others have reported no such effect [ 9 – 12 ] or a reduced risk of preeclampsia in women with a history of abortions [ 13 – 16 ]. Moreover, most these studies have been conducted in high-income countries [ 7 , 9 , 13 , 16 ]. There is a scarcity of data on the history of abortion and preeclampsia in sub-Saharan African countries [ 6 ], and none of these studies have been conducted in Sudan. The risk factors for preeclampsia may differ in different populations. It is therefore necessary to assess these risk factors in different populations. It is important for clinicians, researchers, and health planners to identify the risk factors (including history of spontaneous abortion) for preeclampsia in various settings in order to identify women who are at a higher risk of preeclampsia and to provide optimum care.

The present study aimed to assess the association between previous spontaneous abortion and preeclampsia among pregnant women in Sudan.

Study design and setting

The present case–control study was conducted at Saad Abuelela Hospital, Khartoum, Sudan, from February to December 2020.

Selection of the participants

The patient group included consecutive pregnant women who presented with preeclampsia during the aforementioned period. Preeclampsia was defined as follows, according to the criteria of the American College of Obstetricians and Gynecologists [ 1 ]: (1) average blood pressure levels ≥ 140/90 mmHg on two readings taken at least 6 h apart and (2) proteinuria ≥ 300 mg/24 h in pregnant women. Preeclampsia was considered to be severe in women with average blood pressure levels ≥ 160/110 mmHg on two occasions or proteinuria ≥ 5 g/24 h, in addition to hemolysis, elevated liver enzymes, and low platelet count (HAELLP) syndrome; in all other cases, preeclampsia was considered to be mild [ 1 ]. Moreover, preeclampsia that developed before and after 34 weeks of gestation was defined as early-onset and late-onset preeclampsia, respectively [ 17 ]. A healthy pregnant woman (consecutively to each woman with preeclampsia) without any systemic disease, such as hypertension, thyroid disease, severe anemia (hemoglobin level < 5 g/dl), diabetes mellites, renal disease, or proteinuria, served as a control for each patient with preeclampsia. Women with multiple pregnancies, who were smokers, or whose fetuses had major congenital anomalies were excluded from both the cases and controls.

After the participants signed an informed consent form, they were asked about their sociodemographic, obstetric, and clinical characteristics (such as age, parity, education level, employment status, blood group, history of abortion, history of preeclampsia, and gender of the newborn). The participants’ weight and height were measured using standard procedures to compute the body mass index (BMI) [ 18 ]. The hemoglobin level was measured using an automated hematology analyzer, according to the manufacturer ’ s instructions (Sysmex, KX-21, Japan).

Sample size

A total of 180 women were included in each study group (a ratio of 1:1); the sample size was calculated on the basis of previous data on the history (43.0%) of spontaneous abortions among women with preeclampsia in neighboring Ethiopia [ 6 ]. Therefore, we assumed that 40.0% of women with a history of spontaneous abortion would have preeclampsia and 25.0% of women with a history of spontaneous abortion would not have preeclampsia. This sample size (180 in each study group) was used to achieve 80% power and 5% precision; it was assumed that 10% of the women would not respond or would have incomplete data.

Statistical analysis

Statistical analysis was performed using Statistical Package for the Social Sciences® (SPSS®; IBM SPSS Statistics for Windows, version 22.0; SPSS Inc., New York, United States). The proportions of the studied variables are expressed as frequencies (%). The normality of continuous data was assessed using the Shapiro–Wilk test. Multicollinearity (variance inflation factor < 4) was assessed but was not detected among the variables. Associations between specific variables, such as age, parity, education level, employment status, blood group, history of preeclampsia, history of miscarriage, BMI, gender of the newborn, and preeclampsia, were assessed using univariate analysis. Variables with a p -value ≤ 0.200 in univariate analysis were selected for the construction of multivariate models that considered crude associations between preeclampsia and the variables. Backward elimination (likelihood ratio) was used to adjust the model for covariates. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated. A two-sided p -value ≤ 0.050 was considered to denote statistical significance.

During the study period, 117 (65.0%) and 63 (35.0%) women presented with mild and severe preeclampsia, respectively. There was no significant difference in the age, parity, education level, employment status, blood group, BMI, hemoglobin level, and gender of the newborn between the patient and control groups ( n  = 180 in each). The number of women with a history of spontaneous abortion was lesser in the patient group than in the control group. Forty (22.2%) women with preeclampsia and 68 (37.8%) women in the control group had a history of spontaneous abortion ( p  = 0.001). A higher number of women with preeclampsia had a history of preeclampsia (Table ​ (Table1 1 ).

Univariate analysis of sociodemographic and clinical variables among women with preeclampsia and controls at Saad Abuelela Hospital, Khartoum, Sudan, in 2020

CI Confidence interval, OR Odds ratio

a Median (interquartile range)

Multivariate logistic regression analysis (adjusted) revealed that women with a history of spontaneous abortion had a lower risk of preeclampsia than those without a history of spontaneous abortion (AOR = 0.44, 95% CI = 0.26‒0.73, p  < 0.001). However, women with a history of preeclampsia had a higher risk of recurrence of preeclampsia (AOR = 1.92, 95% CI = 1.11‒3.32, p  = 0.022, Table ​ Table2 2 ).

Multivariate analysis of the adjusted odds ratios for the factors associated with preeclampsia at Saad Abuelela Hospital, Khartoum, Sudan, in 2020

The present study revealed that a history of spontaneous abortion reduced the risk of preeclampsia by 59.0% (AOR = 0.41). This finding is in accordance with that of Lao et al., who reported that prior abortion reduced the risk of preeclampsia by 15.0% among primiparous women in China (adjusted relative risk = 0.85) [ 14 ]. Similarly, Su et al. reported that a history of induced abortion was associated with a lower risk of preeclampsia among nulliparous women in China [ 15 ]. Moreover, as per a report in Norway, although two or more induced abortions reduced the risk of preeclampsia by 64.0%, one induced abortion marginally/moderately reduced the risk of preeclampsia (95% CI = 0.69–1.02] [ 16 ]. In the United States of America (Boston), Parker et al. observed a 10% reduction in the risk of preeclampsia (OR = 0.9) in women with a history of one induced abortion and a 30% reduction (OR = 0.7) in women with a history of three or more induced abortions [ 13 ]. Women with a history of abortion have already experienced changes (hormone levels as well as immunological) in their pregnancy in comparison with primiparous women. The previous experienced changes in hormonal and immunological environment can lead to immune tolerance/adaptation and reduce the risk for preeclampsia [ 19 , 20 ].

However, several studies have reported an association between prior abortion and an increased risk of preeclampsia in Ethiopia [ 6 ], Iran [ 5 ], China [ 8 ], and Scotland [ 21 ]. Interestingly, while one prior miscarriage was not found to be associated with preeclampsia, two or more miscarriages were found to be associated with increased risks of preeclampsia [ 7 ]. On the other hand, Holmlund et al. found no association between induced abortion and preeclampsia in Finland [ 9 ]. Moreover, Clark et al. reported no association between miscarriage and gestational hypertension, even in women with more than two abortions [ 10 ]. In a case–control study involving 200 cases and 100 controls, no significant difference was noted in preeclampsia/eclampsia between women with one prior abortion and those with one prior live birth [ 11 ]. Interestingly, no reduction in the prevalence of preeclampsia was noted following prior induced or spontaneous abortions [ 12 ].

It is worth mentioning that our results should be cautiously compared with those of previous studies. First, while most of these studies assessed the association between induced abortion and preeclampsia, we assessed the association between spontaneous abortion and preeclampsia. Perhaps, spontaneous and induced abortions are two different entities with different pathophysiologies. Because of traditional and religious factors, induced abortion is not practiced in Sudan, with few exceptions for medical reasons. Second, the present study was designed to assess the association between spontaneous abortion and preeclampsia, regardless of the number of miscarriages; however, in several other studies, the association between prior abortion and preeclampsia depended on the number of prior abortions. Third, we need to consider the differences in social and genetic factors among different communities, which may affect the etiology and pathophysiology of preeclampsia in the communities.

In previous studies, prior miscarriages were found to be associated with an increased risk of poor maternal and perinatal outcomes, such as placental dysfunction disorders, stillbirth, small-for-gestational-age fetuses, antepartum hemorrhage, preterm birth, and low birth weight [ 7 , 22 ]. The association between prior abortion and increased risk of preeclampsia (contrary/opposite to our results) could be explained by the hypothesis that placental dysfunction could result in early placentation failure, with poor implantation and placentation, which are common features of both abortion and preeclampsia [ 23 , 24 ]. Moreover, prior abortion may lead to maternal exposure to fetal cells and may induce maternal immune tolerance, which may play an important role in the development of preeclampsia [ 25 ].

There are many limitations in this study. Many factors, such as communicable diseases (e.g., herpes simplex virus type 2 infection and toxoplasmosis), were not assessed in the present study. These diseases have been reported to be associated with preeclampsia [ 26 , 27 ], and they may be associated with abortion itself. We objectively assessed the history of spontaneous abortion in women with preeclampsia. The information regarding abortion and its history may not be accurate, as it depends on recall bias.

Acknowledgements

Authors’ contributions.

AM and IA conceived the study; DAR supervised the work, guided the analysis and critically reviewed the manuscript; NA and IA prepared the analysis plan, performed the data analysis and wrote the first draft of the paper; AM and DAR supervised data collection. All authors reviewed and approved the final manuscript.

Availability of data and materials

Declarations.

The present study was approved by the Research Ethics Committee of Saad Abuelela Hospital, Sudan (#2020,06). All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all women.

Not applicable.

The Correspondence author (professor Ishag Adam) is one of the senior editorial board members in this Journal. All the other authors have no conflict of interest to disclose.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Ahmed Mohamedain, Email: moc.liamtoh@niademahom .

Duria A. Rayis, Email: moc.liamtoh@11airud .

Nadiah AlHabardi, Email: [email protected] .

Ishag Adam, Email: moc.liamtoh@madagahsi .

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Journal Retracts Studies Cited in Federal Court Ruling Against Abortion Pill

The journal found that the studies, which had suggested that medication abortion is unsafe, included incorrect factual assumptions and misleading presentation of the data.

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An orange box of Mifeprex (Mifepristone) sits on a table with papers nearby.

By Pam Belluck

An academic journal publisher this week retracted two studies that were cited by a federal judge in Texas last year when he ruled that the abortion pill mifepristone should be taken off the market .

Most of the authors of the studies are doctors and researchers affiliated with anti-abortion groups, and their reports suggested that medication abortion causes dangerous complications, contradicting the widespread evidence that abortion pills are safe .

The lawsuit in which the studies were cited will be heard by the Supreme Court in March. The high court’s ruling could have major implications for access to medication abortion, which is now the most common method of pregnancy termination.

The publisher, Sage Journals, said it had asked two independent experts to evaluate the studies, published in 2021 and 2022 in the journal Health Services Research and Managerial Epidemiology, after a reader raised concerns.

Sage said both experts had “identified fundamental problems with the study design and methodology, unjustified or incorrect factual assumptions, material errors in the authors’ analysis of the data, and misleading presentations of the data that, in their opinions, demonstrate a lack of scientific rigor and invalidate the authors’ conclusions in whole or in part.”

The publisher also retracted a third study by many of the same authors that was published in 2019 in the same journal, which did not figure in the mifepristone lawsuit.

Sage said that when it had begun examining the 2021 study, it confirmed that most of the authors had listed affiliations with “pro-life advocacy organizations” but had “declared they had no conflicts of interest when they submitted the article for publication or in the article itself.”

Sage said it had also learned that one of the reviewers who evaluated the article for publication was affiliated with the Charlotte Lozier Institute, the research arm of Susan B. Anthony Pro-Life America.

The institute denied that the studies were flawed, as did the lead author, James Studnicki, who is vice president and director of data analytics at the institute.

“Sage is targeting us,” Dr. Studnicki, who has a doctor of science degree and a master’s degree in public health, said in a video defending the team’s work.

Noting that the studies had been used in legal actions, he said: “We have become visible, people are quoting us, and for that reason we are dangerous, and for that reason they want to cancel our work. What happened to us has little or nothing to do with real science and has everything to do with political assassination.”

In a statement, Dr. Studnicki said, “The authors will be taking appropriate legal action,” but he did not specify what that would be.

The lawsuit seeking to bar mifepristone — the first pill in the two-drug medication abortion regimen — was filed against the Food and Drug Administration by a consortium of groups and doctors who oppose abortion. In fighting the lawsuit, the federal government has defended its approval and regulation of mifepristone, provided years of evidence that the pill is safe and effective and argued that the plaintiffs have no legal standing to sue because they are not abortion providers and have not been harmed by mifepristone’s availability.

In his opinion last April, Judge Matthew J. Kacsmaryk cited the 2021 study to support his conclusion that the plaintiffs had legal standing to sue. That study reported a higher rate of emergency room visits after medication abortions than after procedural abortions. Citing it, Judge Kacsmaryk wrote that the plaintiffs “have standing because they allege adverse events from chemical abortion drugs can overwhelm the medical system and place ‘enormous pressure and stress’ on doctors during emergencies and complications.”

In another section of his ruling, Judge Kacsmaryk cited the 2022 study, writing that “plaintiffs allege ‘many intense side effects’ and ‘significant complications requiring medical attention’ resulting from Defendants’ actions.”

Judge Kacsmaryk’s opinion was criticized by many legal experts, and an appeals court struck parts of it but said significant restrictions should be placed on mifepristone that would prevent it from being mailed or prescribed by telemedicine.

Legal experts said it was unclear if Sage’s action would affect the Supreme Court’s decision. Mary Ziegler, a law professor at the University of California, Davis, said the retractions might simply “reinforce a position they were already ready to take.”

For example, she said, there were already strong arguments that the plaintiffs lacked legal standing, so if a justice was “willing to overlook all that other stuff, you may be willing to overlook the retractions too,” she said. For justices already “bothered by various other problems with standing, you probably were potentially going to say the plaintiffs didn’t have standing as it was.”

Similarly, she said, some justices would already have concluded that the vast majority of studies show mifepristone is safe, so if a justice was “prepared to say that, notwithstanding the weight of the evidence, mifepristone is really dangerous, you could easily do that again if you lose a couple of studies.”

Pam Belluck is a health and science reporter, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics. More about Pam Belluck

Association between urinary polycyclic aromatic hydrocarbons and unexplained recurrent spontaneous abortion from a case-control study

Affiliations.

  • 1 China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing 100021, China.
  • 2 Fengtai District Center for Disease Control and Prevention, Beijing 100071, China.
  • 3 China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing 100021, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 4 Institute of Public Health, Henan Provincial Center for Disease Control and Prevention, Zhengzhou, Henan 450016, China.
  • 5 China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing 100021, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: [email protected].
  • 6 China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing 100021, China. Electronic address: [email protected].
  • PMID: 38364758
  • DOI: 10.1016/j.ecoenv.2024.116093

Polycyclic aromatic hydrocarbons (PAHs) have been reported to be associated with adverse pregnancy outcomes. However, there is limited knowledge regarding the effects of single or mixed PAHs exposure on unexplained recurrent spontaneous abortion (URSA). This study aimed to investigate the association between monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and URSA in a case-control study. The results showed that 1-NAP, 2-NAP, 9-FLU, and 1-PYR were detected in 100% of the subjects among measured all sixteen OH-PAHs. Compared with those in the lowest quartiles, participants in the highest quartiles of 3-BAA were associated with a higher risk of URSA (OR (95%CI) = 3.56(1.28-9.85)). With each one-unit increase of ln-transformed 3-BAA, the odds of URSA increased by 41% (OR (95%CI) = 1.41(1.05-1.89)). Other OH-PAHs showed negative or non-significant associations with URSA. Weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile-based g-computation (qgcomp) analyses consistently identified 3-BAA as the major contributor to the mixture effect of OH-PAHs on URSA. Our findings suggest that exposure to 3-BAA may be a potential risk factor for URSA. However, further prospective studies are needed to validate our findings in the future.

Keywords: Case-control study; Mixed exposure analysis; Polycyclic aromatic hydrocarbons; Unexplained recurrent spontaneous abortion.

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

IMAGES

  1. Spontaneous Abortion Nursing Management

    spontaneous abortion case study

  2. Management of Spontaneous Abortion

    spontaneous abortion case study

  3. Spontaneous Abortion Nursing Management

    spontaneous abortion case study

  4. Spontaneous Abortion

    spontaneous abortion case study

  5. Spontaneous Abortion

    spontaneous abortion case study

  6. Spontaneous Abortion: Diagnosis and Treatment: 9780387197128: Medicine

    spontaneous abortion case study

COMMENTS

  1. Early Pregnancy Loss (Spontaneous Abortion)

    [1] [2] Traditionally, spontaneous abortion referred to a natural pregnancy loss before 20 weeks of gestation; however, more recently, the medical literature has been transitioning away from the phrase. [3] Patients prefer the term miscarriage , presumably to avoid the stigma associated with induced abortion. [1]

  2. A case report of spontaneous abortion caused by

    Abstract Background Brucellosis is a worldwide zoonotic disease caused by Brucella spp. Brucella invades the body through the skin mucosa, digestive tract, and respiratory tract. However, only a few studies on human spontaneous abortion attributable to Brucella have been reported.

  3. Factors associated with fetal karyotype in spontaneous abortion: a case

    Abstract Background Most embryos that spontaneously abort during early pregnancy are found to have chromosomal abnormalities. The purpose of this study is to explore the factors involved in chromosome aberrations during embryogenesis. Methods

  4. Coronavirus disease 2019 and first-trimester spontaneous abortion: a

    Coronavirus disease 2019 and first-trimester spontaneous abortion: a case-control study of 225 pregnant patients - PMC Journal List Elsevier - PMC COVID-19 Collection PMC7543983 As a library, NLM provides access to scientific literature.

  5. Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy

    June 15, 2021 This study assesses the immunogenicity of the current COVID-19 mRNA vaccines in pregnant and lactating women against both the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants of concern.

  6. Caffeine Intake and the Risk of First-Trimester Spontaneous Abortion

    The subjects were 562 women who had spontaneous abortion at 6 to 12 completed weeks of gestation (the case patients) and 953 women who did not have spontaneous abortion and were matched...

  7. Coronavirus disease 2019 and first-trimester spontaneous abortion: a

    Coronavirus disease 2019 and first-trimester spontaneous abortion: a case-control study of 225 pregnant patients Am J Obstet Gynecol. 2021 Apr;224 (4):391.e1-391.e7. doi: 10.1016/j.ajog.2020.10.005. Epub 2020 Oct 8. Authors

  8. PDF A case report of spontaneous abortion caused by biovar 3

    Abstract Background: Brucellosis is a worldwide zoonotic disease caused by spp. invades the body through Brucella Brucella the skin mucosa, digestive tract, and respiratory tract. However, only a few studies on human spontaneous abortion attributable to have been reported. In this work, the patient living in Shanxi Province in China who had

  9. PDF Association of spontaneous abortion with all cause and cause specific

    Spontaneous abortion is one of the most common adverse outcomes of pregnancy, with an estimated prevalence of 12-24% Whether spontaneous abortion is associated with a long term risk of premature death (before the age of 70) is unclear Wh thAt Is study Adds Spontaneous abortion was associated with a greater risk of premature death,

  10. Association of spontaneous abortion with all cause and cause specific

    Objective To investigate the association of spontaneous abortion with the risk of all cause and cause specific premature mortality (death before the age of 70). Design Prospective cohort study. Setting The Nurses' Health Study II (1993-2017), United States. Participants 101 681 ever gravid female nurses participating in the Nurses' Health Study II. Main outcomes measures Lifetime ...

  11. Receipt of mRNA Covid-19 Vaccines and Risk of Spontaneous Abortion

    Table 1. Risk of Spontaneous Abortion among Participants in the v-safe Covid-19 Vaccine Pregnancy Registry, December 14, 2020, through July 19, 2021. A total of 2456 participants who were enrolled ...

  12. Association between periodontitis and spontaneous abortion: A case

    Abstract Background: Spontaneous abortion, or miscarriage, is a complication of pregnancy which can severely affect women both physically and psychologically. We investigated the associations of periodontitis and periodontopathic bacteria with spontaneous abortion.

  13. Spontaneous Abortion

    Bleeding in early pregnancy Vaginal Bleeding During Early Pregnancy Vaginal bleeding occurs in approximately 20% of confirmed pregnancies during the first 20 weeks of gestation; about half of these cases end in spontaneous abortion ( 1). Vaginal bleeding is... read more is common; in one study of over 4500 women, bleeding occurred in approximately 25% of first-trimester pregnancies, and 12% of ...

  14. Factors associated with fetal karyotype in spontaneous abortion: a case

    Methods: A case-case study was performed to compare the risk factors for spontaneous abortion with and without embryo chromosome aberration. A total of 160 cases of spontaneous abortion were enrolled from a tertiary general hospital in Kunming.

  15. Psychological distress in women with recurrent spontaneous abortion: A

    Psychological distress in women with recurrent spontaneous abortion: A case-control study - PMC Journal List Turk J Obstet Gynecol v.16 (3); 2019 Sep PMC6792057 As a library, NLM provides access to scientific literature.

  16. The threshold effect of factors associated with spontaneous abortion in

    A case-control study by Kleinhaus K et al. showed that the odds ratio of spontaneous abortion was 1.6 (95% CI = 1.2, 2.0, P = 0.003) when males were ≥ 40 years old and that the risk was ...

  17. MicroRNA mediated regulation of oxidative stress and cytokines in

    Problem. Increased oxidative stress (OS) and inflammatory responses are major underlying factors behind Chlamydia trachomatis-associated recurrent spontaneous abortion (RSA). miRNAs are known to regulate inflammation and OS and their dysregulation has been associated with compromised pregnancies.Therefore, aim of this study was to investigate the expression/correlation of OS biomarkers ...

  18. COVID-19 Booster in Early Pregnancy and Surveillance for Spontaneous

    Key Points. Question Is COVID-19 booster vaccination in early pregnancy associated with an increased risk of spontaneous abortion?. Findings In this case-control surveillance study of more than 100 000 pregnancies at 6 to 19 weeks' gestation from 8 health systems in the Vaccine Safety Datalink, the odds of having received a COVID-19 booster vaccination in either a 28- or 42-day exposure ...

  19. Spontaneous abortion and ectopic pregnancy: Case definition

    1. Preamble. 1.1. Need for developing case definitions and guidelines for data collection, analysis, and presentation for spontaneous abortion and ectopic pregnancy as adverse events following immunization during pregnancy. Vaccine-preventable infectious diseases are responsible for maternal, morbidity and mortality.

  20. The body mass index and the risk of ectopic pregnancy: a 5-year

    Purpose Acknowledging the associated risk factors may have a positive impact on reducing the incidence of ectopic pregnancy (EP). In recent years, body mass index (BMI) has been mentioned in research. However, few studies are available and controversial on the relationship between EP and BMI. Methods We retrospectively studied the EP women as a case group and the deliveries as a control group ...

  21. Non-linear Relationship of Maternal Age With Risk of Spontaneous

    Methods: This was a case-control study based on the China Birth Cohort, we compared 338 cases ending in spontaneous abortion with 1,352 controls resulting in normal live births. The main exposure indicator and outcome indicator were maternal age and spontaneous abortion, respectively.

  22. Case Study on Spontaneous Abortion

    Presentation of a case on Spontaneous Normal Delivery introduction miscarriage, also known in medical terms as spontaneous abortion and pregnancy loss, is the. Skip to document. ... Case Study on Spontaneous Abortion. Course: BS Midwifery. 59 Documents. Students shared 59 documents in this course. University: University of Northern Philippines.

  23. Non-linear Relationship of Maternal Age With Risk of Spontaneous

    Abstract Background Spontaneous abortion is one of the prevalent adverse reproductive outcomes, which seriously threatens maternal health around the world. Objective The current study is aimed to evaluate the association between maternal age and risk for spontaneous abortion among pregnant women in China. Methods

  24. Medication Abortion Using Telehealth Is As Safe As In-Person Care

    The new study comes just weeks before the Supreme Court is scheduled to hear a case that could jeopardize mifepristone's Food and Drug Administration approval and effectively ban its use.

  25. Effectiveness and safety of telehealth medication abortion in ...

    Overall, results from both the complete case analysis and the imputed models found that 97.7% ... In a prospective study across US states where abortion remains legal, telehealth medication ...

  26. Association between previous spontaneous abortion and ...

    PMID: 36123591 DOI: 10.1186/s12884-022-05053-8 Abstract Background: The association between previous spontaneous abortion and preeclampsia is not yet fully understood. The current study was conducted to assess the association between previous spontaneous abortion and preeclampsia among pregnant women in Sudan.

  27. The abortion pill case on its way to the Supreme Court cites a

    The now retracted study used Medicaid claims data to track E.R. visits by patients in the month after having an abortion. The study found a much higher rate of ... Role in abortion pill legal case.

  28. Association between previous spontaneous abortion and preeclampsia: a

    Multivariate logistic regression analysis (adjusted) revealed that women with a history of spontaneous abortion had a lower risk of preeclampsia than those without a history of spontaneous abortion [adjusted odds ratio (AOR) = 0.44, 95% confidence interval (CI) = 0.26‒0.73].

  29. Journal Retracts Studies Cited in Federal Court Ruling Against Abortion

    An academic journal publisher this week retracted two studies that were cited by a federal judge in Texas last year when he ruled that the abortion pill mifepristone should be taken off the market ...

  30. Association between urinary polycyclic aromatic hydrocarbons and

    However, there is limited knowledge regarding the effects of single or mixed PAHs exposure on unexplained recurrent spontaneous abortion (URSA). This study aimed to investigate the association between monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and URSA in a case-control study.