missed abortion case study

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• Published: 10 May 2017

Misoprostol for medical treatment of missed abortion: a systematic review and network meta-analysis

• Hang-lin Wu   ORCID: orcid.org/0000-0001-7882-3072 1 ,
• Sheeba Marwah 2 ,
• Pei Wang 1 ,
• Qiu-meng Wang 1 &
• Xiao-wen Chen 1  

Scientific Reports volume  7 , Article number:  1664 ( 2017 ) Cite this article

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• Drug therapy
• Reproductive disorders

The efficacy and safety of misoprostol alone for missed abortion varied with different regimens. To evaluate existing evidence for the medical management of missed abortion using misoprostol, we undertook a comprehensive review and meta-analysis. The electronic literature search was conducted using PubMed, the Cochrane Library, Embase, EBSCOhost Online Research Databases, Springer Link, ScienceDirect, Web of Science, Ovid Medline and Google Scholar. 18 studies of 1802 participants were included in our analysis. Compared with vaginal misoprostol of 800 ug or sublingual misoprostol of 600 ug, lower-dose regimens (200 ug or 400 ug) by any route of administration tend to be significantly less effective in producing abortion within about 24 hours. In terms of efficacy, the most effective treatment was sublingual misoprostol of 600 ug and the least effective was oral misoprostol of 400 ug. In terms of tolerability, vaginal misoprostol of 400 ug was reported with fewer side effects and sublingual misoprostol of 600 ug was reported with more side effects. Misoprostol is a non-invasive, effective medical method for completion of abortion in missed abortion. Sublingual misoprostol of 600 ug or vaginal misoprostol of 800 ug may be a good choice for the first dose. The ideal dose and medication interval of misoprostol however needs to be further researched.

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Introduction

Missed abortion is defined as unrecognized intrauterine death of the embryo or fetus without expulsion of the products of conception. It constitutes approximately 15% of clinically diagnosed pregnancies 1 . Women experiencing a missed abortion may have no self-awareness due to the lack of obvious symptoms.

With around 95% success rate, surgical evacuation is regarded as the standard treatment for missed abortion, which had been widely performed all over the world in the past 50 years 2 . However, the costs of surgery and hospitalization, as well as the complications associated with surgery and anaesthesia are a major unresolved concern. Besides infection and bleeding, decreased fertility caused by intrauterine adhesions may be unacceptable for women with missed abortion, who have not yet fulfilled their motherhood desires. Some studies have thus suggested that expectant or medical management might be more suitable instead of surgical evacuation 3 , 4 .

Expectant management has been reported with unpredictable success rate ranging from 25–76% 5 , 6 , 7 . Waiting for spontaneous expulsion of the products of conception would waste much time, during which women may suffer uncertainty and anxiety 5 . When additional surgical evacuation is needed owing to failure, they may suffer from an emotional breakdown. It is thus not recommended for missed early miscarriage due to the risks of emergency surgical treatment and blood transfusion 8 .

Misoprostol is a synthetic prostaglandin E1 analogue which was originally developed to prevent non-steroidal anti-inflammatory drugs related gastric ulcers. However it has been used for various other indications in obstetrics and gynaecology. Medical management using misoprostol or combined with mifepristone for missed abortion had been widely researched 9 , 10 , 11 , 12 , 13 . Some studies have reported that medical treatment with mifepristone and misoprostol in women with missed abortion would increase the incidence of excessive bleeding 11 , 12 , 13 . Apart from this, mifepristone is more expensive which will add to unnecessary expenses.

The efficacy and safety of misoprostol alone for missed abortion was established in many studies 14 , 15 , 16 , 17 . However, route of administration of misoprostol and success rates varied among the studies. It could be given by oral, sublingual or vaginal, while the doses ranged from 100 micrograms to 800 micrograms 14 , 15 , 16 , 17 , 18 , 19 . The most suitable route and dose of misoprostol for missed abortion is not yet clear. A single dose of 800 micrograms of misoprostol by vaginal or oral for missed abortion was recommended by National Institute for Health and Care Excellence (NICE) 20 . However some studies reported converse opinion, by pointing out that a lower dose or different routes of misoprostol may be equally effective 21 , 22 .

So we evaluated the existing evidence for the medical management of missed abortion using misoprostol, with the hope of finding alternate suitable management strategies for surgical termination, which must be highly effective and with fewer side effects.

Literature Search

Overall, 1735 articles were identified by the search and 48 potentially eligible articles were retrieved in full text. Of these articles, 35 were excluded for reasons shown in Fig.  1 . The remaining 13 articles met our predefined inclusion criteria. Most of studies compared vaginal route of misoprostol with sublingual or oral route while only one study compared sublingual route with oral route (Fig.  2A ). When it turned to a network meta-analysis, another five articles which compared misoprostol with different doses in the same route were also included in our work. The network diagram of all included studies is shown in Fig.  2B .

Article retrieval and screening.

Network diagram of all studies and studies included in analyses of complete abortion rate within about 24 hours and main side effects. ( A ) Studies comparing different routes of misoprostol. ( B ) Studies comparing different routes or doses of misoprostol. ( C ) Complete abortion rate within about 24 hours. ( D ) Main side effects totally. Studies are classified according to the first dose of misoprostol in both groups; The width of the lines is proportional to the number of trials directly comparing each pair of interventions; The size of each node is proportional to the number of trails comparing a single intervention totally. Interventions are sequenced as follows: A. Oral 400 ug; B. Oral 800 ug; C. Sublingual 400 ug; D. Sublingual 600 ug; E. Sublingual 800 ug; F. Vaginal 200 ug; G. Vaginal 400 ug; H. Vaginal 600 ug; I. Vaginal 800 ug.

Study Characteristics

In all, 18 studies of 1802 participants, published between 1999 and 2016, were included in our analysis. The primary characteristics of the studies are tabulated in Supplementary Table  S1 . Most of the studies were form India and Thailand. The maximum gestational age of participants in all the studies ranged from 8 weeks to 13 weeks, except one study which reported the outcomes separately according to different trimesters 23 . Interventions in the groups varied in terms of routes, doses and medication intervals and we used the first dose to classify them. In most of studies, complete abortion was defined as complete expulsion of the products of conception without surgical intervention. However in four studies, a less than 15 mm intrauterine tissue diameter on ultrasound scan was taken as the cutof f  24 , 25 , 26 , 27 , while one research adopted the criterion for endometrial thickness less than 10 mm 28 . Not all trials reported the same outcomes, especially for the follow-up time. A complete abortion rate within about 24 hours (24 to 28 hours) was mostly mentioned. We calculated it as our primary outcome. There was insufficient data to evaluate for complete abortion rate within 12 hours, 48 hours or 7 days.

For the reported side effects, we could only compare the incidence of nausea or vomiting, diarrhoea and fever. There was insufficient data to analyze other side effects. The mean time taken to abortion was difficult to evaluate due to different follow-up time. For each outcome we have indicated the number of trials contributing data to the network meta-analysis (Fig.  2C and D ). Complete abortion rate within about 24 hours of any intervention and side effects of all the interventions in the analysis are presented in Supplementary Table  S2 .

Risk of bias was summarized in Supplementary Table  S3 . It was categorized the risk of bias as unclear when no related information reported could be used. Most of the included trials described adequate randomization processes; however most of them were assessed as having an unclear risk of bias for allocation concealment and blinding.

Meta-analysis

The results of the network meta-analysis for the outcomes are presented as forest plots in Fig.  3 . Compared with vaginal misoprostol of 800 ug, lower-dose regimens (200 ug or 400 ug) by any route of administration tend to be significantly less effective in producing abortion within about 24 hours. Similar results can be seen in another comparison with sublingual misoprostol of 600 ug. For the comparison between the two regimens, there is no significant difference (RR 1.01, 95% CI 0.86 to 1.19). For the same dose of 600 ug, administration by vaginal route seems to be less effective than sublingual route, however it is not significant (RR 0.81, 95% CI, 0.65 to 1.01). For vaginal misoprostol, doses of 600 ug and 800 ug have no significant differences in producing miscarriage within about 24 hours (RR 0.82, 95% CI 0.63 to 1.07). In the analysis of main side effects, significant difference could be seen only in the comparison of vaginal and sublingual misoprostol of 400 ug (RR 0.54, 95% CI 0.32 to 0.90). For the same dose of 600 ug, administration by vaginal route seems to accompany with fewer side effects than sublingual route, which is not significant again (RR 0.49, 95% CI, 0.22 to 1.06). In detailed comparison for nausea or vomiting, there were no significant differences observed amongst all the regimens (Supplementary Figure  S1 ). For the incidence of diarrhoea, sublingual route seems to be more common than vaginal route with same doses of 600 ug and 400 ug (Supplementary Figure  S2 ). For the incidence of fever, sublingual route also seems to be more common than vaginal or oral route with a same dose of 400 ug (Supplementary Figure  S3 ).

Network meta-analysis of complete abortion rate within about 24 hours and main side effects. Interventions are sequenced as follows: A. Oral 400 ug; C. Sublingual 400 ug; D. Sublingual 600 ug; E. Sublingual 800 ug; F. Vaginal 200 ug; G. Vaginal 400 ug; H. Vaginal 600 ug; I. Vaginal 800 ug.

Tests of consistency showed that there was no difference between the direct and indirect estimates in all close loops in the analysis of complete abortion rate (Supplementary Figure  S4 ). The comparison-adjusted funnel plots of the network meta-analysis for complete abortion rate were not suggestive of any publication bias or small study effect (Supplementary Figure  S5 ). The percentage contribution of each direct and indirect comparisons is presented as a table in Supplementary Figure  S6 . Inconsistency could be seen in a close loop (sublingual misoprostol of 600 ug, vaginal misoprostol of 600 ug and 800 ug) in the analysis of main side effects (Supplementary Figure  S7 ). It was due to the inconsistency in the analysis of nausea or vomiting (Supplementary Figure  S8 ). No publication bias or small study effect was found in the analysis of main side effects (Supplementary Figure  S9 ).

The results of sensitivity analyses of complete abortion rate were shown in Supplementary Table  S4 . In the first sensitivity analysis we excluded one study in which gestational age of the participants was below 8 weeks while in the second we excluded another study in which complete abortion was defined as complete expulsion of the products of conception and endometrial thickness <10 mm. The results were robust for the two sensitivity analyses. When we excluded studies in which only single dose of misoprostol was used in both groups, pre-existed significantly differences disappeared and some of the confidence intervals were wide and across the null line. We reviewed studies related in the close loop with inconsistency, it was impossible to exclude any study for a reasonable argument. In the sensitivity analysis excluding studies with only single dose of misoprostol, the significant difference between vaginal and sublingual misoprostol of 400 ug still existed (Supplementary Table  S5 ).

The ranking of interventions based on cumulative probability plots and surfaces under the cumulative ranking curve (SUCRAs) is presented in Fig.  4 . In terms of efficacy, the most effective treatment was sublingual misoprostol of 600 ug and the least effective was oral misoprostol of 400 ug. In terms of tolerability, vaginal misoprostol of 400 ug was reported with fewer side effects and sublingual misoprostol of 600 ug was reported with more side effects.

Ranking of all the interventions in network meta-analysis. Information of ranking is located at the intersection of the column-defining outcome and the row-defining intervention; The number in the first row is the ranking of all the interventions; The first number below in brackets is the surface under the cumulative ranking curve (SUCRA) while the second is the probability of the intervention to be the best.

This network meta-analysis represents the most comprehensive synthesis of data for medical treatment using misoprostol for missed abortion. It was found that higher-dose regimens were associated with higher complete abortion rate and more sides effects. Sublingual misoprostol of 600 ug or vaginal misoprostol of 800 ug as the first dose was more effective in producing complete abortion within about 24 hours. However the superiority decreased with multiple doses. It could be explained that a single high-dose of misoprostol might have produced complete abortion in most of women 29 , 30 , 31 . If multiple doses were given, more women with lower-dose misoprostol would convert into complete abortion, which was confirmed by Kovavisarach 30 . We found that the least effective treatment was the oral misopristol of 400 ug. It was due to the liver first-pass effect which greatly reduced the bioavailability of the drug. Alternative routes of administration like vaginal and sublingual avoid the liver first-pass effect because they allow drugs to be absorbed directly into the systemic circulation.

Side effects were most likely to appear in sublingually or orally administered misoprostol. A low dose vaginal misoprostol was reported with the fewest side effects, accompanied by low complete abortion rate 32 . Compared with vaginally or orally administered misoprostol, sublingual misoprostol of 600 ug or 400 ug was associated with more frequent diarrhoea and fever. It was due to the pharmacokinetics of misoprostol, which showed that sublingual misoprostol had the shortest onset of action, the highest peak concentration and greatest bioavailability among the routes of administration 33 .

Vaginal misoprostol of 800 ug was recommend for missed abortion by National Institute for Health and Care Excellence(NICE) and some clinical guidelines 8 , 20 . The results of our meta-analysis lead support to this regimen for medical treatment of missed abortion, however the question of whether sublingual misoprostol of 600 ug is better raises. Apart from this, the incidence of side effects reported was still higher than we expected for these regimens. A variety of methods were researched to increase the efficacy of misoprostol in order to reduce the dose. Some studies discussed the administration of different types of misoprostol, such as gel form and powder form, however the efficacy was not improved 34 , 35 . Some studies discussed the efficacy of moistened misoprostol by acetic acid or normal saline, conclusion was made that vaginal misoprostol either moistened with normal saline or acetic acid was comparable in terms of efficacy and adverse effects 36 , 37 , 38 . Some studies reported different methods to combine misoprostol with laminaria tents or castor oil, however these studies did not focus on the efficacy of these methods to produce abortion for women with missed abortion 39 , 40 .

Limited articles could be found about the efficacy and tolerability of sublingual or oral misoprostol of 800 ug which made us difficult to evaluate. Only in one study it was compared with vaginal misoprostol of 800 ug, the authors found that sublingual misoprostol was as effective as vaginal misoprostol and most side effects were similar in both groups, but heavy bleeding was more common in the sublingual group 41 . Two studies reported that oral misoprostol or vaginal of 800 ug was comparable in terms of efficacy while more side effects were reported in oral misoprostol of 800 ug in one study 42 , 43 . Further research on the efficacy and tolerability of sublingual or oral misoprostol of 800 ug is needed. At present, these regimens should not be regarded as the first-line of medical treatment of missed abortion.

In our work, complete abortion rate was calculated within about 24 hours. Seldom studies reported complete abortion rate within longer follow-up time, they suggested follow-up care to be offered one week following drug administration to ensure the highest success rate 43 , 44 , 45 . Due to the limited amounts of studies, it is difficult to draw any conclusions. The security of waiting at home needs further researched, especially for the incidence of excessive bleeding. For women needed emergency operation, cervical ripening was prepared due to the medical treatment and it is convenient to perform dilatation and curettage 24 , 26 .

Despite the foregoing advantages, serious consideration should be given to the contraindication before planning for medical treatment for women with missed abortion. A missed early miscarriage (<14 weeks of gestation) should be defined by ultrasound findings and suspected ectopic pregnancy must be excluded. Women with unstable hemodynamics, signs of pelvic infections or sepsis also need to be excluded. Detailed medical histories, including the distance between home and hospital, past medical history, previous surgical history, allergic history, medication history, should be recorded. Medical treatment can only be considered in women without following contraindications: known allergy to misoprostol, previous caesarean section, mitral stenosis, hypertension, glaucoma, bronchial asthma, use of non-steroidal drugs and remote areas without hospital around.

All women must be informed of the advantages and disadvantages of surgical and medical treatment. For women who choose medical treatment, hospitalization is not necessary, but the follow-up period will be more important. Pain killers and anti-emetics, such as paracetamol and metoclopramide, should be offered to them as needed 20 . All women should be advised to contact the doctor in case of heavy bleeding or signs of infection. A follow-up visit is recommended to perform within 2 weeks after treatment. Pregnancy test, physical examination of the uterus, and ultrasound should be performed to confirm the status of abortion. In the event of failure, surgical management maybe needed.

One of the strengths of our study is the inclusion of only randomized clinical trial data in a specific population (i.e., women with missed abortion of no more than 14 weeks of gestation). Our meta-analysis included all studies published so far on this topic and statistical tests showed no significant potential publication biases. The protocol of this review was registered on the International Prospective Register of Systematic Reviews before the selection of articles.

Limitations of this analysis are obvious. For a net-work meta-analysis, only 18 studies were included in this analysis which might affect the accuracy of the results. For this reason, comparisons could not be performed for some results. Most of the included studies were not double blind. This was therefore a considerable source of bias that may have affected treatment or performance of these women. We classified the interventions according to the first dose, however it is obvious that different max doses or medication intervals will affect the results.

The relation between max doses or medication intervals with complete abortion rate or side effects need to be further researched. Another remaining question is whether there are methods to reduce the incidence of side effects when treated with misoprostol. Further studies should focus on the quality of trails, especially for the blinding of participants and researchers.

In conclusion, misoprostol is a non-invasive, effective medical method for completion of abortion in missed abortion. Sublingual misoprostol of 600 ug or vaginal misoprostol of 800 ug may be a good choice for the first dose. The ideal dose and medication interval of misoprostol however needs to be further researched.

Search strategy and selection criteria

For this meta-analysis, we searched PubMed, the Cochrane Library, Embase, EBSCOhost Online Research Databases, Springer Link, ScienceDirect, Web of Science, Ovid Medline and Google Scholar for randomized controlled trials (RCTs) published from the date of database inception to August 15th, 2016, comparing different routes of administration of misoprostol in the medical management of missed abortion. We also searched some related journals. No language or publication type limits were applied. The reference lists of selected articles were hand searched to identify any relevant articles. Study authors were contacted to supplement incomplete reports of the original papers. Detailed search strategy can be found in Supplementary Table  S6 .

Considering the gestational weeks available for surgical evacuation, women with missed abortion of no more than 14 weeks of gestation who received misoprostol treatment were assessed for inclusion into our meta-analysis. Women with incomplete abortion, threatened abortion or excessive uterine bleeding were excluded. Studies involving medical management with both mifepristone and misoprostol were also excluded.

We considered complete abortion rate for our primary analyses. Complete abortion was defined as complete expulsion of the products of conception without surgical intervention. Our secondary outcome was the side effects of misoprostol reported. The mean induction-abortion time would be also analyzed, if applicable.

Data extraction and quality assessment

Two researchers (H-L.W. and P.W.) performed their own search independently. Data extraction and check for accuracy were resolved by other two researchers (Q-M.W. and X.-W.C.). Duplicate or irrelevant articles were excluded by screening of titles and abstracts. All remaining articles were screened in full text. Relevant information from the included trials was extracted with a predefined data extraction sheet. All researchers assessed the risk of bias independently according to the Cochrane Handbook for Systematic Reviews of Interventions 46 . Specifically, attention was focused on seven domains, i.e., random sequence generation, allocation concealment blinding of participants and personnel, blinding of the outcome assessments, incomplete outcome data, selective reporting and other biases. The review authors’ judgments were categorized as low risk, high risk, or unclear risk of bias. We categorized the risk of bias as unclear when no reported information could be used. The article was reviewed and revised by another researcher (S.M.). Any discrepancies were resolved by discussion within the review team.

Statistical analysis

This study was registered with PROSPERO, number CRD42016046221. The full dataset is available online. After screening of the articles, we found the interventions in included articles were so varied in both the routes and doses of misoprostol that we could not carry out a direct comparison. We chose to perform a network meta-analysis instead. The strategies for data synthesis remained unchanged and the predefined analysis of subgroups with different doses was cancelled.

This network meta-analysis used all the available evidence, both direct and indirect, to evaluate relative effects of different routes or doses of misoprostol 47 , 48 . Statistical analysis was performed with STATA (version 12.0). We used a continuity correction for studies with no events by adding 0.5 to both the events count and the total sample size. We presented results as summary risk ratio (RR) for dichotomous data and the mean difference (MD) for continuous data, both with 95% confidence intervals (CIs). Inconsistency between direct and indirect sources of evidence was statistically assessed by calculation of the difference between direct and indirect estimates in all closed loops in the network. Random effects models were used to estimate the inconsistency. If there was no inconsistency between direct and indirect sources of evidence, fixed effects models would be used in further analysis, otherwise random effects models would still be used and sensitivity analyses would be performed to exclude studies with possibilities of causing bias in the close loops. A comparison-adjusted funnel plot was used to detect publication bias and small study effect. We estimated the ranking probabilities for all treatments of being at each possible rank for each intervention and the treatment hierarchy was summarized and presented as surface under the cumulative ranking curve 49 .

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Wu, Hl., Marwah, S., Wang, P. et al. Misoprostol for medical treatment of missed abortion: a systematic review and network meta-analysis. Sci Rep 7 , 1664 (2017). https://doi.org/10.1038/s41598-017-01892-0

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• Published: 09 August 2022

Risk factors for missed abortion: retrospective analysis of a single institution’s experience

• Wei-Zhen Jiang 1 ,
• Xi-Lin Yang 2 &
• Jian-Ru Luo 1  

Reproductive Biology and Endocrinology volume  20 , Article number:  115 ( 2022 ) Cite this article

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To explore the risk factors including the difference between mean gestational sac diameter and crown-rump length for missed abortion.

Hospitalized patients with missed abortion and patients with continuing pregnancy to the second trimester from Chengdu Women's and Children's Central Hospital from June 2018 to June 2021 were retrospectively analyzed. The best cut-off value for age and difference between mean gestational sac diameter and crown-rump length (mGSD-CRL) were obtained by x-tile software. Univariate and multivariate logistic regression analysis were adopted to identify the possible risk factors for missed abortion.

Age, gravidity, parity, history of cesarean section, history of recurrent abortion (≥ 3 spontaneous abortions), history of ectopic pregnancy and overweight or obesity (BMI > 24 kg/m 2 ) were related to missed abortion in univariate analysis. However, only age (≥ 30 vs < 30 years: OR = 1.683, 95%CI = 1.017–2.785, P  = 0.043, power = 54.4%), BMI (> 24 vs ≤ 24 kg/m 2 : OR = 2.073, 95%CI = 1.056–4.068, P  = 0.034, power = 81.3%) and mGSD-CRL (> 20.0vs ≤ 11.7 mm: OR = 2.960, 95% CI = 1.397–6.273, P  = 0.005, power = 98.9%; 11.7 < mGSD-CRL ≤ 20.0vs > 20.0 mm: OR = 0.341, 95%CI = 0.172–0.676, P  = 0.002, power = 84.8%) were identified as independent risk factors for missed abortion in multivariate analysis.

Patients with age ≥ 30 years, BMI > 24 kg/m 2 or mGSD-CRL > 20 mm had increasing risk for missed abortion, who should be more closely monitored and facilitated with necessary interventions at first trimester or even before conception to reduce the occurrence of missed abortion to have better clinical outcomes.

Missed abortion was a special type of spontaneous abortion that the embryo or fetus has already died but remained in the uterus for days or weeks and with a closed cervical ostium [ 1 ]. Patients might present with or without subtle clinical symptoms such as vaginal bleeding or abdominal pain. Missed abortion, occuring in approximately 8–20% of clinically confirmed intrauterine pregnancies [ 2 ], was often confirmed using ultrasonography.

Missed abortion was undoubtedly a huge physical and psychological setback for women with fertility requirements. Therefore, early identification of women at high risk of missed abortion was pivotal, which might aid in providing possible theoretical basis for implementing clinical measures to prevent missed abortion. Previous studies have revealed that Human Chorionic Gonadotropin(HCG), Estradiol(E2), progesterone, gestational sac diameter(GSD), Crown-Rump Length(CRL), fetal heart rate and yolk sac diameter might be predictive for early pregnancy loss [ 3 , 4 , 5 ] . In addition, the predictive value of mGSD-CRL for early pregnancy outcome in in vitro fertilization(IVF) treatment has been established [ 6 ]. However, most of the current studies have performed univariate analysis to identify the risk factors for early pregnancy loss [ 3 , 4 , 5 , 6 ].

Therefore, we conducted this study to more comprehensively explore the possible high risk factors relating to developing of missed abortion using multivariate logistic regression analysis, hopefully it could be of great help to identification and intervention.

Materials and methods

Data sources.

We reviewed patients from Chengdu Women's and Children's Central Hospital from June 2018 to June 2021. Inclusion criteria of missed abortion group were listed as follows: (1) Not more than 12 weeks gestation; (2) Crown-rump length ≥ seven mm without heartbeat or (3) mean sac diameter ≥ 25 mm without embryo or (4) absence of embryo with heartbeat ≥ two weeks after a scan that showed a gestational sac without a yolk sac or (5) absence of embryo with heartbeat ≥ 11 days after a scan that showed a gestational sac with a yolk sac [ 7 ]. Exclusion criteria of missed abortion group were listed as follows: (1) Incomplete information; (2) multiple pregnancy. Patients with the following inclusion and exclusion criteria were enrolled as control group: (1) Patients continued pregnancy to the second trimester were included; (2) Incomplete information and multiple pregnancy were excluded. After excluding patients with incomplete information, 307 patients were finally included with 160 patients having missed abortion and 147 with continuing pregnancy to second trimester. Due to the retrospective nature of the study, informed consent was waived, but this study was granted by the ethics committee of Chengdu Women's and Children's Central Hospital and the ethics approval number was B2021(26).

Collection of data

Patients’ information regarding age, gravidity, parity, history of vaginal delivery, history of cesarean delivery, history of recurrent abortion (≥ 3 spontaneous abortions), history of induced abortion, history of medication abortion, history of midtrimester induction, history of ectopic pregnancy, history of smoking, history of alcohol consumption, history of other uterine operations, mode of conception, BMI, mGSD-CRL not more than 12 weeks with live embryo were collected.

Statistical analysis

Categorical variables were described as percentages or frequencies and compared using Pearson χ2 test; continues variables were described as medians with interquartile range (IQR) and compared with t test. We identified the cut-off value for age and mGSD-CRL via X-tile software (version 3.6.1; Yale University, New Haven, CT, USA) once maximal chi-square value reached, which was considered to represent the greatest difference in outcomes prediction among the subgroups [ 8 ].

Logistic regression was used to determine independent risk factors for missed abortion. Statistically significant variables from univariate logistic regression analysis ( P  < 0.1) were included in the multivariate analysis. Pearson χ2 test, t test and logistic regression were performed using SPSS (version 25.0, SPSS, Chicago, IL, USA), X-tile software was uesed to calculate cut-off value. G*Power Analysis program (version 3.1, The G*Power Team, Belgium) was used for power calculation. A two-tailed P  < 0.05 was recognized as statistically significant.

Study cohort

A total of 307 patients were finally included in the study with 160 cases having missed abortion and 147 with continuing pregnancy to second trimester (Supplementary Fig.  1 ). The characteristics was listed in Supplementary Table 1 . As a result, 30 years old was the cut-off value for age via X-tile software. Therefore, age was split as age ≥ 30 years and age < 30 years. Similarl y , mGSD-CRL was divided into three subgroups: GSD-CR < 11.7 mm, 11.7 mm ≤ mGSD-CRL ≤ 20.0 mm, GSD-CR > 20.0 mm (Fig.  1 ). Nearly half of the patients were over 30 years old (49.2%). 38.4% of the patients were having first pregnancy, and the majority of the patients had never delivered (71.0%). 11.1% of the patients had a history of vaginal delivery, however, 18.2% of the patients had a history of cesarean section. Of note, 16% of the patients had a BMI > 24 kg/m 2 , 29.6% of the patients had a mGSD-CRL < 11.7 mm and 18.9% had a mGSD-CRL > 20 mm. Moreover, 2.6% of the patients suffering from recurrent abortion and 4.2% had a history of ectopic pregnancy. Besides, 39.1% of the patients had a history of curettage. In total, 52.1% of the patients developed missed abortion (Table 1 ).

mGSD-CRL at diagnosis stratification by X-tile software

Risk factors for missed abortion

In the univariate logistic regression analysis, Age, gravidity, parity, history of cesarean section, history of recurrent abortion, history of ectopic pregnancy, overweight or obesity (BMI > 24 kg/m 2 ) and mGSD-CRL were significantly related to increased risk factors for missed abortion. Furthermore, risk factors identified in the univariate logistic regression analysis were included in the multivariate analysis, which revealed that Age (≥ 30 vs < 30 years: OR = 1.683, 95%CI = 1.017–2.785, P  = 0.043, power = 54.4%), BMI (> 24 vs ≤ 24 kg/m 2 : OR = 2.073, 95%CI = 1.056–4.068, P  = 0.034, power = 81.3%), mGSD-CRL (> 20.0vs ≤ 11.7 mm: OR = 2.960, 95% CI = 1.397–6.273, P  = 0.005, power = 98.9%; 11.7 < mGSD-CRL ≤ 20.0vs > 20.0 mm: OR = 0.341, 95%CI = 0.172–0.676, P  = 0.002, power = 84.8%) were independent risk factors for missed abortion (Table  2 ).

Missed abortion, normally presenting without symptoms of threatened abortion such as abdominal pain and vaginal bleeding, was a kind of spontaneous abortion, which were frequently diagnosed using ultrasonography. In this study, we retrospectively analyzed the data of 160 missed abortion patients and 147 pregnant women who didn’t have abortion in the first trimester in order to fully establish the possible risk factors for missed abortion, and provide evidence for early identification and intervention for patients with high risk of missed abortion.

In previous studies, it was believed that advanced age was a high risk factor for missed abortion, which might result from the decline of ovarian function and corpus luteum function as age accrued [ 1 , 9 ]. However, previous study also showed that advanced age was not a high risk factor for spontaneous abortion [ 10 ], in which age was divided into advanced age group (> 35 years) and non-advanced age group (≤ 35 years old). Therefore, we hypothesized that there might be a more meaningful cutoff value other than 35 years old to divide the age into two subgroups. As a result, 30 years old, calculated via x-tile, showed significant value in the final multivariate logistic analysis (OR = 1.683, 95%CI = 1.017–2.785, P = 0.043). As controversial regarding age existed in previous studies, our result showing that age > 30 was an independent risk factor for missed abortion seemed solid. And the dropping from 35 to 30 in terms of cut-off value for age might be related to factors like increasing pressure, unhealthy living habits and environmental pollution resulting from social developing [ 2 , 11 ]. Although the cut-off value in our study were not consistent with previous ones, the consensus on older age was a high risk factor for missed abortion was basically reached.

A meta-analysis including 16 studies demonstrated that BMI > 25 kg/m 2 was a high risk factor for abortion [ 12 ], which reported that the missed abortion rate of overweight or obese women was as high as 25–37% [ 13 ]. The participants from our study were childbearing age women from China, so the definition of overweight or obese as BMI > 24 kg/m 2 was used for grouping though the World Health Organization(WHO) defined overweight or obesity as BMI > 25 kg/m 2 [ 14 ]. And the result showed that patients with BMI > 24 kg/m 2 were more likely to have missed abortion than BMI ≤ 24 kg/m 2 (OR = 2.073, 95% CI = 1.056–4.068, P = 0.034), which was consistent with previous studies [ 11 , 12 ]. Therefore, weight control before pregnancy was usually recommended.

Although the effect of mGSD and CRL on missed abortion had been reported [ 3 , 4 , 15 , 16 , 17 , 18 ], there was few studies working on the relationship between mGSD-CRL and missed abortion. Bromley et al.firstly proposed the concept of "small gestational sac" [ 19 ]. And their work revealed that mGSD-CRL < 5 mm in the first trimester was a high risk factor for missed abortion. However, the extremely limited number of included patients in their study might impede the generalization of the conclusion. Similarly, the research from Kapfhamer el also showed that mGSD-CRL < 5 mm was a high risk factor for early pregnancy loss, and further demonstrated that mGSD-CRL > 10 mm was a protective factor for early pregnancy loss [ 6 ]. However, Zhao et al. believed that "large gestational sac"(mGSD-CRL ≥ 18 mm) was related to increasing risk for spontaneous abortion [ 20 ]. Therefore, we used x-tile to find the two optimal cutoff values for mGSD-CRL, which showed that patients with mGSD-CRL > 20 mm was more more likely to have missed abortion than patients with mGSD-CR ≤ 20 mm. And there was no statistical difference between mGSD-CRL < 11.7 mm group and 11.7 ≤ mGSD-CRL ≤ 20.0 mm group. In summary, we were inclined to believe that increasing mGSD-CRL was associated with increasing risk of missed abortion, which should be further validated in the future due to the differences in sample size from previous studies [ 6 , 19 , 20 ].

Age, gravidity, parity, history of cesarean section, history of recurrent abortion, history of ectopic pregnancy, BMI and mGSD-CRL were identified in the univariate analysis. However, only age, BMI and mGSD-CRL were still meaningful in multivariate analysis. What was inconsistent with previous studies in our study was that recurrent abortion was not a high risk factor for missed abortion [ 21 ], which might result from the low incidence of recurrent abortion (missed abortion group vs non-missed abortion group: 7 vs 1) in our study.

One major strength of this study was that stratifying age by x-tile rather than 35 years were firstly recognized for high risk of missed abortion. Other strengths included that mGSD-CRL were analyzed instead of mGSD or CRL independently. On the contrary, This study was inevitably limited by the retrospective nature. In addition, the pathogenic factors for missed abortion was complicated, and some possible high risk factors like immunological or genetic factors could not be obtained.

It is well known that missed abortion is a special type of spontaneous abortion and the ultimate outcome is embryonic arrest. The current knowledge of the missed abortion mostly relates to prevention and treatment, but the classification and severity have not been covered yet according to existing literature and guidelines. The purpose of this paper is to explore the high-risk factors of missed abortion, therefore treatment was barely involved, and we will do more research on the treatment of missed abortion in future work. Overall, We hope that the present study could aid in abortion prediction and treatment decision-making for clinicians.

Conclusions

This study demonstrated that age ≥ 30 years old, BMI > 24 kg/m 2 and mGSD-CRL > 20 mm were independent risk factors for missed abortion. This study provided a theoretical basis for clinicians to deliver prompt interventions in childbearing age women during the first trimester or even before pregnancy, so as to reduce the incidence of missed abortion.

Availability of data and material

All data that support the findings of this study were available from the corresponding author via E-mail due to appropriate request.

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Acknowledgements

The authors wish to thank the participants, Chengdu Women's and Children's Central Hospital hospital staff, and whoever contributed to this study.

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Contributions

Conception/design: Wei-Zhen Jiang. Provision of study material or patients: Wei-Zhen Jiang. Collection and/or assembly of data: Wei-Zhen Jiang, Xi-Lin Yang. Data analysis and interpretation: Wei-Zhen Jiang, Xi-Lin Yang. Manuscript writing: Wei-Zhen Jiang. Manuscript revision: Jian-Ru Luo. Final approval of manuscript: All authors.

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Correspondence to Jian-Ru Luo .

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Due to the retrospective nature of the study, informed consent was waived, but this study was granted by the ethics committee of Chengdu Women's and Children's Central Hospital and the ethics approval number was B2021(26).

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Written informed consent for publication was obtained from all participants.

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The authors have declared that there is on potential conflicts of interest.

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Supplementary Information

Additional file 1: supplementary figure 1..

Flow chart depicting for inclusion of studysubjects. Supplementary Table1.  Clinical characteristicsof participants.

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Jiang, WZ., Yang, XL. & Luo, JR. Risk factors for missed abortion: retrospective analysis of a single institution’s experience. Reprod Biol Endocrinol 20 , 115 (2022). https://doi.org/10.1186/s12958-022-00987-2

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ORIGINAL RESEARCH article

How many missed abortions are caused by embryonic chromosomal abnormalities and what are their risk factors.

• 1 Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
• 2 Chengdu University of Traditional Chinese Medicine, Chengdu, China
• 3 West China Second University Hospital, West China Women’s and Children’s Hospital, Chengdu, China
• 4 Chengdu Jinniu Maternal and Child Health Care Hospital, Chengdu, China
• 5 The Eighth Affiliated Hospital of Sun Yat Sen University, Shenzhen, China

Introduction: Though embryonic chromosome abnormalities have been reported to be the most common cause of missed abortions, previous studies have mainly focused on embryonic chromosome abnormalities of missed abortions, with very few studies reporting that of non-missed abortion. Without chromosome studies of normal abortion samples, it is impossible to determine the risk factors of embryo chromosome abnormalities and missed abortion. This study aimed to investigate the maternal and embryonic chromosome characteristics of missed and non-missed abortion, to clarify the questions that how many missed abortions are caused by embryonic chromosomal abnormalities and what are their risk factors.

Material and methods: This study was conducted on 131 women with missed or non-missed abortion from the Longitudinal Missed Abortion Study (LoMAS). Logistic regression analysis was used to identify the association between maternal covariates and embryonic chromosomal abnormalities and missed abortions. Data on the characteristics of women with abortions were collected.

Results: The embryonic chromosome abnormality rate was only 3.9% in non-missed abortion embryos, while it was 64.8% in missed-abortion embryos. Assisted reproductive technology and prior missed abortions increased the risk of embryonic chromosome abnormalities by 1.637 (95% CI: 1.573, 4.346. p = 0.010) and 3.111 (95% CI: 1.809, 7.439. ( p < 0.001) times, respectively. In addition, as the age increased by 1 year, the risk of embryonic chromosome abnormality increased by 14.4% (OR: 1.144, 95% CI: 1.030, 1.272. p = 0.012). Moreover, advanced age may lead to different distributions of chromosomal abnormality types.

Conclusion: Nearly two-thirds of missed abortions are caused by embryonic chromosomal abnormalities. Moreover, advanced age, assisted reproductive technology, and prior missed abortions increase the risk of embryonic chromosomal abnormalities.

Introduction

Missed abortion, also known as overdue abortion, refers to the fact that the embryo or fetus has died and remains in the uterine cavity without natural discharge, before 12 weeks of gestation ( Allen et al., 2022 ; Herkiloglu et al., 2022 ). As a special type of spontaneous abortion, missed abortions account for 10%–20% of spontaneous abortions, while 25% of women undergo spontaneous abortion ( Practice Committee of the American Society for Reproductive, 2012 ; Shahine and Lathi, 2015 ; Mohammad-Akbari et al., 2022 ). The incidence rate of missed abortions has shown an obvious upward trend in recent years ( Alnafisah and Alalfy, 2018 ; Zhao et al., 2021 ; Torres-Miranda et al., 2022 ), which has seriously affected the physical and mental health of the patients, family, and social happiness.

Current research shows that missed abortion is mainly caused by four factors: embryonic factors (chromosome abnormalities), maternal factors (systemic diseases, abnormal reproductive organs, endocrine abnormalities, unhealthy lifestyle, and abnormal immune function), paternal factors (sperm chromosome abnormalities), and environmental factors ( Segawa et al., 2017 ; Zhao et al., 2017 ; Fang et al., 2018 ; Fu et al., 2018 ; Yang et al., 2021a ; Gong et al., 2021 ; He et al., 2021 ; Liu et al., 2022 ). Though embryonic chromosome abnormalities have been reported to be the most common cause of missed abortions, previous studies have mainly focused on embryonic chromosome abnormalities of missed abortions, with very few studies reporting that of non-missed abortion. In statistical analysis, the risk factors and their odds ratios of missed abortion can be better determined by comparing the patient characteristics of missed abortion and non-missed abortion. Clarifying the cause of missed abortions is conducive to alleviating the psychological burden of patients, and to carry out reasonable treatment and genetic counseling of these patients for the next pregnancy, by predicting the risk of missed abortions in the subsequent pregnancies ( Ashaat and Husseiny, 2012 ; Hu et al., 2015 ; Li et al., 2018a ).

Chromosome analysis techniques were developed from the earliest karyotype analysis, fluorescence in situ hybridization (FISH), chromosome microarray analysis (CMA), and the latest high-throughput sequencing technology ( Authors Anonymous, 1988 ; Dube, 1990 ; Borgatta et al., 2000 ; Halder and Fauzdar, 2006 ; Ashaat and Husseiny, 2012 ; Segawa et al., 2017 ; Li et al., 2018b ; Dai et al., 2019 ; Cheng et al., 2021 ). High-throughput sequencing technology, with its outstanding advantages of high accuracy, throughput, and sensitivity, has been widely used in the field of medical diagnosis ( Quintero-Ronderos and Laissue, 2020 ). In the detection of chromosomal abnormalities in missed abortion villi, high-throughput sequencing technology can detect aneuploidy, large fragment structural abnormalities, chromosome microduplication and microdeletion, and submicroscopic aberrations up to 100 kb, which is relatively superior to other technologies ( Ye et al., 2019 ).

Therefore, in this study, we aimed to investigate the maternal and embryonic chromosome characteristics in missed and non-missed abortion, using high-throughput sequencing technology. Given the findings reported for our cohort, we also aimed to study the impact of maternal characteristics on embryonic chromosomal abnormalities and missed abortions. This data supports the viewpoint that the elimination of altered karyotypes via missed abortion represents a strategy to ensure the integrity of karyotype coding ( Ye et al., 2019 ).

Materials and methods

Study design and participants.

The present study was embedded in the Longitudinal Missed Abortion Study (LoMAS), an ongoing pregnancy and birth cohort study conducted in Chengdu, aiming to determine the relative contributions of genes and the environment to missed abortions (Chinese Clinical Trial Registry: ChiCTR2200060959) approved by the Ethics Committee of the Chengdu Women’s and Children’s Central Hospital (No. 201952). This prospective cohort study was conducted at the Chengdu Women’s and Children’s Central Hospital and included all women with missed abortions as confirmed by ultrasound between March 2021 and December 2021. Written informed consent was obtained from all the participants. This subgroup study included pregnant women who were diagnosed with missed abortions by ultrasound and some matched non-missed abortion women. Non-missed abortions are defined as the normal embryos within 14 weeks of pregnancy terminated pregnancy according to the patient’s requirements and conducted D&C abortions (This is legal in Chinese law). Twin pregnancies were eliminated because it was difficult to separate the villi completely; therefore, women with abortions only in singleton pregnancies were included in this study. Due to the exorbitant rate of abnormal embryos in Perimenopausal women (>45 years old), only women aged 16–45 years were included in the cohort. Women with chromosomal abnormality, chronic metabolic or genetic diseases were not included in the study.

Data collection

Maternal sociodemographic data (age, height, weight, education, occupation, parity, and mode of conception), lifestyle behaviors before pregnancy (smoking and alcohol use), and preexisting conditions were collected using standardized questionnaires and electronic medical records before D&C abortions. The standardized questionnaire was self-designed for the LoMAS cohort study; detailed information is presented in Supplementary File S1 .

Diagnostic criteria of missed abortion

With the development and popularization of ultrasonic technology, ultrasonic examination has become a common method for clinical diagnosis of missed abortions. According to the French College of Gynaecologists and Obstetricians (CNGOF) ( Delabaere et al., 2014 ), missed abortion can be diagnosed when ultrasound meets any of the following criteria: First, the embryonic head-hip diameter is greater than or equal to 7 mm, and there is no primitive heart tube pulsation; second, the diameter of the gestational sac is more than 25 mm, and no embryo is found; third, ultrasound examination shows that there is no yolk sac in the gestational sac and there is still no embryo with heartbeat after 2 weeks; fourth, ultrasound examination shows that there is a yolk sac in the gestational sac and there is no embryo with heartbeat after at least 11 days.

Specimen collection and detection process

Villus samples of missed and non-missed abortion patients who terminated pregnancy in the outpatient operating room were collected under strict aseptic conditions. The specimens were transported to the hospital laboratory under refrigeration, where they were washed with normal saline to obtain clean villus tissues. The villi were dried with sterile gauze and frozen at −80° refrigerators.

After all the samples were collected, the villi were processed as follows: villus DNA was extracted using the Universal Genomic DNA Purification Mini Spin Kit (D0063, Beyotime, China). Agarose gel electrophoresis was used to analyze the degree of DNA degradation and RNA contamination, and Qubit was used to detect the total amount and concentration of DNA (standard: total amount of DNA ≥800 ng, DNA concentration ≥10 ng/μL).

Multiplex fluorescent PCR using short tandem repeat (STR) markers (Guangzhou Darui Biotechnology, GuangZhou, China) was performed to exclude maternal cell contamination. High-throughput sequencing for copy number variations (CNV) was performed as previously described. After library preparation, the samples were sequenced using the pair end 150 bp method (PE150) on the Illumina HiSeq platform (Illumina, San Diego, United States) according to the manufacturer’s instructions. Raw image files were processed using BclToFastq (Illumina) for the base calling and raw data generation. The reads were then mapped to the GRCh37/hg19 human reference genome using BWA software. Candidate CNVs were classified using a five-tiered system according to a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).

Statistical methods

All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, United States). The chi-squared or Fisher’s exact test was used to assess categorical data, which were reported as counts and percentages. The means and standard deviations of continuous variables were calculated using the Student’s t -test, one-way analysis of variance, or the non-parametric test. Binary logistic regression analysis was used to detect the influence of women’s characteristics on missed abortions and embryonic chromosome abnormalities. Covariates were selected according to the different variables in univariate analysis and the factors reported in previous studies that would affect missed abortion or embryonic chromosome abnormality. All tests were two-tailed, and statistical significance was set at p < 0.05 .

The selection process of the study population is shown in Figure 1 . A total of 171 women with missed or non-missed abortion were initially recruited into this subgroup study as part of the LoMAS study. After excluding patients who did not match the inclusion criteria and cases of failure to extract embryonic DNA, the final analysis included 131 women with missed or non-missed abortion. Descriptive data of the study participants are shown in Table 1 . The average patient age at delivery was 28.34 ± 5.48 years, and the average gestational age was 8.93 ± 1.85 weeks. Furthermore, 19.1% of patients conceived via assisted reproductive technology (ART), and 96.2% of patient parity was less than or equal to two due to the Chinese previous two-child policy. Finally, 54 (41.2%) missed abortions and 77 (58.8%) normal abortion cases were included in the analysis.

FIGURE 1 . The selection process for this study.

TABLE 1 . Description of the abortion women’s characteristics.

In the patients with missed abortions, nearly two-third of the patients whose embryos were accompanied by chromosome abnormality, 25.9% had conceived via ART, and 13.0% had a previous missed abortion; this group with higher age and pre-pregnancy BMI had a higher incidence of antenatal bleeding but less parity. Specific abnormal chromosomal types are shown in Figure 2 . The top five prevalent chromosomal abnormalities were as follows: 22.86% X monosomy, 22.86% trisomy 16, 11.43% trisomy 22, 8.57% trisomy 2, 8.57% trisomy 15. These five types of chromosomal abnormalities account for three-quarters of all chromosomal abnormalities ( Tables 2 , 3 ).

FIGURE 2 . The types of specific chromosomal abnormalities. (A) It shows the types of all the chromosomal numerical abnormalities of the aborted embryos; (B–D) According to missed abortion, maternal age and ART, the types of chromosome abnormalities were displayed.

TABLE 2 . Description of the abortion women’s characteristics by type of abortions.

TABLE 3 . Description of the chromosome of villi by type of abortions.

A significant difference in the patient’s age, pre-pregnancy BMI, mode of conception parity, prior missed abortion, and embryonic chromosome abnormality was found between the missed and normal abortion groups ( Tables 2 , 3 ). Binary logistic regression showed that missed abortions were significantly associated with age, mode of conception, and parity (OR: 0.691, 95% CI: 0.500, 0.955. p = 0.025), prior missed abortions, and embryonic chromosomal abnormalities, but were not found to be correlated with BMI, smoking, conception season, gravidity, D&C abortions. Notably, due to too few samples in falling ill, taking special drugs, and exposure to hazardous substances during pregnancy, we cannot clearly infer their relationship with missed abortion. ART, prior missed abortions, and embryonic chromosome abnormalities increased the risk of missed abortions by 2.110 (95% CI: 1.395, 5.598. p = 0.034), 3.040 (95% CI: 1.068, 8.654. p < 0.001) and 16.352 (95% CI: 11.230, 40.409. p < 0.001) times, respectively. Moreover, as the age increased by 1 year, the risk of missed abortion increased by 15% (OR: 1.150, 95% CI: 1.055, 1.254. p < 0.001) ( Table 4 ).

TABLE 4 . Association between the maternal covariates and missed abortion.

Moreover, microdeletions and microduplications of embryonic chromosomes were analyzed in our cohort using high-throughput sequencing technology. Although the embryonic chromosome microduplication rate in the missed abortion group (9.3%) was higher than that in the normal abortion group (5.2%), there was no significant difference between the two groups ( Table 3 ). The likely pathogenic chromosomal deletions and duplications in this study are shown in Table 5 .

TABLE 5 . Likely pathogenic and pathogenic CNVs detected by high-throughput sequencing technology.

Considering that nearly two-thirds of the embryos were accompanied by chromosomal abnormalities in women with missed abortions, binary logistic regression was used to analyze the factors influencing embryonic chromosome abnormalities. The results showed that embryonic chromosome abnormalities were significantly associated with age, mode of conception, and parity (OR: 0.754, 95% CI: 0.591, 0.962. p = 0.023) and prior missed abortions. ART and prior missed abortions increased the risk of embryonic chromosome abnormalities by 1.637 (95% CI: 1.573, 4.346. p = 0.010) and 3.111 (95% CI: 1.809, 7.439. p < 0.001) times, respectively. In addition, as age increased by 1 year, the risk of embryonic chromosome abnormality increased by 14.4% (OR: 1.144, 95% CI: 1.030, 1.272. p = 0.012) ( Figure 3A ).

FIGURE 3 . The maternal risk factors for embryonic chromosome abnormalities. (A) Binary logistic regression showed that ART and prior missed abortion increased the risk of embryonic chromosome abnormality by 1.6 and 3.1 times, respectively. Besides, with an increase in age by 1 year, the risk of embryonic chromosome abnormality increased by 14.4%; (B) 28 (24.8%) women had embryonic chromosomal numerical abnormalities and two (1.8%) had embryonic structural abnormalities in the normal age group, while seven (38.9%) had embryonic chromosomal numerical abnormalities and one (5.6%) had embryonic structural abnormalities in the advanced maternal age group; (C) 24 (22.6%) women had embryonic chromosomal numerical abnormalities and two (1.9%) had embryonic structural abnormalities in the natural conception group, whereas 11 (44.0%) had embryonic chromosome numerical abnormalities and one (4.0%) had embryonic structural abnormalities in the ART group.

In our cohort, 28 (24.8%) women had embryonic chromosomal numerical abnormalities and two (1.8%) had embryonic structural abnormalities in the normal age group, while seven (38.9%) had embryonic chromosomal numerical abnormalities and one (5.6%) had embryonic structural abnormalities in the advanced maternal age group ( Figure 3B ). Moreover, 24 (22.6%) women had embryonic chromosomal numerical abnormalities and two (1.9%) had embryonic structural abnormalities in the natural conception group, whereas 11 (44.0%) had embryonic chromosome numerical abnormalities and one (4.0%) had embryonic structural abnormalities in the ART group ( Figure 3C ).

Considering that the incidence of embryonic chromosomal abnormalities is significantly increased in the advanced maternal age and ART groups, further analysis focused on the effects of age and ART on the types of embryonic chromosome abnormalities. Surprisingly, the distribution and proportion of chromosome abnormalities in the ART group were not significantly different from those in the natural conception group, while there was an evidently different type and distribution of chromosome abnormalities between the normal and advanced maternal age groups ( Figures 2B–D ).

In this prospective preliminary study, we investigated the maternal and embryonic chromosome characteristics in missed and non-missed abortion using high-throughput sequencing technology. Given the findings reported for our cohort, we found effects of maternal age, ART, prior missed abortion on embryonic chromosome abnormality, and missed abortion.

Previous studies have shown that the incidence of embryonic chromosome abnormalities in missed abortion was 50%–60% ( Delabaere et al., 2014 ; Yang et al., 2021b ; Voorhies et al., 2022 ), which is consistent with the 64.8% reported in our study. In addition, we characterized embryonic chromosomes from non-missed abortion, which were not included in previous studies. This is crucial because the chromosomal abnormality rate of missed abortions is 64.8%, which cannot be attributed to embryonic chromosome abnormalities alone. The “cause and effect” relationship between missed abortion and embryonic chromosome abnormality is undefined when the rate of embryonic chromosome abnormalities in normal abortion has not been detected. In our cohort, the chromosome abnormality rate was only 3.9% in non-missed abortion embryos, while it was 64.8% in missed abortion embryos. Embryonic chromosome abnormality increased the risk of missed abortion by 16.352 times. Based on this result, it can be concluded that embryonic chromosomal abnormalities are the main cause of missed abortions. Recently, the concept of karyotype coding is proposed to illustrate the importance of the normal karyotype, as any altered karyotype can alter the genomic network, some of which is closely associated with disease conditions ( Ye et al., 2019 ). Thus, the high rate of missed abortion can effectively eliminate the altered genome systems ( Gorelick and Heng, 2011 ).

Previous studies have shown that conception with the help of ART may result in a higher rate of missed abortions and embryonic chromosome abnormalities ( Askerov, 2016 ; Li et al., 2018b ), which is consistent with our study. After the implementation of Chinese two-child and three-child policies ( Chen et al., 2022 ; Long et al., 2022 ), many women who cannot get pregnant naturally due to previous tubal ligation or advanced age get pregnant by ART. Further research is necessary to clarify the relationship between ART and embryonic chromosome abnormalities to promote the development of ART technology.

In our cohort, with an increase in maternal age, the rate of missed abortions and embryonic chromosome abnormalities gradually increased ( Yang et al., 2021a ; Salman et al., 2021 ; Allen et al., 2022 ), which is consistent with previous studies. However, although ART and advanced age increase the incidence of chromosomal abnormalities, the types of chromosomal abnormalities are different. The distribution and proportion of chromosomal abnormalities in the ART group were not significantly different from those in the natural conception group, while there was an evidently different type and distribution of chromosomal abnormalities between the normal age and advanced maternal age groups. However, due to the relatively limited sample size in this study, it cannot be concluded that advanced age may lead to different distributions of chromosomal abnormalities. Further research is needed to determine the effect of advanced age on the localization of embryonic chromosomal abnormalities.

Based on our study, previous missed abortions may increase the risk of missed abortions in subsequent pregnancies. To a certain extent, this is consistent with the lower risk of missed abortions in women who have successfully delivered in the past. Embryo chromosome abnormalities arise mainly due to sperm or egg chromosome abnormalities or the influence of external environmental factors in early pregnancy ( Del Carmen Nogales et al., 2017 ; Shen et al., 2019 ; Wang et al., 2021 ). Some of these factors are similar in two pregnancies in the same woman, which means that if a woman has two or more missed abortions, both partners need to have a more detailed pre-pregnancy examination before the next pregnancy. Moreover, although some microdeletions and microduplications of embryonic chromosomes have been reported to lead to missed abortion ( Cui et al., 2021 ; Familiari et al., 2021 ; Kokkonen et al., 2021 ; Baba et al., 2022 ; Yue et al., 2022 ), and the chromosome microduplication rate of the missed abortion group was higher than that of the normal abortion group in our cohort, there was no significant difference between the two groups.

The merits of our study include the inclusion of a specialized study population. Study participants were screened using strict inclusion and exclusion criteria. Non-singleton pregnant women were excluded because it was difficult to separate the villi completely. Additionally, we collected maternal sociodemographic data and carried out chromosome analysis of both missed- and non-missed abortion women, resulting in a comprehensive study design. Because of the difficulty in obtaining normal aborted embryo villi and the high cost of high-throughput sequencing technology, obtaining embryonic villi specimens and detecting them is time-consuming and costly. It is relatively challenging to recruit participants, collect specimens, detect embryonic chromosomes, and follow up for 1 year.

This preliminary study has significantly contributed to our understanding of the impact of maternal characteristics on embryonic chromosome abnormalities and missed abortions, but also has several limitations that need to be acknowledged. First, compared to some epidemiological surveys, the sample size in this study was relatively modest. Second, the 1 year follow-up of their next pregnancy in women with missed abortions is still ongoing; these data will be reported after finishing the follow-up. Third, due to China’s geomorphic and ethnic diversity, missed abortion-related variables, such as living region altitude and nationality, were limited. To further understand the relevant maternal characteristics of embryonic chromosome abnormalities and missed abortions in China, a large-scale study involving more regions and nationalities, conducted in multiple centers, is required.

In conclusion, this study suggests that nearly two-thirds of missed abortions are indeed caused by embryonic chromosomal abnormalities. Moreover, advanced age, ART, and prior missed abortions increase the risk of embryonic chromosomal abnormalities.

Data availability statement

The original contributions presented in the study are included in Supplementary Data Sheet S2 . Further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving human participants were reviewed and approved by the Ethics Committee of the Chengdu Women’s and Children’s Central Hospital (No. 201952). The patients/participants provided their written informed consent to participate in this study.

Author contributions

XL and HK designed the research protocol; HY and TL conducted the study; QH and XY analyzed the data; YG and WS drafted the manuscript; HG and XZ critically revised the manuscript; KL and YX provided funding resources. All authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Financial support of this work was provided by Chengdu Science and Technology Bureau (2021-YF09-00048-SN), and Sichuan Provincial Science and Technology Bureau (23ZDYF1365 and 23ZDYF1360). The funding agencies did not have any role in the design of the study, collection, analysis, and interpretation of data, and in writing the manuscript.

Acknowledgments

The authors would like to thank all the participants and researchers who contributed to this cohort study.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgene.2022.1058261/full#supplementary-material

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Keywords: missed abortion, chromosome abnormality, assisted reproductive technology, advanced age, gene

Citation: Li X, Kang H, Yin H, Liu T, Hou Q, Yu X, Guo Y, Shen W, Ge H, Zeng X, Lu K and Xiong Y (2023) How many missed abortions are caused by embryonic chromosomal abnormalities and what are their risk factors?. Front. Genet. 13:1058261. doi: 10.3389/fgene.2022.1058261

Received: 30 September 2022; Accepted: 08 December 2022; Published: 04 January 2023.

Reviewed by:

Copyright © 2023 Li, Kang, Yin, Liu, Hou, Yu, Guo, Shen, Ge, Zeng, Lu and Xiong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Kangmu Lu, [email protected] ; Ying Xiong, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Killed by abortion laws: five women whose stories we must never forget

As the US supreme court threatens to undo 49 years of access to safe and legal terminations, five women who died because of bans on abortion stand as warnings of what is at stake globally

Savita Halappanavar , Ireland

Savita Halappanavar was 31 years old when she died of blood poisoning nearly a week after she arrived at University Hospital Galway (UHG) in Ireland complaining of intense back pain.

Halappanavar, a dentist from Karnataka, in south-west India, was 17 weeks pregnant with her first child and went to hospital with her husband, Praveen, on Sunday 21 October 2012. Within hours, doctors said a miscarriage was inevitable, even though a foetal heartbeat could be heard. By this point, Halappanavar was in “unbearable” pain and “very upset”, according to healthcare staff. The plan was, she was told, to “wait and see” if she would miscarry naturally.

At the time, Irish law stated that abortions were permitted only if there was a “real and substantive” threat to a woman’s life. By Tuesday, there had been no miscarriage. The couple asked whether one could be induced but were told by the doctor: “Under Irish law, if there’s no evidence of risk to the life of the mother, our hands are tied so long as there’s a foetal heart[beat].”

Halappanavar developed a high fever. On the Wednesday morning, the medical team diagnosed infection and, later, septic shock. Her condition was deteriorating rapidly.

A plan was made, but not enacted, to give Halappanavar a drug to induce abortion. According to the Health Service Executive inquiry , by this point, the death of the foetus was certain and the appropriate treatment was to terminate the pregnancy because of the risk to Halappanavar’s life.

Halappanavar spontaneously miscarried mid-afternoon on Wednesday and was admitted to intensive care. She was now critically ill with severe sepsis and multiple organ failure. She suffered a cardiac arrest and died in the early hours of Sunday 28 October, almost a week after being admitted.

The case sparked outrage in Ireland and highlighted how the law put women with life-threatening medical conditions at risk in Irish hospitals. In media interviews, Halappanavar’s husband revealed that he and his wife had repeatedly asked for the pregnancy to be terminated but had been refused and told: “This is a Catholic country.”

Protesters took to the streets , calling for accountability and change, accusing the Irish state of failing to protect its citizens. An Amnesty International report in 2015 said her “entirely preventable death was a consequence of Ireland’s restrictive abortion law”.

Anti-abortion campaigners said the case was being exploited by those with an agenda to liberalise Ireland’s laws, and the Catholic church declared that a woman had no more right to life than the foetus .

The government, under intense public scrutiny, carried out multiple inquiries into Halappanavar’s death. In the HSE’s final report , the investigation team stated that a termination of pregnancy was medically indicated and would have been performed in “other jurisdictions”.

In May 2018, Ireland voted by a landslide to repeal its near-total ban on abortion . The referendum – in which 66.4% voted Yes, a majority of 706,349 – drew the highest turnout for a ballot on social issues.

Olga Reyes , Nicaragua

Olga Reyes, 22, waited in pain for hours at the hospital ward in 2006. She had already been turned away from one hospital but arrived at the next one with the proof that she needed urgent care: an ultrasound scan from a private clinic that showed an ectopic pregnancy was rupturing her fallopian tube.

The fertilised egg had implanted itself outside her womb and the embryo, at about six weeks old, could not survive but was threatening her life: Reyes was bleeding to death. Doctors delayed treatment, fearful of the repercussions of the ban on therapeutic abortions that had been introduced only months earlier, in November 2006. By the time they took Reyes for surgery it was too late.

The 22-year-old law student, who had celebrated her wedding only two months earlier, suffered repeated heart attacks during the operation and died from cerebral arrest due to haemorrhaging.

In a report published the same year on the banning of therapeutic abortions in Nicaragua, the rights organisation Human Rights Watch said she should have been treated immediately under government rules on ectopic pregnancies, but the contradictory new ban on therapeutic abortions meant doctors feared intervening.

Only days after the law was changed, another young woman, the same age as Reyes, spent days asking for treatment from a local hospital without success. When she was transferred to another hospital it was, again, too late. She died of a cardiac arrest.

The penal code Nicaragua introduced to enforce its ban included prison sentences for anyone performing abortions, as well as the women seeking them, regardless of whether their lives were in danger. It was because of this, her husband told the media, that Reyes was left bent double in agony in the hospital ward.

The young women’s deaths did not alter the course of Nicaraguan law. After the ban on therapeutic abortions in 2006, more amendments brought a blanket ban by 2008, with no exceptions for saving the woman’s life.

‘Izabela’ , Poland

The morning before her death, Izabela* texted her mother from the hospital. “The child weighs 485g. For now, because of the abortion law, I have to stay in bed and they can’t do anything,” she wrote. “They will wait for the baby to die or for something to start happening. If it doesn’t then great, I can expect sepsis.”

Izabela, 30, owned a hair salon in Pszczyna, a small town in Silesia. On her Instagram account Pani Iza, as she was known to customers, would regularly post photos of her influencer-worthy wedding coiffures and hair transformation. Her clients did not spare compliments. “The best hairdresser in the world, you can see that she loves her job,” reads one of the last online reviews dated June 2021, a month before Izabela died. “Thanks to her, I went from black to blonde and my hair survived!”

When her waters broke at 22 weeks, Izabela thought it was stress. She had spent the day at hospital with her nine-year-old daughter, who had fallen from her scooter. Izabela was taken to hospital the next day, though no treatment was undertaken until the next morning.

“They can’t do anything, because then it’ll look like they did it on purpose,” she texted her mother, to explain why doctors were not inducing the birth hours after the waters broke.

“They have to wait for it to happen on its own. And if it doesn’t, then we’re waiting for the heart to stop beating,” she wrote. “The woman is like an incubator. And the baby is suffering too – it has nothing to breathe with.”

According to a Polish law introduced in 2021, abortion is legal to save the health or life of the mother and in cases where the pregnancy is a result of rape. Previously, the procedure could also be legally carried out in cases of severe foetal abnormalities.

Although the doctors could have legally aborted, they chose not to until it was too late. The law that would have allowed them to do this was “difficult to apply in practice”, says Jolanta Budzowska, the lawyer representing Izabela’s family in a court case against the hospital. “If they carry out an abortion too early and the prosecutors then decide that there was no danger to the mother [at that point] they can face up to three years in prison. Consequently, doctors are more cautious in their decisions.”

As doctors waited for the foetal heartbeat to stop, women on Izabela’s ward recall her pleading with the staff. “She felt that something was not right. But they kept telling her that the heart is beating, and that as long as the heart is beating this is the way it must be,” one woman told Polish media.

“I can still hear her words to this day: that she wants to live, she doesn’t want to die, that she has people to live for,” the woman said.

After nationwide protests, the hospital where Izabela died was fined 650,000złoty (£120,000) by the Polish health service. The court case against the doctor responsible for Izabela during her stay at the hospital is ongoing. The hospital’s director resigned in March.

‘Manuela’ , El Salvador

Manuela*, a mother of two from El Salvador , did what most people would do when she fell ill while pregnant in 2008: she went to hospital. Tragically, she miscarried, but instead of medical and social support, she was handcuffed to her hospital bed and interrogated by police.

Manuela, 33, whose full name has never been made public, was charged with aggravated homicide under El Salvador’s draconian anti-abortion laws, and sentenced to 30 years in prison. She died of cancer two years later – a disease that activists say was ignored and left untreated during her incarceration.

“The stories of women in El Salvador who have been unjustly criminalised for experiencing obstetric emergencies, as happened to Manuela, should also serve as a global example of the terrible consequences of criminal restrictions on access to a service such as abortion,” says Carmen Martínez, an associate director in Latin America for the Center For Reproductive Rights, a US-based human rights organisation.

Last November, the Inter-American Court of Human Rights (IACHR) ruled that the state was responsible for Manuela’s death , having violated her rights to life, health, judicial protections and guarantees, freedom from discrimination and gender violence. The court ordered El Salvador to pay reparations to the young woman’s family and to reform its strict abortion laws and healthcare policies.

“There is no doubt that Manuela suffered an obstetric emergency,” stated the landmark ruling. “Such situations, as they are medical conditions, cannot lead to a criminal sanction.”

El Salvador has some of the world’s most restrictive abortion laws. Since 1998, the procedure has been banned without exception, including in cases of rape and incest. Over the past 20 years, more than 180 women have been jailed for murder for having an abortion after suffering obstetric emergencies, according to rights groups.

“I remember my mum, she gave us advice and never left us alone. It is painful to grow up without a mother because that love is incomparable,” Santos de Jesús, Manuela’s eldest son, said in a statement before the hearing in March last year. “I ask the state not to do these things because they left us abandoned without a mother.”

At the time of the ruling, many women’s rights activists believed that the Americas could be on the path to further liberalisation of abortion laws – and decriminalisation gains in Colombia and Argentina fuelled those hopes.

However, the leak of the US supreme court’s draft opinion to overturn Roe v Wade has many rights groups worried that progressive policies may remain out of reach.

“The threats to abortion rights in the US matter to all of us because it is a terrible precedent at the international level,” Martinez, one of the lawyers who argued Manuela’s case before the IACHR, says. “This does not mean that what happens in a court like the one in that country can affect the achievements we have made in El Salvador and throughout Latin America, and for which we will continue to work with more enthusiasm.

“Roe v Wade must be protected as well as all laws that have advanced in the decriminalisation of abortion in the world. The fight for our rights has no borders.”

‘Mildred’ , Kenya

Mildred* was a 15-year-old girl from Manyani estate in the Kenyan city of Nakuru. She was admitted at the Nakuru Level 5 hospital last summer with acute abdominal pains and uncontrollable vomiting. She died writhing in pain, 20 weeks into a pregnancy she had tried and failed to end using herbs and salt.

Her anguished father, David, explained that the family did not know about her pregnancy. Mildred had travelled to the family’s rural home in Bungoma, where, her family believe, she tried to end the pregnancy with the help of an older woman she knew there.

“I did not know that my daughter attempted to terminate her pregnancy using a mixture of herbs, concentrated drinks and salt, a secret she kept close to her heart,” her father says.

“I wish my daughter had accessed a safer abortion … terminating the pregnancy was a better option to her happiness than trading her life with herbs that caused her infection and painful death,” he says.

At the same hospital, two years ago, Betty* died after trying to use detergent to end her pregnancy. The pain of the loss is still raw for her mother, from Racecourse estate, in Nakuru. “I thought my daughter was suffering from malaria. She was vomiting and complained of a severe headache,” she says.

Betty died on 19 May 2020 in agony. “It is sad that my daughter suffered in silence. I would have supported and walked with her in her pregnancy journey, and guaranteed her a safe delivery,” says her mother. “It pains me that she died such a painful death, yet I could have helped raise the baby as she continued with her studies.”

Her mother claims Betty was encouraged to take the detergent by her peers for fear of being forced to drop out of school and the stigma that comes with a teenage pregnancy. Kenyan society views teenage mothers as failures, with a number being denied education and forced into early marriages, often with abusive men.

“I wish there was a way of stopping my daughter from dying,” says her mother. “I trusted she would save me from poverty.”

In Kenya, abortion is outlawed under the constitution, with the exception of pregnancy from rape, pushing women and girls into crude methods of abortions, risking their health and their lives. According to the most recent Demographic Health Survey, 35% of maternal deaths in 2014 were as a result of unsafe abortions.

Dr Susan Gitau, chair of the Department of Counselling Psychology at Africa Nazarene University , says many of those who survive such unsafe procedures suffer lasting trauma. “Psychological counselling is key, counselling that should be done within 48 hours,” she says, “because abortion is illegal, girls do not access this.”

* Names have been changed to protect identities.

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How florida and arizona supreme court rulings change the abortion access map.

Selena Simmons-Duffin

Hilary Fung

In a few weeks, Florida and Arizona are set to join most states in the southern U.S. in banning abortion. It's a significant shake up to the abortion legal landscape, and data shared exclusively with NPR maps and quantifies what the changes will mean for millions of Americans.

On Tuesday, the Arizona Supreme Court cleared the way for an 1864 law to be enforced. That law completely bans abortion except when someone's life is in danger. Last week, the Florida Supreme Court made its decision to allow a ban on abortions after six weeks gestation to take effect on May 1.

Caitlin Myers , an economics professor at Middlebury College in Vermont, has been tracking abortion facilities and travel distances since 2009. She analyzed how these latest rulings will affect the access map.

"Because of these bans, it's about 6 million women of reproductive age who are experiencing an increase in distance of more than 200 miles," she says.

She points out that Floridians who are seeking abortions after six weeks will have to travel nearly 600 miles to North Carolina, which has a 72-hour waiting period. "So we're talking about a day's drive to a state that requires you to engage in this multi-day process," Myers says. "A lot of people might end up going several hundred miles further to Virginia."

For people in Arizona, after the 1864 law takes effect, "their nearest destinations are pretty long drives. They're going to be facing hundreds of miles to reach southern California, New Mexico, Colorado," Myers says. "I think Arizona spillover is likely to affect California in a way that California hasn't yet been affected by bans."

Myers helms the Myers Abortion Facility Database . She has gathered data about facilities – including clinics, doctors, and hospitals that publicly indicated that they provide abortions – going back more than a decade, using data licensure databases, directories, and Wayback Machine captures of websites from years past. She uses a team of undergraduate research assistants to periodically call facilities and make sure the information is up to date.

Numbers of abortions rise in Florida, decline in Arizona

Although Florida and Arizona have historically both been politically purple states and both have had 15-week abortion bans since 2022, the states have been on different trajectories when it comes to abortion and play very different roles in their regions.

There were about 12,000 abortions in Arizona in 2023, according to the Guttmacher Institute , a research organization that supports abortion rights. Out-of-state travel accounted for 3% of abortions in the state, and the overall number of abortions has been declining there in recent years, Guttmacher finds.

By contrast, there were nearly 85,000 abortions in Florida in 2023, according to state data , just a few thousand fewer than Illinois, which has positioned itself as a haven for people seeking abortions in the post- Roe era. And the number of abortions happening in the state has been on the rise. "The majority of the increase has been driven by out-of-state travel into Florida because of bans in surrounding states," explains Isaac Maddow-Zimet , a Guttmacher data scientist. "That really speaks to the role that Florida has played in the region where there really aren't many other options."

The Alliance Defending Freedom, which brought the case in Arizona, frames those affected by the new laws in a different way. "We celebrate the Arizona Supreme Court's decision that allows the state's pro-life law to again protect the lives of countless, innocent unborn children," the organization wrote in a statement this week .

Even with new bans in place, there are a few ways residents of Florida and Arizona will be able to access abortion without driving hundreds of miles. People with means will be able to fly to states where abortion access is protected. Others will be able to use telehealth to connect with providers in those states and receive abortion medication in the mail – a practice that has been growing in popularity in recent months. Telehealth medication abortions, though, could be curtailed by a pending case before the U.S. Supreme Court. (A decision in that case is expected this summer.)

In Florida, some will be able to get abortions before the six-week gestational limit, which is about two weeks after a missed period. "Folks have a really narrow window in order to meet that gestational duration limit if they even know about their pregnancy in time," Maddow-Zimet of Guttmacher explains. "And that's something that's particularly difficult in Florida because Florida requires an in-person counseling visit 24 hours before the abortion."

'A substantial barrier'

Many thousands of people in Florida and Arizona will be unable to navigate those options and will carry their pregnancies instead, Myers says.

"It's easy to think – if an abortion is so important to somebody, they will find a way, they will figure it out," she says, but research on people seeking abortions illustrates why that's not always possible. "[Many] are low income. They're in very difficult life circumstances. They're experiencing disruptive life events like the loss of a job or breaking up with a partner or threatened eviction. Many of them are parenting and have difficulty obtaining child care." One large study showed about 80% of people seeking abortions had subprime credit scores.

"If you think about all that, it is perhaps not so surprising that the results of my research and other people's research shows very strongly and unequivocally that distance is a substantial barrier to people who are seeking abortions," Myers says.

Mary Ziegler , a law professor and historian of reproductive rights at the University of California - Davis, says it's worth noting how these states both came to have new bans. "The common denominator is conservative state supreme courts reaching decisions contrary to what voters would want, interestingly, in an election year when those judges are facing retention elections," she says.

Voters in Florida will have a chance to weigh in on abortion access in November, when an amendment to their state constitution will be on the ballot. An effort to put an abortion amendment on the ballot in Arizona is also underway. Abortions rights opponents in both states have pledged to fight the measures.

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• Published: 02 May 2018

A case report of spontaneous abortion caused by Brucella melitensis biovar 3

• Hong-Xia Yang 1 , 3 ,
• Jun-Jun Feng 2 ,
• Qiu-Xiang Zhang 1 ,
• Rui-E Hao 1 ,
• Su-Xia Yao 1 ,
• Rong Zhao 1 ,
• Dong-Ri Piao 3 ,
• Bu-Yun Cui 3 &
• Hai Jiang 3  

Infectious Diseases of Poverty volume  7 , Article number:  31 ( 2018 ) Cite this article

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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. In this work, the patient living in Shanxi Province in China who had suffered a spontaneous abortion was underwent pathogen detection and Brucella melitensis biovar 3 was identified.

Case presentation

The patient in this study was 22 years old. On July 16, 2015, she was admitted to Shanxi Grand Hospital, Shanxi Province, China because of one day of vaginal bleeding and three days of abdominal distension accompanied by fever after five months of amenorrhea. A serum tube agglutination test for brucellosis and blood culture were positive. At the time of discharge, she was prescribed oral doxycycline (100 mg/dose, twice a day) and rifampicin (600 mg/dose, once daily) for 6 weeks as recommended by the World Health Organization (WHO). No recurrence was observed during the six months of follow-up after the cessation of antibiotic treatment.

Conclusions

This is the first reported case of miscarriage resulting from Brucella melitensis biovar 3 isolated from a pregnant woman who was infected through unpasteurized milk in China. Brucellosis infection was overlooked in the Maternity Hospital because of physician unawareness. Early recognition and prompt treatment of brucellosis infection are crucial for a successful outcome in pregnancy.

Multilingual abstract

Please see Additional file  1 for translation of the abstract into the five official working languages of the United Nations.

Brucellosis is a worldwide zoonotic disease caused by Brucella spp. The Law of the People’s Republic of China on Prevention and Treatment of Infectious Diseases classifies it as a Class B infection. Brucella invades the body through the skin mucosa, digestive tract, and respiratory tract. Livestock infected with Brucella often undergo spontaneous abortion and infertility, and have low reproductive and survival rates. Humans infected with Brucella mainly manifest fever, sweating, fatigue, and arthralgia, and can also suffer damages to the nervous, circulatory, and reproductive systems [ 1 ]. However, only few studies on spontaneous abortion attributable to Brucella have been reported. In this work, a patient living in Shanxi Province in China who had suffered a spontaneous abortion underwent pathogen detection to analyse the genetic characteristics of the spontaneous abortion-related Brucella strain. This helps to provide a scientific basis for the prevention and control of Brucella infection in pregnant women.

The patient in this study was 22 years old. She was admitted to Shanxi Grand Hospital, Shanxi Province, China, on July 16, 2015 because of one day of vaginal bleeding and three days of abdominal distension accompanied by fever after five months of amenorrhea. This patient had a history of regular menstruation, and her last menstrual period had been on February 20, 2015. An immunoassay showed her urine to be positive for human chronic gonadotrophin. The patient had no fever during early pregnancy and did not have a history of exposure to toxic, harmful, or radioactive materials. Down’s syndrome screening performed as part of a regular second-semester prenatal checkup showed no obvious fetal abnormality. The patient had abdominal distension with fever and received anti-infective treatment at a local hospital three days before coming to Shanxi Grand Hospital. One day before coming to Shanxi Grand Hospital, she suffered vaginal bleeding. She was given conventional tocolytic treatment, but the outcome was poor. The patient was examined after hospital admission and had a body temperature of 39 °C, pulse rate of 120 beats/min, breath rate of 21 breaths/min, and blood pressure of 90/53 mmHg, but no cardiopulmonary or abdominal abnormalities. Specialist examinations showed minor abdominal swelling, irregular contraction of the uterus palpable at two fingers under the uterus and umbilicus, and a small amount of vaginal bleeding. The fetal membrane was slightly ruptured, and the fetal heart rate was 170–180 beats/min. A complete blood count showed 16.6 × 10 9 /L white blood cells, 78.4% neutrophils, 16.5% lymphocytes, 4.9% monocytes, 3.63 × 10 12 /L erythrocytes, 106 g/L hemoglobin, 202.1 × 10 9  g/L platelets, and 102.16 mg/L C reaction protein. Intravenous ceftriaxone (2 g/d), 25% magnesium sulfate, and antipyretic treatments were administered to the patient after her admission to Shanxi Grand Hospital, but the patient had a miscarriage and vaginal delivery of a female fetus on July 19. Her body temperature continued to fluctuate after admission, increasing to 39.3 °C the afternoon of July 19. Further questions about the patient’s medical history showed that this patient had sheep at home but never came into direct contact with them. However, she had begun to drink unpasteurized goat milk during her fourth month of pregnancy and was thus suspected of having Brucella infection. A serum tube agglutination test (SAT) for brucellosis and blood culture were immediately performed. The SAT result was 1:800, confirming brucellosis. This patient was given antibiotic treatment for three consecutive days. She was discharged from the hospital on July 24 because the fever stopped. At the time of discharge, she was prescribed oral doxycycline (100 mg/dose, twice a day) and rifampicin (600 mg/dose, once daily) for 6 weeks as recommended by the World Health Organization (WHO). No recurrence was observed during the six months of follow-up after the cessation of antibiotic treatment. The onset, diagnosis, and treatment of the disease in this patient are shown in Fig.  1 .

The onset and outcome of disease, diagnosis, and treatment

Serological testing

The diagnosis of brucellosis was based on the serum standard tube agglutination test (SAT). The SAT result was 1:800.

Pathogen detection

Five milliliters of venous blood from the patient were collected and injected into a two-phase culture flask for culture. After detecting bacterial growth in the culture, traditional biological methods were used for the isolation and identification of the bacteria [ 2 ]. With the reference to the standard strain B. melitensis 16 M, colony morphology, Gram stain reaction, CO 2 requirements, H 2 S production, inhibition of growth by basic Fuchsin and Thionin, agglutination with monospecific antisera, and phage lysis testing were performed. Serum and bacteriophage were provided by the Brucellosis Laboratory, National Institute for Communicable Disease Control and Prevention, and the Chinese Center for Disease Control and Prevention.

Specific sequences of the 16 MLVA primers are described in previous work [ 3 ]. The reaction system for genotyping included 10 μl 2 ×  Taq PCR Mastermix, 0.4 μl each of the 10 pmol/μl primers, and 1 μl DNA template, with sterile distilled water to a total volume of 20 μl. The amplification conditions were: 95 °C denaturation; 40 cycles of denaturation at 95 °C for 30 s, annealing at 60 °C for 30 s, and elongation at 72 °C for 30 s. Amplification products were analysed by microsatellite sequencing to convert the repeated unit according to the size of the PCR products. BioNumerics (Version 5.0) software was used for cluster analysis to perform an online comparison between the typing and the Brucella database. Nucleic acid extraction was performed using a bacterial whole genome nucleic acid extraction kit [Tiangen Biotech (Beijing) Co., Ltd., Beijing, China]. MLVA primers were synthesized by Sangon Biotech (Shanghai) Co., Ltd. (Shanghai, China), and STR microsatellite sequencing was performed by Tianyi HuiYuan Biotech Co., Ltd. (Beijing, China).

Seven housekeeper genes ( dnaK , gyrB , trpE , aroA , cobQ , gap , and glk ), one outer membrane protein gene ( omp25 ), and one intergenic region int-hyp were used as the target genes of MLST for synthesis of the corresponding primers and for PCR [ 4 ]. PCR products were purified and subjected to bidirectional sequencing. The sequencing was completed by Tianyi HuiYuan Biotech Co., Ltd.. The tested sequences were compared to the sequences of allelic genotypes of the corresponding genes. The MLST online tool ( http://pubmlst.org/perl/mlstanalyse/mlstan-alyse.=pubmlst ) was used to analyse the alleles in the sequence.

Five milliliters of whole blood were extracted from the patient on July 20 and were found to have bacterial growth on July 26. The colonies were collarless and transparent, round in shape, and with smooth surfaces. Conventional identification by microscopy showed colonies to be gram-negative short bacilli that did not produce hydrogen sulfide and had positive monospecific antisera agglutination. The basic Fuchsin and Thionin tests and the bacteriophage Bk test were positive, while the Tb and Wb tests were negative, indicating that the colony was B. melitensis biovar 3, commonly found in sheep and goats. For MLVA-16 typing (Additional file 2 : Table S1), panel 1 showed the sample to be a type 42 (1–5–3-13-2-2-3-2), belonging to the Eastern Mediterranean type; panel 2 typing showed the sample to be a 4–40–8-4-4-3-8-5, which was completely identical to the goat type 3 Brucella (2012167) strain in MLVA genotyping [ 5 ]. For MLST, the ST allele spectrum was 3–2–3-2-1-5-3-8-2, and MLST sequence typing was ST8 (Additional file 3 ) , which is a common sequence type found in China [ 6 ].

Discussion and conclusions

Spontaneous abortion is a common complication of brucellosis in animals. The infection tends to localize to the placenta, which is associated with erythritol (a bovine growth stimulant). Although erythritol is not present in human placental tissues, brucellosis can lead to spontaneous abortion in human, especially in early pregnancy [ 7 ]. Khan et al. studied 92 cases of brucellosis during pregnancy in a hospital in Saudi Arabia during 1983–1995 and found a rate of spontaneous abortion in the first and second trimesters of 43% [ 8 ]. Roushan et al. studied 19 cases of brucellosis during pregnancy in the Babol region in Iran and observed 10 cases of spontaneous abortion, accounting for 53% of all cases [ 9 ]. Al-Tawfiq et al. reviewed the literature covering brucellosis during pregnancy from 1954 to 2011 and found that the incidence of spontaneous abortion and stillbirth among 430 cases ranged from 31 to 46%, which was much higher than in other pregnant women [ 10 ]. However, Gulsun et al. conducted a case-control study on brucellosis during pregnancy from 2003 to 2010 and showed no significant differences in fetal congenital malformations and/or mortality between patients infected with Brucella and the control group, but Brucella did cause premature birth and low birth weight [ 11 ]. The present case study of brucellosis-induced spontaneous abortion in the second trimester provides clinical evidence for miscarriage caused by Brucella infection. The B. melitensis biovar 3 isolated from the blood culture belonged to the dominant strain found in Shanxi Province. Further study of the mechanism underlying miscarriage caused by Brucella will be necessary, and genome sequencing is in progress.

Milk from cattle, goats, and other animals with brucellosis contains large numbers of Brucella . It is possible to acquire brucellosis through the consumption of unpasteurized milk and dairy products [ 12 ]. The symptoms of brucellosis are atypical, and cases are easily misdiagnosed. In this study, the patient was treated in our hospital due to miscarriage and atypical symptoms of brucellosis. However, during her hospitalization, the patient did not immediately mention consuming goat’s milk. Although our staff had been actively looking for the cause of the fever, we only suspected Brucella infection after the patient’s miscarriage. We confirmed the diagnosis five days after her admission to the hospital.

It is difficult for antibiotics and antibodies to enter cells, so single-drug therapy cannot completely eliminate the bacteria. The WHO Expert Committee recommends brucellosis be treated using a combination of doxycycline (200 mg oral admission daily) and rifampicin (600–900 mg oral admission daily) for six weeks [ 7 ]. In this study, the patient was given combination therapy of doxycycline and rifampicin for six weeks and showed no recurrence during follow-up. The basic factor in the treatment of brucellosis is to ensure the effectiveness and adequate course of antibiotic treatment. Patients are urged to complete their full course.

In summary, this is the first reported case of miscarriage resulted from Brucella melitensis biovar 3 isolated from a pregnant woman who was infected through unpasteurized milk in China. Brucellosis infection was easily overlooked in the Maternity Hospital because of physician unawareness. The early recognition and prompt treatment of brucellosis infection are crucial for a successful outcome in pregnancy.

Abbreviations

Multilocus sequencing typing

Multiple-locus variable number tandem repeat analysis

Sequencing typing

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Acknowledgements

We are grateful to Hong-Yan Zhao and Guo-Zhong Tian for experimental guidance.

This study was supported by the Science and Technology Project of the Shanxi Province Health and Family Planning Commission (No. 2011077) and the National Natural Science Foundation of China (No. 81271900). The funders contributed to the study design and data collection.

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Hong-Xia Yang, Qiu-Xiang Zhang, Rui-E Hao, Su-Xia Yao & Rong Zhao

Clinical Laboratory, Shanxi Dayi Hospital, Taiyuan, China

Jun-Jun Feng

State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China

Hong-Xia Yang, Dong-Ri Piao, Bu-Yun Cui & Hai Jiang

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Contributions

H-X Y performed the majority of the pathogen detection testing, coordinated all work related to the study, performed data analysis, drafted the manuscript, and participated in the design of the study; J-J F collected the case clinical data; R-E H, S-X Y, R Z, and D-R P performed MLVA and MLST and participated in data analysis; B-Y C participated in the design of the study and critically reviewed the manuscript. H J participated in the design of the study and managed the project. All of the authors read and approved the final manuscript.

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Correspondence to Hai Jiang .

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This research was carried out according to the principles of the Declaration of Helsinki and was approved by the Ethics Committees of the National Institute for Communicable Disease Control and Prevention and the Chinese Center for Disease Control and Prevention (No.: ICDC-2014005). No animal work was carried out as part of this study.

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Additional files

Additional file 1:.

Multilingual abstracts in the five official working languages of the United Nations. (PDF 502 kb)

Additional file 2:

Table S1. Product size and repeat unit of 16 loci. (DOCX 68 kb)

Additional file 3:

ST sequence data of 9 genes. (DOCX 17 kb)

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Yang, HX., Feng, JJ., Zhang, QX. et al. A case report of spontaneous abortion caused by Brucella melitensis biovar 3. Infect Dis Poverty 7 , 31 (2018). https://doi.org/10.1186/s40249-018-0411-x

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DOI : https://doi.org/10.1186/s40249-018-0411-x

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Estimating the visibility rate of abortion: a case study of Kerman, Iran

Maryam zamanian.

1 Modeling in Health Research Center, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran

Mohammad Reza Baneshi

Aliakbar haghdoost.

2 HIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran

Farzaneh Zolala

Abortion is a sensitive issue; many cultures disapprove of it, which leads to under-reporting. This study sought to estimate the rate of abortion visibility in the city of Kerman, Iran—that is, the percentage of acquaintances who knew about a particular abortion. For estimating the visibility rate, it is crucial to use the network scale-up method, which is a new, indirect method of estimating sensitive behaviours more accurately.

Materials and methods

This cross-sectional study was conducted in Kerman, Iran using various methods to ensure the cooperation of clinicians and women. A total of 222 women who had had an abortion within the previous year (74 elective, 74 medical and 74 spontaneous abortions) were recruited. Participants were asked how many of their acquaintances were aware of their abortion. Abortion visibility was estimated by abortion type. 95% CIs were calculated by a bootstrap procedure. A zero-inflated negative binomial regression analysis was conducted to assess the variables related to visibility.

The visibility (95% CI) of elective, medical and spontaneous abortion was 8% (6% to 10%), 60% (54% to 66%) and 50% (43% to 57%), respectively. Women and consanguineal family were more likely to be aware of the abortion than men and affinal family. Non-family members had a low probability of knowing about the abortion, except in elective cases. Abortion type, marital status, sex of the acquaintance and closeness of the relationship were the most important determinants of abortion visibility in the final multifactorial model.

Conclusions

This study shows the visibility rate to be low, but it does differ among social network members and by the type of abortion in question. This difference might be explained through social and cultural norms as well as stigma surrounding abortion. The low visibility rate might explain the low estimates of abortion rates found in other studies.

Strengths and limitations of this study

• This is a rare study estimating abortion visibility in Iran—as well as in the rest of the world; the results could draw policy makers' attention to appropriate policies by providing a more realistic picture of abortion.
• The most important challenge faced in this study was low participation from women who had abortions and reproductive health providers because of stigma and severe legal restrictions. As a result, we tried to encourage their participation using different strategies.
• We were unable to assess other cases of abortion (eg, women who used traditional and herbal medicines, as well as cases performed by non-medical providers or the woman herself). The visibility of abortion in such cases may be different from the cases we considered.

Introduction

Self-reporting and direct methods of measuring health events are prone to high levels of under-reporting bias. This bias is much more common for behaviours that are sensitive or subject to social disapproval, occurring more often among women. 1 2 Abortion can be classified as a sensitive issue because of the high level of stigma related to it and legal restrictions in many communities. 3

Abortion can be divided into two overarching categories, spontaneous and induced, with the latter further divided into two types, medical and elective. 4 Medical abortion is performed in cases of fetal anomaly or to safeguard the mother's health, whereas elective abortion is performed at the request of the mother for other than therapeutic reasons. Elective abortion, which has also been called intentional, criminal or illegal abortion, garners greater stigma in many societies. 3 5 Stigma causes women to hide their experience of abortion from acquaintances and healthcare providers. 6 Even in communities where abortion is legal, a comparison of medical records and self-reported abortion rates shows a high discrepancy of ∼70%. 7 This rate may be much higher in societies where abortion is illegal, which results in under-reporting and unsafe abortions that can jeopardise the mother's life. 8

Iran—a Middle Eastern country governed by the Islamic state—culturally, religiously and legally prohibits elective abortion. Because of these conditions, many elective abortions are performed at home or under unsafe conditions, 9 which could lead to the mother's death or irreparable complications. 3 These abortions can never be registered if they are performed successfully, and, in cases of referral to a hospital for a critical complication endangering the mother's health, the mothers often report spontaneous abortion rather than elective. 9 In addition, a new population growth policy in Iran is encouraging families to have more children, as the Iranian population has declined in recent years. 10 This, in turn, could increase legal restrictions and ultimately lead to even more under-reporting of abortion. Last but not least, not all cases of spontaneous abortion are recorded in the registration system. 5

While the data derived from direct survey methods and from the registration system represent just the tip of the iceberg, an accurate estimate of abortion is necessary to inspire more effective planning and policymaking to reduce unsafe abortion and to improve maternal health. Such an estimate is also needed for purposes such as accurate estimation of pregnancy rates, levels of unintended pregnancy (UP) (UP itself includes two main categories: unwanted pregnancy and mistimed pregnancy) and contraceptive failure rate. 11

How can better estimates for sensitive issues be obtained? An effective alternative method to self-reporting and direct techniques is the network scale-up (NSU) method, an indirect technique. In this method, a representative sample of the general population is questioned about the number of the target population in their active social network—it does not require direct questioning of the target population. 12 For example, the participants are asked, ‘among your acquaintances, how many women have had abortion experiences?’ This indirect and anonymous question could desensitise the respondents to the topic and increase response rates and accuracy for two reasons: first, the question is not directly about the respondents themselves but about other people; second, they are not required to name those acquaintances or their relation to them; they merely provide the number. 12 13 The NSU method is based on the idea that the proportion of individuals known by participants is linearly proportional to the real size of the same subpopulation in the society. 12 However, one of the basic NSU assumptions, perfect awareness of their acquaintances' behaviours, is often not met; hence, visibility bias remains a major source of bias in estimations of hard-to-count populations. 14

Visibility bias describes respondents not being aware of all the behaviours among their active social network. This occurs more often for stigmatised or illegal behaviours. For example, respondents may not be aware of abortions that have happened in their network. 15 In the case of the NSU method, the obtained crude estimate should be adjusted accordingly. For example, if the visibility of a hidden behaviour was estimated at 50%, the NSU method's crude estimate should be doubled. Thus far, visibility rates have been estimated for hidden populations such as men who have sex with men (MSM), injection drug users (IDUs) and commercial sex workers (CSWs), as well as for certain types of cancer. 12 16–18 Only one study has estimated the visibility of abortion by asking gynaecologists and midwives to guess the visibility rate of abortion. 19 However, to the best of our knowledge, no study has used the standard method to estimate the abortion visibility (AV) rate. Therefore, in this study, we sought to estimate the visibility rate and its determinants for all types of abortion in an Iranian population to provide a more accurate estimate of abortion.

Study setting and study population

This cross-sectional study was part of a larger ongoing study in Kerman, Iran in 2015, the primary aim of which was to estimate the frequency of abortion. Kerman is the capital of the largest province of Iran and is located in the southeastern part of the country. Eligible participants were female residents of Kerman over the past 5 years who had a history of abortion during the previous year. A total of 222 women who had an abortion of any type within the previous year (74 elective, 74 medical and 74 spontaneous) were recruited. To obtain the study sample, both private and public centres were approached, including referral hospitals, private offices of gynaecologists and midwives. The critical factor in this study was gaining the trust of the reproductive health providers, so that they felt comfortable cooperating with data collection for elective abortion cases. This was difficult owing to the severe legal restrictions on abortions in Iran. Therefore, we held several meetings to explain the study method and assure them that their confidentiality and anonymity were paramount. They were also provided with financial incentives. Subsequently, these providers introduced us to women who had had an abortion and consented to be interviewed. Most participants were interviewed in person, but 33 (∼15%) were interviewed on the phone to further protect their privacy. After explaining the purpose of the study to the participants, reassuring them of their anonymity and the confidentiality of information, and obtaining verbal informed consent, we were permitted to collect data.

To obtain a sample of non-elective abortions—participants whose medical records listed a medical or spontaneous abortion within the previous year—we sought the help of gynaecologists and midwives in referral hospitals throughout the city. These participants were interviewed after they provided verbal consent. Written consent forms were not used owing to the cultural sensitivity of this topic and to help increase both participation and accuracy of responding. 20 All interviews were conducted in a private room at the same centre. Despite all these safeguards, the participation rates for elective, medical and spontaneous abortions were 39%, 70% and 62%, respectively. We are cognisant that non-random sampling and the relatively low response rate for elective cases, which were almost unavoidable, could affect the generalisability of the results; therefore, the estimated AV rate cannot be generalised to the whole population of women living in Kerman. The data were collected using a structured interview instrument administered by a trained female interviewer. The study protocol was approved by the ethics committee of Kerman University of Medical Sciences (ir.kmu.rec.1394.223).

Data collection

The interview form included four sections. The first provided an overview of the study and its objectives. In the second, a table listed the participant's active social network relationships in the rows. In the NSU method, the standard definition of an active social network is ‘people whom you know and who know you by name, with whom you can interact, if needed, and with whom you have had contact over the last two years personally, or by telephone or e-mail’. 12 13 For ease of recall and therefore increased accuracy, we divided the entire active social network into a list of comprehensive relationships and two main categories: family and non-family. The family group included consanguineal 1 and affinal 2 family. Both consanguineal and affinal family included two subgroups: immediate family (sometimes known as first-degree relatives, including parents, siblings and children) and extended family (including grandparents, aunts, uncles, cousins, nieces, nephews, etc). The non-family group included male and female friends from school, friends from university, friends from their neighbourhood, acquaintances from work, acquaintances from their husband's work, friends of their husband and other friends or acquaintances. The table included three columns (A, B and C). The first (column A) tallied the total number of persons from each relationship. The next column (B) indicated the number of adults (persons 18 years old and over) from each relationship, and the last (column C) indicated the number of adults who were aware of the abortion. (Participants were not asked about the awareness of those under 18 years old because any lack of knowledge on their part is more likely due to their age than to a low visibility rate.) Participants were prompted with questions such as ‘How many cousins do you have? How many of them are adults? And how many of these adults are aware of your abortion?’.

The third section assessed the abortion type. In addition, participants were asked whether their pregnancy was intended (planned), why the pregnancy was unintended, the number of children they already have, any previous pregnancies, age, marriage age, marital status, career, husband's career, and their level of education.

The last section included more sensitive questions. This section included questions to be completed in cases of elective abortion (such as the reason for the abortion, whether the man involved in the pregnancy (MIP) was aware and consented to the abortion, and what their marital status was at the time of the abortion). A self-completion form and a ballot box were used for this section in order to maintain the participant's privacy and to improve the accuracy of the data. The form was piloted in two studies and revised accordingly to increase acceptability and comprehension.

Data analysis

We estimated AV using formula (1):

AV and 95% CI were estimated for each type of abortion and by different subgroups divided by abortion type ( table 1 and figure 1 ). The 95% CIs were computed by a bootstrapping procedure, drawing 1000 independent samples with replacement. The calculations for AV and 95% CI were performed separately for different demographic characteristics.

Table 1

Abortion visibility by demographic characteristics

*Immediate family of consanguineal and affinal family.

†Extended family of consanguineal and affinal family.

AV, abortion visibility.

Abortion visibility in the city of Kerman, in 2015, divided by abortion type. (A) Abortion visibility, divided by abortion type. (B) Comparison of abortion visibility among women's husbands and female and male members of their social network, divided by abortion type. (C) Comparison of abortion visibility among women's consanguineal family, affinal family and non-family, divided by abortion type. (D) Comparison of abortion visibility among women's immediate and extended consanguineal family, divided by abortion type. The y axis shows abortion visibility as a percentage, which is calculated by dividing the number of adults who were aware of the abortion by the total number of adults listed in any given category. E, elective; M, medical; S, spontaneous; H, husband; F, females; M, males; CF, consanguineal family; AF, affinal family; NF, non-family; ICF, immediate consanguineal family; ECF, extended consanguineal family.

A zero-inflated negative binomial regression analysis was used to model the potential determinants of AV because so many acquaintances were not aware of the abortion, generating excess zero responses, and because of the large difference between the mean and variance of the data. To adjust for the correlation between each participant's responses about the members of her network, each participant was defined as a cluster layer, and cluster robust SE was used. Potential determinants of AV were tested in univariate analyses, and those with p values less than 0.2 were entered into a multifactorial model using backward elimination variable selection. We performed these analyses for each type of abortion separately; the results were similar in terms of effect sizes and levels of significance. Hence, we performed one regression for all of the data (including all types of abortion). The analyses were performed using Stata software (V.11.2) and Microsoft Excel (2007).

In this study, 222 women with a history of abortion in the previous year, including elective, medical and spontaneous abortions (74 cases of each type), were recruited. The mean (SD) age of elective, medical and spontaneous abortion cases was 31.4 (7.8), 29.0 (5.1) and 29.1 (6.5), respectively, and the respondents' mean years of education were 13.9, 12.6 and 11.8 years, respectively. The employment percentages were 31.1, 23.0 and 14.9 for respondents who had had elective, medical and spontaneous abortions, respectively. While all of the women with medical and spontaneous abortions were married, the corresponding figure was 82.4% for elective abortions; 9.5% of these participants were single, and 8.1% were divorced or widowed. While pregnancies ending in spontaneous and medical abortions were mainly intended (90.5% and 81.1%, respectively), most pregnancies terminated by elective abortion were unintended, with some of those being unwanted (31.1%) and mistimed (27.1%) pregnancies ( table 2 ). Elective abortions were conducted mainly with the agreement of both parents (66.2%). However, 31.1% were undertaken based only on the mother's wishes, and, in one-third of these cases, the MIP was not informed about the abortion. The remainder of the abortions were performed based only on the wish of the MIP (2.7%).

Table 2

Elective abortion visibility divided by the reason for abortion

*Unintended pregnancy.

†Pregnancy outside of marriage.

‡Pregnancy in girls whose marriages are legally recorded but they do not yet share accommodation with their husbands.

§Intended pregnancy.

¶Not calculated because of small sample size.

The number of family members in the participants' social networks totalled 25 974, consisting of 60% adults. Of the adults, 20% were immediate family members and 80% were extended family members. The corresponding figure for non-family adults was 6609. The average percentage of each subgroup in a participant's active social network was husband 1%, consanguineal family 42%, affinal family 27%, and non-family members 30%. The sex ratio of the participants' active social network was 48% male to 52% female ( table 1 ).

The visibility (95% CI) of elective, medical and spontaneous abortion was 8% (6% to 10%), 60% (54% to 66%) and 50% (43% to 57%), respectively ( figure 1 A). All abortion types were much more visible to husbands than to other members of the active social network (in the case of elective abortion, the difference between husbands and other members of the network was much higher than for the other two types of abortion) ( figure 1 B). The visibility of all abortion types was lower for non-family than for family, except for elective abortions, which were more visible to non-family than to family ( figure 1 C). The visibility of all types of abortion was higher for consanguineal family than for affinal family (although this difference was smaller for spontaneous abortion) ( figure 1 C); among consanguineal family members, all abortion types were more visible to immediate family than to extended family (but in elective cases, this difference was much higher than for the other two types) ( figure 1 D). With the exception of the husband, abortion was always more visible to women than to men in participants' networks ( figure 1 B). The difference in visibility between women and men who were immediate consanguineal family was not sizable for medical and spontaneous abortions, but the difference was high for elective abortion (55% for women vs 13% for men), meaning mothers and sisters were more likely to know about elective abortions than fathers and brothers.

In the univariate analysis, the visibility of abortion was not significantly (at the 0.2 level) associated with the participant's age and education or with the husband's occupation and education (results not shown). Therefore, these variables were not included in the multifactorial analysis. The number of children did not remain significant after adjustment for other variables in the multifactorial analysis.

The final multivariate model—after being adjusted for potential factors and backward elimination—showed that non-elective abortions were approximately twice as visible as elective ones (medical abortion was 98% (95% CI 1.58 to 2.48) and spontaneous abortion 96% (95% CI 1.56 to 2.46) more visible than elective abortion). In addition, the abortions of unmarried women were 66% (95% CI 0.22 to 0.52) less visible than those of married women. The abortions of self-employed women were 14% (95% CI 1.03 to 1.27) more visible than those of housewives. Abortions of intended pregnancies were 17% (95% CI 0.70 to 0.98) less visible than those of UPs, yet increasing the number of UPs decreased visibility (1 UP vs 0 UPs was 17% (95% CI 0.72 to 0.95) less visible and two or more UPs vs 0 UPs was 30% (95% CI 0.57 to 0.88) less visible).

Among acquaintances, compared with men, women were 19% (95% CI 1.13 to 1.26) more informed about abortions. Compared with non-family members in active social networks, the husband, immediate family members and extended family members were 91% (95% CI 1.69 to 2.18), 47% (95% CI 1.34 to 1.62) and 13% (95% CI 1.03 to 1.24) more informed about abortions ( table 3 ).

Table 3

Determinants of abortion visibility

AV, abortion visibility; RR, rate ratio; Unmarried, single/divorced/widowed.

This study found that the visibility of abortion, particularly elective abortion, was very low in Kerman in 2015. Of all members of the participants' active social networks, their husbands had a very high probability of being informed about the abortion. In addition, women and consanguineal family were more likely to be informed of the abortion than men and affinal family. Non-family members had a low probability of being informed, yet non-family had the highest possibility of being informed of elective abortions. Other factors affecting visibility were marital and employment status, as well as the type of pregnancy and frequency of UPs.

To the best of our knowledge, only one study in the world has estimated the visibility of abortion, but it used a different method: Rastegari and coworkers 19 used gynaecologists’ and midwives' guesses to calculate the visibility rate of abortion in Iran. Their study estimated visibility at 20–34% for elective abortion (termed abortions without medical indications), which was higher than our estimate, and 43–75% for other types of abortion (termed abortions with medical indications), which was similar to our estimate but had wide variability and did not differentiate between spontaneous and medical abortions. Although that study was the first attempt to estimate AV, it is reasonable to suppose that this issue is best sourced not from clinicians but by the woman herself, as she knows far more about her own pattern of disclosure. Another study in Iran used a method similar to that used in this study to estimate the visibility of cancer, finding a cancer visibility rate of 86%. 18 Other studies have estimated visibilities of 1.4 for MSM in Japan, 76 for IDUs in Brazil, and 24, 57 and 34 for MSM, IDUs and CSWs, respectively, in Ukraine. 12 16 17 The observed differences in these visibility rates indicate variation in the stigma of each behaviour in different cultures. The visibility rate of abortion in this study was similar to, or even lower than, those of other stigmatised behaviours, which highlights that abortion is highly stigmatised in the study setting.

The rest of the literature has mainly compared self-reporting and medical record data, and they have also concluded that abortions are under-reported. 21 22 These studies have shown that most women who have a history of abortion (listed in their medical records) did not self-report the abortion. This is the case even in countries where there are no legal restrictions for abortion. 7 Abortion under-reporting, which could be an indicator of low AV, in addition to the sensitive nature of sexual matters such as abortion, is also due to social, cultural, religious and legal factors that are more pertinent in traditional, religious countries such as Iran. In Iran, sexual relationships outside marriage are highly stigmatised, particularly for women. 9 Hence, the stigma related to abortion differs by marital status. Married women are stigmatised for elective abortion because it is against religious law. 9 However, women who experience non-elective abortions could be labelled infertile or could be blamed by others. 23 24 In Iran, the expression ‘ojagh koor’ (which has a negative meaning and is pejorative) is applied to both men and women who are unable to have children. ‘This metaphoric expression is according to popular belief in Iran that an infertile couple will never have a house with a ‘warm kitchen’ (ojaghe koor)’. 23 As a result, many women hide their abortions from acquaintances. This might also explain the low visibility of intended pregnancies leading to abortion compared with UPs. On the other hand, a higher number of previous UPs decreased the level of visibility. Recently, Iranian families have tended to consider fewer children as a sign of higher social class; 10 therefore, informing others about repeated UPs could decrease their social standing and lead to humiliation for violating childbearing norms.

Unmarried women (single, divorced and widowed) tell a very different story; having sexual relationships outside marriage is the main reason for the stigma attached to abortions, regardless of the type. This stigma can be very devastating and can disrupt a person's life. For example, a pregnant single woman may lose the chance to be married and have a normal social life. This could even disgrace her family name. She is very likely to be blamed, rejected and subjected to physical or mental punishment by acquaintances. 9 The social stigma of abortion for unmarried women is much heavier than for married women, which explains the lower visibility in these women. Severe social stigma exists even for girls whose marriages are legally recorded but who do not yet share accommodation with their husbands and during which they still live with their parents (the ‘Aghd’ period). In this period, there is no legal restriction against having a sexual relationship with her husband and getting pregnant; however, from a traditional point of view, they should abstain from sexual activity until they share accommodation. 9 These norms could explain the low visibility observed for this group. Furthermore, current Iranian rules based on Islamic laws prohibit elective abortion, and there are legal penalties for reproductive health providers who perform abortions. 3 9 A new Iranian population growth policy 10 could enforce such restrictions, which could ultimately decrease AV further.

The visibility of abortion was significantly higher among self-employed women, those with no affiliation with the government. As abortion is unlawful, women who have government jobs might perceive it as a threat to their job, which would lead them not to disclose it and be more conservative than self-employed women. Moreover, in self-employed professions, such as hair styling, women might have more opportunities to speak with other women and to talk about personal issues 25 than do women in government jobs.

The highest AV was observed for husbands. This is due to his special position as the MIP and the provider of support for the woman in such a situation. 9 However, ∼10% of elective abortions were performed without informing the MIP. This could be explained by the father's religious prejudice or by different levels of involvement in the tasks of childbearing: in many societies, such as Iran, women are more often thought to be solely responsible for this task. 9 Other studies conducted in Iran have also found that men were less satisfied with their wives' terminating UPs and that women who had failed to gain their husband's consent were likely to obtain an abortion without. 9 With the exception of their husband, the women in this study were more likely to disclose their abortion to women than men. Other studies report that, in general, female-to-female disclosure is higher than female-to-male disclosure. 26 Moreover, the shame of disclosing sexual and reproductive issues to members of the opposite gender contributes to different levels of disclosure between men and women. Furthermore, the women disclosed their abortions to more consanguineal family members than affinal family members, which might be due to women being more likely to be blamed by affinal families than by consanguineal families. 24 27 However, in the case of elective abortions, the participants were more likely to disclose their abortion to non-family members than to family members, even consanguineal family members (which are the closest family members). This difference may be because women trust their peers and very close friends enough to disclose sensitive personal issues; 28 29 in addition, family members might be more likely than non-family members to want to prevent women from obtaining an elective abortion.

Strengths and limitations

We acknowledge that our study has several limitations; the most important challenge in this study was the low participation rates of women who had had abortions and reproductive health providers. Reproductive health providers were often unwilling to cooperate because of the severe legal restrictions on abortion in Iran. As a result, we tried to encourage their participation using different strategies, such as holding meetings to explain the study method, assuring them of confidentiality and anonymity protection, and providing financial incentives. We also had difficulty obtaining women's consent to participate, particularly in cases of elective abortion and for unmarried women. Sometimes women who had been introduced by the midwife or gynaecologist as a patient who had obtained an elective abortion denied the intentionality of the abortion; the midwife or gynaecologist had to reassure them of the confidentiality of the study.

Furthermore, it is very common in Iranian society to use herbal medicines that do not require prescriptions. We have not assessed these traditional methods of abortion, nor have we considered abortions performed by non-medical providers or by the woman herself. The visibility of abortion in such cases might differ from that of other cases, perhaps affected by factors such as low socioeconomic status because of the high costs of elective abortion services.

We also note two points for consideration, although they do not affect the level of visibility. The first is the possibility of recording elective abortions as non-elective (if the physician and patient agree to do so). 9 However, this did not affect our results for visibility because these women pretended their abortion was medical, and their disclosing behaviour is similar to that of women who had had a medical abortion. The second point is that some married women who became pregnant outside of marriage and thus obtained an elective abortion may have reported it as an unwanted or mistimed pregnancy. This could affect the classification of the reasons for abortion but not the visibility.

Despite these limitations, this is one of the rare studies estimating AV in Iran, or even the world. It can be considered a first step in highlighting the extent of the problem in a developing and traditional society, and even beyond such societies; the results could direct policymakers to appropriate policies by providing a more realistic picture of abortion.

In this study, AV was low, but differed among social network members and by the type of abortion. This difference might be explained by social and cultural norms and the stigma surrounding abortion. The low visibility rate that we observe might explain the low estimates of abortion rates found in other studies, and this issue should be considered by policymakers when planning women's healthcare services.

Contributors: MZ collected the data. MZ, MRB and AAH analysed the data. MZ and FZ wrote the manuscript. All the authors approved the final version of the manuscript.

Competing interests: None declared.

Ethics approval: Ethics committee of Kerman University of Medical Sciences.

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

Data sharing statement: No additional data are available.

1 Blood-related family.

2 Marriage-related family, also called in-laws—that is, the husband's relatives.

The risk of missed abortion associated with the levels of tobacco, heavy metals and phthalate in hair of pregnant woman: A case control study in Chinese women

Affiliation.

• 1 School of Public Health, Guangxi Medical University Department of Gynaecology and Obstetrics, The People Hospital of Guangxi Zhuang Autonomous Region Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Guangxi Medical University Nanning Center of Disease for Control, Nanning School of Public and Managment, Youjiang Medical University for Nationalites, Baise, Guangxi Yongning Center of Disease of Control of Nanning, Yongning Region, Nanning, China.
• PMID: 29390543
• PMCID: PMC5758245
• DOI: 10.1097/MD.0000000000009388

To assess the association between exposure to the tobacco, heavy metals and phthalate on early pregnancy and missed abortion.42 women with missed abortion and 57 matched controls (women with normal pregnancies) were recruited between March and May 2012, from the Department of Gynecology and Obstetrics, First Affiliated Hospital of Guangxi Medical University and the People Hospital of Guangxi Zhuang Autonomous Region. The questionnaire survey was carried on to learn about the basic conditions, as well as smoking history of all participants. The levels of tobacco, heavy metal, and phthalate exposure were compared between the 2 groups by measuring nicotine, cocaine, cadmium (Cd), manganese (Mn), plumbum (Pb) and dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), di-2-ethyl hexyl phthalate (DEHP) in the hair samples.Out results showed that significant differences in age (P = .042), premarital examination (P = .041), passive smoking (P = .021), and heavy metal exposure (P = .022) were found in the case group compared to the control. In addition, the concentration of nicotine (P = .037), cotinine (P = .018), Cd (P = .01), Pb (P = .038) and DEHP (P = .001) in the hair were significantly higher in the case group. Furthermore, logistic analysis revealed that age [Odds Ratio (OR) 1.172, 95% confidence interval (CI) 1.036-1.327], Cd (OR 8.931, 95% CI 2.003-39.811), Cotinine (OR 4.376, 95% CI 1.159-16.531), DEHP (OR 1.863, 95% CI 1.103-3.146) were important factors contributing to the missed abortion (P < .05).It was demonstrated that high gestational age, passive smoking, heavy metals, and the phthalate exposure were the risk factors for missed abortion, while the premarital health examination was a protective factor. Avoiding these harmful substances before getting pregnant and during the early stages of pregnancy, might help prevent missed abortions.

Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Publication types

• Observational Study
• Abortion, Missed / etiology*
• Case-Control Studies
• Environmental Exposure / adverse effects*
• Environmental Exposure / analysis
• Environmental Pollutants / analysis
• Environmental Pollutants / toxicity*
• Hair / chemistry
• Logistic Models
• Metals, Heavy / analysis
• Metals, Heavy / toxicity*
• Middle Aged
• Nicotine / analysis
• Nicotine / toxicity*
• Phthalic Acids / analysis
• Phthalic Acids / toxicity*
• Protective Factors
• Risk Factors
• Tobacco Smoke Pollution / adverse effects*
• Tobacco Smoke Pollution / analysis
• Environmental Pollutants
• Metals, Heavy
• Phthalic Acids
• Tobacco Smoke Pollution

New Rules for Pregnant Workers Fairness Act Include Divisive Accommodations for Abortion

Workers are entitled to time off and other job accommodations for abortions under the Pregnant Workers Fairness Act, according to finalized federal regulations published Monday

Jeff Roberson

FILE - An exam room is seen inside Planned Parenthood on March 10, 2023, in Fairview Heights, Ill. Workers are entitled to workplace accommodations for abortions and some pregnancy-related conditions under the Pregnant Workers Fairness Act, according to federal regulations published Monday, April 15, 2024. (AP Photo/Jeff Roberson)

NEW YORK (AP) — Workers are entitled to time off and other job accommodations for abortions — along with pregnancy-related medical conditions like miscarriage, stillbirth and lactation — under the Pregnant Workers Fairness Act, according to finalized federal regulations published Monday.

The regulations provide guidance for employers and workers on how to implement the law, which passed with robust bipartisan Congressional support in December 2022 but sparked controversy last year when the Equal Employment Opportunity Commission included abortions in its draft rules. The language means that workers can ask for time off to obtain an abortion and recover from the procedure.

The EEOC says its decision to keep the abortion provisions in its final rules, despite criticism from some conservatives, is consistent with its own longstanding interpretation of Title VII, as well as court rulings. The federal agency added that the new law does not obligate employers or employer-sponsored health plans to cover abortion-related costs, and that the type of accommodation that most likely will be sought under the Pregnant Workers Fairness Act regarding an abortion is time off to attend a medical appointment or for recovery, which does not have to be paid.

The act requires most employers with 15 or more employees to provide "reasonable accommodations" for a worker’s known limitations related to pregnancy, childbirth, or related medical conditions — including fertility and infertility treatments in some cases — unless the accommodation will cause the employer an undue hardship. The EEOC's regulations will go into effect on June 18.

Labor advocates hailed the new law as especially important for women of color who are most likely to work in low-wage, physically demanding jobs but are often denied accommodations for everything from time off for medical appointments to the ability to sit or stand on the job. Major business groups also supported the law, citing the need for clarity about the accommodations that employers are required to give pregnant workers.

Photos You Should See - April 2024

“No one should have to risk their job for their health just because they are pregnant, recovering from childbirth, or dealing with a related medical condition,” said EEOC Chair Charlotte A. Burrows on Monday.

But Republican lawmakers and anti-abortion activists denounced the EEOC’s inclusion of abortion after the agency first released its proposed rule in August for a monthslong public commentary period. Abortion rights proponents, meanwhile, applauded the provision as critical at time when abortion rights have been curtailed in many states following the U.S. Supreme Court’s 2022 decision to overturn Roe v. Wade. The EEOC is composed of three Democratic commissioners and two Republican commissioners.

Sen. Bill Cassidy of Louisiana, the lead Republican sponsor of the Pregnant Workers Fairness Law, accused the Biden administration on Monday of "shocking and illegal" disregard of the legislative process to promote a political agenda. The Alliance Defending Freedom, a conservative Christian legal organization, said the Biden administration was trying to “smuggle an abortion mandate” into the law.

But in comments submitted to the EEOC, the American Civil Liberties Union applauded the agency for “recognizing that abortion has for decades been approved under the law as a ‘related medical condition’ to pregnancy that entitles workers to reasonable accommodations, including time off to obtain abortion care.”

The EEOC said it had received 54,000 comments urging the commission to exclude abortion from its definition of medical condition related to pregnancy, but it also received 40,000 comments supporting its inclusion. While the commission said it understood that both sides were expressing “sincere, deeply held convictions,” it cited numerous federal cases that it said supported its interpretation that abortion is a pregnancy-related condition deserving of protection.

The new rules include extensive details on the types of accommodations that pregnant workers can request, from temporary exemption from jobs duties like heavy lifting to considerations for morning sickness.

Women's right advocates had campaigned for years for the law, arguing that the 1978 Pregnancy Discrimination Act offered inadequate protection for pregnant workers. The 1978 law, which amended Title VII of the Civil Rights Act of 1964, prohibited discrimination on the basis of pregnancy and marked a major shift for gender equality at time when pregnant women were routinely denied or pushed out of jobs.

But in order to receive workplace accommodations, pregnant women had to demonstrate that co-workers had received similar benefits for comparable needs, since the act stated only that pregnant workers must be treated similarly to other employees, not that they deserved special consideration. That put a burden of proof that many women found impossible to meet, forcing them to work in unsafe conditions or quit their jobs, according to A Better Balance , one of the most vocal advocates for the Pregnant Workers Fairness Act.

The new law makes clear that that pregnant workers are entitled to accommodations to keep doing their jobs, mirroring the process for workers with disabilities. It places the burden on employers to prove “undue hardship” if they deny requests for modifications.

The EEOC typically handles between 2,000 and 4,000 pregnancy discrimination charges a year, many involving denial of workplace accommodations. A study conducted by A Better Balance found that in two-thirds of pregnancy discrimination cases that followed the 2015 Supreme Court ruling, courts determined the employers were allowed to deny accommodations under the Pregnancy Discrimination Act.

In a prepared statement, A Better Balance Co-President Dina Bakst applauded the EEOC “for issuing robust final regulations that appropriately recognize the broad scope of the Pregnant Workers Fairness Act.”

The Associated Press’ women in the workforce and state government coverage receives financial support from Pivotal Ventures. AP is solely responsible for all content. Find AP’s standards for working with philanthropies, a list of supporters and funded coverage areas at AP.org .

Copyright 2024 The  Associated Press . All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

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