Unexposed Pregnancies Research Articles

Lithium Exposure During Pregnancy and the Postpartum Period: A Systematic Review and Meta-Analysis of Safety and Efficacy Outcomes.

Uncertainty surrounds the risks of lithium use during pregnancy in women with bipolar disorder. The authors sought to provide a critical appraisal of the evidence related to the efficacy and safety of lithium treatment during the peripartum period, focusing on women with bipolar disorder and their offspring. The authors conducted a systematic review and random-effects meta-analysis assessing case-control, cohort, and interventional studies reporting on the safety (primary outcome, any congenital anomaly) or efficacy (primary outcome, mood relapse prevention) of lithium treatment during pregnancy and the postpartum period. The Newcastle-Ottawa Scale and the Cochrane risk of bias tools were used to assess the quality of available PubMed and Scopus records through October 2018. Twenty-nine studies were included in the analyses (20 studies were of good quality, and six were of poor quality; one study had an unclear risk of bias, and two had a high risk of bias). Thirteen of the 29 studies could be included in the quantitative analysis. Lithium prescribed during pregnancy was associated with higher odds of any congenital anomaly (N=23,300, k=11; prevalence=4.1%, k=11; odds ratio=1.81, 95% CI=1.35-2.41; number needed to harm (NNH)=33, 95% CI=22-77) and of cardiac anomalies (N=1,348,475, k=12; prevalence=1.2%, k=9; odds ratio=1.86, 95% CI=1.16-2.96; NNH=71, 95% CI=48-167). Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion (N=1,289, k=3, prevalence=8.1%; odds ratio=3.77, 95% CI=1.15-12.39; NNH=15, 95% CI=8-111). Comparing lithium-exposed with unexposed pregnancies, significance remained for any malformation (exposure during any pregnancy period or the first trimester) and cardiac malformations (exposure during the first trimester), but not for spontaneous abortion (exposure during the first trimester) and cardiac malformations (exposure during any pregnancy period). Lithium was more effective than no lithium in preventing postpartum relapse (N=48, k=2; odds ratio=0.16, 95% CI=0.03-0.89; number needed to treat=3, 95% CI=1-12). The qualitative synthesis showed that mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations. The risk associated with lithium exposure at any time during pregnancy is low, and the risk is higher for first-trimester or higher-dosage exposure. Ideally, pregnancy should be planned during remission from bipolar disorder and lithium prescribed within the lowest therapeutic range throughout pregnancy, particularly during the first trimester and the days immediately preceding delivery, balancing the safety and efficacy profile for the individual patient.

Birth outcomes in women who have taken adalimumab in pregnancy: A prospective cohort study.

BackgroundInformation is needed on the safety of adalimumab when used in pregnancy for the treatment of certain autoimmune diseases.Methods and findingsBetween 2004 and 2016, the Organization of Teratology Information Specialists Research Center at the University of California San Diego conducted a prospective controlled observational cohort study in 602 pregnant women who had or had not taken adalimumab. Women in the adalimumab-exposed cohort had received at least one dose of the drug in the first trimester for the treatment of rheumatoid arthritis or Crohn’s Disease (N = 257). Women in the disease comparison cohort had not used adalimumab in pregnancy (N = 120). Women in the healthy comparison cohort had no rheumatic or inflammatory bowel diseases (N = 225). Women and their infants were followed to one year postpartum with maternal interviews, medical records abstraction, and physical examinations. Study outcomes were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, pre and post-natal growth deficiency, serious or opportunistic infections and malignancies. 42/602 (7.0%) of pregnancies were lost-to-follow-up. 22/221 (10.0%) in the adalimumab-exposed cohort had a live born infant with a major birth defect compared to 8/106 (7.5%) in the diseased unexposed cohort (adjusted odds ratio 1.10, 95% confidence interval [CI] 0.45 to 2.73). Women in the adalimumab-exposed cohort were more likely to deliver preterm compared to the healthy cohort (adjusted hazard ratio [aHR] 2.59, 95% CI 1.22 to 5.50), but not compared to the diseased unexposed cohort (aHR 0.82, 95% CI 0.66 to 7.20). No significant increased risks were noted with adalimumab exposure for any other study outcomes.ConclusionsAdalimumab exposure in pregnancy compared to diseased unexposed pregnancies was not associated with an increased risk for any of the adverse outcomes examined. Women with rheumatoid arthritis or Crohn’s Disease were at increased risk of preterm delivery, irrespective of adalimumab exposure.

Pregnancy Outcomes After Human Papillomavirus Vaccination in Periconceptional Period or During Pregnancy: A Systematic Review and Meta-analysis

ABSTRACT Background: National immunization schedules in many countries recommend HPV vaccination for females until the age of 26 years, and thus substantial numbers with reproductive age may be exposed to HPV vaccines. Objective: To assess whether inadvertent HPV vaccine exposures in the periconceptional period or during pregnancy were associated with increased risks for adverse pregnancy outcomes. Search strategy: A search of PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), and WanFang databases (until March 31, 2019) was performed. Selection criteria: Studies that assess the risk of adverse pregnancy outcomes in HPV vaccine exposed/unexposed pregnancies were included. The adverse pregnancy outcomes included spontaneous abortion, stillbirth, small for sestational age, preterm birth, and birth defects. Data collection and analysis: The pooled relative risk (RR) was applied for the effect measure of the study. RRs and 95% confidence interval (CI) were measured when the paper did not report the effect. Heterogeneity between studies was assessed using the Cochrane’s Q and I2 statistics. Main results: Of 374 identified citations, 8 met inclusion criteria. Compared with the unexposed pregnancies, HPV vaccine exposed pregnancies were associated with no higher risk for spontaneous abortion (RR, 0.99 [95% CI, 0.90 to 1.08]); stillbirth (RR, 1.16 [95% CI, 0.71 to 1.90]); small for gestational age (RR, 0.96 [95% CI, 0.86 to 1.07]); preterm birth (RR, 1.04 [95% CI, 0.91 to 1.18]); or birth defects (RR, 1.18 [95% CI, 0.97 to 1.43]). Conclusions: Inadvertent bivalent/quadrivalent HPV vaccination during pregnancy was not associated with significantly greater risks of adverse pregnancy outcomes.

Gestational Exposure to Benzodiazepines, 1: The Risk of Spontaneous Abortion Examined Through the Prism of Research Design.

A recent, large, case-control study found that, after adjusting for measured confounds, early gestational exposure to benzodiazepines was associated with a nearly doubled odds of spontaneous abortion. The risks differed little between pregnancies exposed to short- and long-acting benzodiazepines. The risks were elevated for all benzodiazepines for which data were adequate for analysis. The risks were higher with higher daily doses. These findings indicate that early gestational exposure to benzodiazepines is a marker for the risk of spontaneous abortion. These findings are not evidence for a cause-effect relationship because analyses in studies such as this can adjust for only measured confounds; therefore, unmeasured, inadequately measured, and unknown confounds will continue to contaminate the interpretation of findings. It follows, therefore, that replication of the study with the same study design using data extracted from other databases will serve no purpose. So, innovative research designs should be considered, such as the examination of risk associated with benzodiazepine exposure in the year before pregnancy, examination of risk in previously unexposed pregnancies, examination of risk in discordant sibling pairs, and examination of risk associated with paternal exposure. Such research designs have the potential to indirectly partially address unmeasured and unknown confounds, including those related to genetics and the family environment.

Chasing the ongoing consequences of the cascade of intervention during labour and birth

Previous research reported greater risk of adverse perinatal outcomes associated with first trimester exposure to angiotensin converting enzyme inhibitors (ACEIs) in comparison to unexposed pregnancies among non-hypertensive women. We examined the relationship between first trimester exposure to ACEIs and angiotensin receptor blockers (ARBs), and maternal and perinatal outcomes, whilst controlling for the underlying hypertension.We performed a population-based cohort study among 130,061 pregnancies resulting in birth in NSW, Australia between 2005 and 2012. Birth data were linked to hospital discharge and pharmaceutical dispensing records. After restricting to women with chronic hypertension, 67 and 73 pregnancies exposed to ACEIs and ARBs respectively during the first trimester were compared with 316 pregnancies exposed to methyldopa.Preterm delivery, caesarean section, low birth weight, small for gestational age and Apgar score <7.Compared to pregnancies exposed to methyldopa, the adjusted odds ratio (aOR) for ACEI exposure was 0.5 (95% CI: 0.2–1.1) for preterm delivery, 1.6 (0.8–3.1) for caesarean section, 0.6 (0.2–1.3) for LBW and 0.8 (0.4–1.9) for SGA. The corresponding aORs and confidence intervals for ARB exposure were 0.7 (0.3–1.5), 1.2 (0.6–2.6), 1.3 (0.7–2.6), and 1.2 (0.6–2.4).No association between early pregnancy exposure to ACEIs and ARBs and perinatal outcomes was observed, however, the possibility of an association cannot be ruled out due to limited power. Nonetheless, this study suggests that the magnitude of risk is smaller than that reported previously.

Pregnancy outcomes in DMARD-exposed patients with juvenile idiopathic arthritis-results from a JIA biologic registry.

To investigate the courses and outcomes of pregnancies involving JIA patients who were exposed to DMARDs. In the Juvenile arthritis MTX/Biologics long-term Observation study, pregnant patients or male patients with pregnant partners were identified. Standardized patient interviews were conducted, and the course and outcome of pregnancy were assessed. Prospectively collected physician- and patient-reported data were also considered in the analysis. The study sample included 152 pregnancies in 98 women with JIA and 39 pregnancies involving 21 male patients as partners. The majority of patients had polyarticular-onset/-course JIA (61%). The average age of patients at first pregnancy was 24.1 (4.5) years, and their mean disease duration was 13.8 (5.9) years. Patients had been exposed to DMARDs for 9.5 (5.6) years, and 90% of these patients had received biologics before. Half of the pregnancies occurred during DMARD exposure, mostly with etanercept. Significant differences in pregnancy outcomes between DMARD-exposed and -unexposed pregnancies were not observed. Spontaneous abortion (13.1%) and congenital anomaly (3.6%) rates were not suggestive of increased risk compared with expected background rates. However, the rates of premature birth (12.3%) and caesarean section (37.7%) were slightly above those in the German birthing population. The disease activity of female patients remained relatively stable in pregnancy, with mean cJADAS-10 scores of 5.3, 7.1 and 5.6 in each trimester, respectively. Young adults with JIA often become pregnant or become fathers of children while still being treated with DMARDs. Data suggest no increased risk of major adverse pregnancy outcomes.

Identifying pregnancies in insurance claims data: Methods and application to retinoid teratogenic surveillance.

The purpose of the study is to develop an algorithm to identify pregnancies in administrative databases and apply it to assess pregnancy rates and outcomes in women prescribed isotretinoin or tretinoin. Using the 2011 to 2015 Truven Health MarketScan Database, we identified pregnancies, including losses and terminations. In a cohort design, nonpregnant women filling a prescription for isotretinoin or tretinoin were matched to five women without either prescription. Women were followed for 365 days or until conception, medication discontinuation, or enrollment discontinuation ("prescription episode"). Rates of pregnancy, risks of pregnancy losses, and prevalence of infant malformations at birth were assessed by exposure. We identified 2 179 192 livebirths, 8434 stillbirths, 2521 mixed births, 415 110 spontaneous abortions, 124 556 elective terminations, and 8974 unspecified abortions. There were 86 834 isotretinoin and 973 587 tretinoin episodes, matched to 5 302 105 unexposed women. Pregnancy rates were 3 (isotretinoin), 19 (tretinoin), and 34 (unexposed) per 1000 person-years. Risk of spontaneous pregnancy losses were similar; however, terminations were more common in the isotretinoin-exposed (28% [95% CI: 21%-36%]) than the tretinoin-exposed (10% [95% CI: 9%-11%]) or unexposed pregnancies (6%). Malformations occurred in 4.5% (95% CI: 3.5%-5.6%) of the tretinoin-exposed pregnancies and 4.2% of the unexposed pregnancies (adjusted odds ratio: 1.16 [95% CI: 0.85-1.58]); isotretinoin-exposed births were too few to assess malformations. Administrative databases can complement risk evaluation and mitigation strategies (REMS) for known teratogens and contribute to safety surveillance for other medications. Here, isotretinoin-exposed pregnancy rates were low, but existent, and many pregnancies were terminated. Tretinoin exposure was not associated with a meaningfully elevated risk of losses or malformations as compared with unexposed pregnancies.

In utero exposure to antibiotics and risk of congenital malformations: a population-based study

Antibiotics are commonly prescribed during pregnancy. Although the safety of most penicillins is well established, some controversy and uncertainty are associated with the use of other commonly prescribed antibiotics. To determine the risk of congenital malformations following first-trimester in utero exposure to 10 commonly prescribed antibiotics in Denmark. This was a cohort study comprising all singleton liveborn children in Denmark between 2000 and 2015. Data on malformations were collected through 2016. Merging validated and comprehensive populationwide Danish healthcare and civic registries, we merged data on pregnancy, prescription drugs purchases during first trimester and congenital malformations. Using logistic regression, we calculated the odds ratio for congenital malformations (any), major congenital malformations, and cardiac congenital malformations for the 10 most commonly prescribed antibiotics (excluding 4 penicillins that served as control). In the primary analysis, the exposed cohort was compared to a cohort exposed to any of 4 penicillins considered safe during pregnancy (ampicillin, pivampicillin, benzylpenicillin, and phenoxymethylpenicillin). In sensitivity analysis, the exposed cohort was compared to an unexposed cohort. Covariate adjustments were made for maternal age at delivery, year of delivery, parity, pre-pregnancy body mass index, smoking, educational status, employment status, and annual personal income. We found no increased risk of congenital malformations to be related to first-trimester in utero exposure to the 10 most commonly prescribed antibiotics in Denmark compared to a cohort of pregnant women exposed to penicillins that are considered safe during pregnancy. Compared to unexposed pregnancies, small increased risks for major malformations and cardiac malformations were apparent for pivmecillinam (odds ratio, 1.13; confidence interval, 1.06-1.19; and odds ratio, 1.15; confidence interval, 1.04-1.28, respectively), sulfamethizole (odds ratio, 1.15; confidence interval, 1.07-1.24; and odds ratio, 1.22; confidence interval, 1.07-1.39, respectively), and azithromycin (odds ratio, 1.19, confidence interval, 1.03-1.38; and odds ratio, 1.29, confidence interval, 0.99-1.67, respectively). In this large populationwide cohort study, we found, with a high degree of precision, no increased risk of congenital malformations following first-trimester exposure to 10 commonly prescribed systemic antibiotics.

Abstract TP152: Maternal Morbidity Outcomes in Moyamoya Syndrome in New York State

Background: Pregnancy is associated with increased stroke risk in young women. Idiopathic moyamoya syndrome (IMMS) is a rare condition characterized by progressive narrowing of large cerebral arteries resulting in flimsy collaterals prone to rupture or thrombosis. Data are limited on pregnancy outcomes in women with IMMS. We hypothesized that IMMS would be associated with increased pregnancy morbidity, including stroke. Methods: Using the New York State Department of Health Statewide Planning and Research Cooperative System data from 2000-2014 we identified all women aged 18 and older with diagnoses of IMMS (ICD-9 437.5) who had hospitalizations for delivery at any time either prior, concomitant or subsequent to IMMS diagnosis. We considered a pregnancy to be IMMS-exposed if it occurred ≤ 3 years prior to, or any time after, IMMS diagnosis. We defined pregnancy morbidity as admission within 1 year of delivery for any of the Center for Disease Control and Prevention’s severe maternal morbidity indicators, including stroke. We compared the morbidity of IMMS-exposed pregnancies to unexposed pregnancies occurring in the same cohort &gt;3 years prior to IMMS diagnosis. We used conditional logistic regression to calculate odds ratio (OR) and 95% confidence intervals (95%CI), adjusting for women with both exposed and unexposed pregnancies. Results: We identified 134 patients with IMMS, with 117 exposed pregnancies and 147 unexposed pregnancies. Severe maternal morbidity was higher for exposed pregnancies (33.3% vs 19.0%, OR: 2.1, 95%CI: 1.2-3.7). After adjusting for maternal morbidity, exposed pregnancies had more caesarean sections (44.4% vs 23.0%, OR: 4.2, 95%CI: 2.3-7.6). Complications occurring during and after exposed pregnancies included stroke, acute myocardial infarction, cardiac arrest, cardiac arrhythmia requiring conversion, eclampsia, pulmonary edema, and adult respiratory distress syndrome. Conclusion: Pregnancies within 3 years prior or any time after IMMS diagnosis had increased maternal morbidity within 1 year of delivery. Prospective studies are needed to better characterize increased maternal risks for women with moyamoya syndrome and develop preventive strategies.

Pregnancy outcome in women undergoing liver biopsy during pregnancy: A nationwide population-based cohort study.

Apart from a moderately increased risk of preterm birth and small for gestational age, there was no association between liver biopsy during pregnancy and adverse pregnancy outcome; potential excess risks should be weighed against the advantages of having a liver biopsy that may influence clinical management of the patient and indirectly fetal health. (Hepatology 2017).

Risk of preterm delivery and small-for-gestational-age births in women with autoimmune disease using biologics before or during pregnancy: a population-based cohort study

ObjectivesTo assess the risk of preterm delivery and small-for-gestational-age (SGA) births in women with autoimmune diseases using biologics before or during pregnancy.MethodsUsing population-based administrative data in British Columbia, Canada, women...

Placental Complications Associated With Psychostimulant Use in Pregnancy.

To evaluate whether psychostimulants used to treat attention-deficit/hyperactivity disorder (ADHD) are associated with risk of adverse placental-associated pregnancy outcomes including preeclampsia, placental abruption, growth restriction, and preterm birth. We designed a population-based cohort study in which we examined a cohort of pregnant women and their liveborn neonates enrolled in Medicaid from 2000 to 2010. Women who received amphetamine-dextroamphetamine or methylphenidate monotherapy in the first half of pregnancy were compared with unexposed women. We considered atomoxetine, a nonstimulant ADHD medication, as a negative control exposure. To assess whether the risk period extended to the latter half of pregnancy, women who continued stimulant monotherapy after 20 weeks of gestation were compared with those who discontinued. Risk ratios and 95% CIs were estimated with propensity score stratification to control for confounders. Pregnancies exposed to amphetamine-dextroamphetamine (n=3,331), methylphenidate (n=1,515), and atomoxetine (n=453) monotherapy in early pregnancy were compared with 1,461,493 unexposed pregnancies. Among unexposed women, the risks of the outcomes were 3.7% for preeclampsia, 1.4% for placental abruption, 2.9% for small for gestational age, and 11.2% for preterm birth. The adjusted risk ratio for stimulant use was 1.29 for preeclampsia (95% CI 1.11-1.49), 1.13 for placental abruption (0.88-1.44), 0.91 for small for gestational age (0.77-1.07), and 1.06 for preterm birth (0.97-1.16). Compared with discontinuation (n=3,527), the adjusted risk ratio for continuation of stimulant use in the latter half of pregnancy (n=1,319) was 1.26 for preeclampsia (0.94-1.67), 1.08 for placental abruption (0.67-1.74), 1.37 for small for gestational age (0.97-1.93), and 1.30 for preterm birth (1.10-1.55). Atomoxetine was not associated with the outcomes studied. Psychostimulant use during pregnancy was associated with a small increased relative risk of preeclampsia and preterm birth. The absolute increases in risks are small and, thus, women with significant ADHD should not be counseled to suspend their ADHD treatment based on these findings.

Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.

The aim of this study was to determine if there are any differences between the types of pregnancy loss experienced by women who have been prescribed a statin just before or early in pregnancy compared with those who have not. A retrospective cohort study using the General Practice Research Database was carried out. Women aged 10-49years at pregnancy start who received a prescription for a statin in the 3months before and/or during the first trimester of pregnancy were matched to up to 10 pregnancies on age at start date, diabetes and hypertension status before pregnancy. Pregnancies occurring between 1/1/1992 and 31/3/2009 were included. Pregnancy losses were identified and categorised as spontaneous (including miscarriage), induced for medical, other or unknown reasons. Freetext was used to determine the type of loss where this was not clear from the coded medical records. Two hundred eighty-one pregnancies potentially exposed to statins were identified and matched to 2643 unexposed pregnancies. About 54.45% of pregnancies potentially exposed to a statin resulted in a delivery compared with 62.81% of those not exposed. 25.27% of all pregnancies potentially exposed to a statin resulted in a spontaneous loss compared with 20.81% in those not exposed. Using a time to event analysis with exposure as a time-dependent covariate gave an adjusted hazards ratio of 1.64 (95%CI 1.10 to 2.46) of spontaneous pregnancy loss in the statin exposed group. This study is the first to report the differences in types of pregnancy loss following the potential exposure to a statin just before or early in pregnancy. Copyright © 2017 John Wiley & Sons, Ltd.

Outcomes of Pregnancies for Women Undergoing Endoscopy While They Were Pregnant: A Nationwide Cohort Study

Endoscopy is an integral part of the investigation and management of gastrointestinal disease. We aimed to examine outcomes of pregnancies for women who underwent endoscopy during their pregnancy. We performed a nationwide population-based cohort study, linking data from the Swedish Medical Birth Registry (for births from 1992 through 2011) with those from the Swedish Patient Registry. We identified 3052 pregnancies exposed to endoscopy (2025 upper endoscopies, 1109 lower endoscopies, and 58 endoscopic retrograde cholangiopancreatographies). Using Poisson regression, we calculated adjusted relative risks (ARRs) for adverse outcomes of pregnancy according to endoscopy status using 1,589,173 unexposed pregnancies as reference. To consider the effects of disease activity, we examined pregnancy outcomes (preterm birth, stillbirth, small for gestational age, or congenital malformations) in women who underwent endoscopy just before or after pregnancy. Secondary outcome measures included induction of labor, low birth weight (<2500 g), cesarean section, Apgar score <7 at 5 minutes, and neonatal death within 28 days. To consider intrafamilial factors, we compared pregnancies within the same mother. Exposure to any endoscopy during pregnancy was associated with an increased risk of preterm birth (ARR, 1.54; 95% confidence interval [CI], 1.36-1.75) or small for gestational age (ARR, 1.30; 95% CI, 1.07-1.57) but not of congenital malformation (ARR, 1.00; 95% CI, 0.83-1.20) or stillbirth (ARR, 1.45; 95% CI, 0.87-2.40). None of the 15 stillbirths to women with endoscopy occurred <2 weeks after endoscopy. ARRs were independent of trimester. Compared to women with endoscopy <1 year before or after pregnancy, endoscopy during pregnancy was associated with preterm birth (ARR, 1.16) but not with small for gestational age (ARR, 1.19), stillbirth (ARR, 1.11), or congenital malformation (ARR, 0.90). Restricting the study population to women having an endoscopy during pregnancy or before/after, and only analyzing data from women without a diagnosis of inflammatory bowel disease, celiac disease, or liver disease, endoscopy during pregnancy was not linked to preterm birth (ARR, 1.03; 95% CI, 0.84-1.27). Comparing births within the same mother, for which only 1 birth had been exposed to endoscopy, we found no association between endoscopy and gestational age or birth weight. In a nationwide population-based cohort study, we found endoscopy during pregnancy to be associated with increased risk of preterm birth or small for gestational age, but not of congenital malformation or stillbirth. However, these risks are small and likely due to intrafamilial factors or disease activity.

Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes.

Fetal safety of magnetic resonance imaging (MRI) during the first trimester of pregnancy or with gadolinium enhancement at any time of pregnancy is unknown. To evaluate the long-term safety after exposure to MRI in the first trimester of pregnancy or to gadolinium at any time during pregnancy. Universal health care databases in the province of Ontario, Canada, were used to identify all births of more than 20 weeks, from 2003-2015. Magnetic resonance imaging exposure in the first trimester of pregnancy, or gadolinium MRI exposure at any time in pregnancy. For first-trimester MRI exposure, the risk of stillbirth or neonatal death within 28 days of birth and any congenital anomaly, neoplasm, and hearing or vision loss was evaluated from birth to age 4 years. For gadolinium-enhanced MRI in pregnancy, connective tissue or skin disease resembling nephrogenic systemic fibrosis (NSF-like) and a broader set of rheumatological, inflammatory, or infiltrative skin conditions from birth were identified. Of 1 424 105 deliveries (48% girls; mean gestational age, 39 weeks), the overall rate of MRI was 3.97 per 1000 pregnancies. Comparing first-trimester MRI (n = 1737) to no MRI (n = 1 418 451), there were 19 stillbirths or deaths vs 9844 in the unexposed cohort (adjusted relative risk [RR], 1.68; 95% CI, 0.97 to 2.90) for an adjusted risk difference of 4.7 per 1000 person-years (95% CI, -1.6 to 11.0). The risk was also not significantly higher for congenital anomalies, neoplasm, or vision or hearing loss. Comparing gadolinium MRI (n = 397) with no MRI (n = 1 418 451), the hazard ratio for NSF-like outcomes was not statistically significant. The broader outcome of any rheumatological, inflammatory, or infiltrative skin condition occurred in 123 vs 384 180 births (adjusted HR, 1.36; 95% CI, 1.09 to 1.69) for an adjusted risk difference of 45.3 per 1000 person-years (95% CI, 11.3 to 86.8). Stillbirths and neonatal deaths occurred among 7 MRI-exposed vs 9844 unexposed pregnancies (adjusted RR, 3.70; 95% CI, 1.55 to 8.85) for an adjusted risk difference of 47.5 per 1000 pregnancies (95% CI, 9.7 to 138.2). Exposure to MRI during the first trimester of pregnancy compared with nonexposure was not associated with increased risk of harm to the fetus or in early childhood. Gadolinium MRI at any time during pregnancy was associated with an increased risk of a broad set of rheumatological, inflammatory, or infiltrative skin conditions and for stillbirth or neonatal death. The study may not have been able to detect rare adverse outcomes.

Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth.

Vaginal candidiasis is common during pregnancy. Although intravaginal formulations of topical azole antifungals are first-line treatment for pregnant women, oral fluconazole is often used despite limited safety information. To study the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth. Nationwide register-based cohort study in Denmark, 1997-2013. From a cohort of 1,405,663 pregnancies, oral fluconazole-exposed pregnancies were compared with up to 4 unexposed pregnancies matched on propensity score, maternal age, calendar year, and gestational age (based on gestational age at first day of treatment with eligible controls surviving through this date). To test for confounding by indication, pregnancies exposed to intravaginal formulations of topical azoles were used as an additional comparator group. Filled prescriptions for oral fluconazole were obtained from the National Prescription Register. Hazard ratios (HRs) for spontaneous abortion and stillbirth, estimated using proportional hazards regression. Among 3315 women exposed to oral fluconazole from 7 through 22 weeks' gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women. There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95% CI, 1.23-1.77). Among 5382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth (HR, 1.32 [95% CI, 0.82-2.14]). Using topical azole exposure as the comparison, 130 of 2823 women exposed to fluconazole vs 118 of 2823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26-2.07]); 20 of 4301 women exposed to fluconazole vs 22 of 4301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64-2.16]). In this nationwide cohort study in Denmark, use of oral fluconazole in pregnancy was associated with a statistically significant increased risk of spontaneous abortion compared with risk among unexposed women and women with topical azole exposure in pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further.

Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV Vaccine Trial

Objective To examine the effect of the bivalent human papillomavirus (HPV) vaccine on miscarriage.Design Observational long term follow-up of a randomized, double blinded trial combined with an independent unvaccinated population...

Use of Antiepileptic Drugs During Pregnancy and Risk of Spontaneous Abortion and Stillbirth

Objective To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth. Design Population based cohort study. Setting Register based study in Denmark, 1997-2008. Participants 983 305 pregnancies identified in the Danish medical birth register and the Danish national hospital discharge register from 1 February 1997 to 31 December 2008 were linked to the Danish Register of Medicinal Product Statistics to obtain information on use of antiepileptic drugs. Main outcome measures Risk ratio of spontaneous abortion and stillbirth after use of antiepileptic drugs during pregnancy, estimated by using binomial regression adjusting for potential confounders of maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse. Results Antiepileptic drugs were used in a total of 4700 (0.5%) pregnancies. 16 out of 100 pregnant women using antiepileptics and 13 out of 100 pregnant women not using antiepileptics experienced a spontaneous abortion. After adjusting for potential confounders pregnant women using antiepileptics had a 13% higher risk of spontaneous abortions than pregnant women not using antiepileptics (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). However, the risk of spontaneous abortion was not increased in women with an epilepsy diagnosis (0.98, 0.87 to 1.09), only in women without a diagnosis of epilepsy (1.30, 1.14 to 1.49). In an analysis including women with at least two pregnancies with discordant antiepileptic drug use (for example, use in the first pregnancy but not in the second), the adjusted hazard ratio for spontaneous abortion was 0.83 (0.69 to 1.00) for exposed pregnancies compared with unexposed pregnancies. Stillbirth was identified in 18 women who used antiepileptic drugs (unadjusted risk ratio 1.29, 0.80 to 2.10). Conclusion Among women with epilepsy and when analysing the risk in antiepileptic drug discordant pregnancies in the same woman, we found no overall association between the use of antiepileptic drugs during pregnancy and spontaneous abortions. Therefore unmeasured confounding may explain the slight increased risk for spontaneous abortion with any antiepileptic drug use (among women both with and without epilepsy). We found no association between antiepileptic drug use during pregnancy and stillbirth, but the statistical precision was low.

Risk of Fetal Death after Treatment with Antipsychotic Medications during Pregnancy.

BackgroundAntipsychotic medications are increasingly used during pregnancy. Nevertheless, fetal risks are still not fully studied. It is currently unclear whether the antipsychotic treatment might induce a higher risk of fetal death. We aimed to determine if use of antipsychotic medication during pregnancy is associated with an increased risk of spontaneous abortion or stillbirth.MethodsIn a historical cohort study, we identified all clinically recognized pregnancies registered in the nationwide Danish registries from 1997 to 2008 (N = 1,005,319). Exposure was defined as any prescription of antipsychotic medications redeemed by the pregnant women during the exposure window, and recorded in the Danish National Prescription Register. Outcome was defined as any spontaneous abortion or stillbirth recorded in the Danish National Hospital Register and the Danish Medical Birth Register respectively.ResultsWomen exposed to antipsychotic medications during pregnancy had a 34% higher risk of spontaneous abortion (adjusted relative risk = 1.34; 95% confidence interval = 1.22; 1.46) compared to unexposed women, but a similar risk compared to women exposed prior to (but not during) pregnancy (adjusted relative risk = 1.04; 95% confidence interval = 0.93; 1.17). The risk of spontaneous abortion was not increased in exposed pregnancies when compared to unexposed pregnancies in the same women (adjusted hazard ratio = 1.11; 95% CI = 0.94; 1.31). A twofold higher risk of stillbirth was found in women exposed to antipsychotic medications compared with unexposed women (relative risk = 2.27; 95% confidence interval = 1.45; 3.55) and compared with women exposed only prior to pregnancy (relative risk = 2.06; 95% confidence interval = 1.01; 4.19).ConclusionsThe increased risk of spontaneous abortion found in women treated with antipsychotic medications during pregnancy is most likely due to confounding factors. The risk of stillbirth was twofold higher in pregnancies exposed to antipsychotic medication during pregnancy. Treatment with antipsychotic medications during pregnancy requires careful consideration.

Complicaciones obstétricas y perinatales de la amniocentesis genética del segundo trimestre en las gestaciones gemelares

Objetivo: Evaluar el resultado de la amniocentesis del segundo trimestre en las gestaciones gemelares. Diseño: Estudio descriptivo retrospectivo. Institución: Unidad de Diagnóstico Prenatal, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud, Zaragoza, España. Participantes: Mujeres con gestaciones gemelares. Métodos: Se realizó un estudio mediante la base de datos informatizada y la revisión de las historias clínicas de las pacientes atendidas entre enero de 2004 y febrero de 2008. Las gestaciones gemelares sometidas a amniocentesis fueron comparadas con las gestaciones simples también sometidas a la técnica y con las gestaciones gemelares no sometidas a amniocentesis. Principales medidas de resultados: Complicaciones obstétricas y perinatales. Resultados: Durante los cuatro años del estudio se realizaron 4 263 amniocentesis, de las cuales 112 casos correspondieron a gestaciones gemelares y 4 151 a gestaciones simples. La edad materna avanzada y la ansiedad fueron las indicaciones más frecuentes de amniocentesis. La pérdida fetal durante las 4 semanas posteriores al procedimiento fue de 1,78% para las gestaciones gemelares y 0,40% para las gestaciones únicas. Las gestaciones gemelares que se sometieron a una amniocentesis genética no presentaron otras complicaciones obstétricas ni peores resultados perinatales. Conclusiones: Basándonos en nuestros datos y los reflejados por estudios previos podemos decir que las gestaciones gemelares sometidas a una amniocentesis del segundo trimestre tienen un riesgo de pérdida fetal ligeramente superior a las gestaciones simples. No obstante, en manos de operadores experimentados, la amniocentesis es una técnica segura y efectiva para el diagnóstico prenatal en las gestaciones gemelares.