Objective
High‐dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases ...remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX.
Methods
Pregnancy outcome in women taking MTX (≤30 mg/week) either after conception or within the 12 weeks before conception was evaluated in a prospective observational multicenter cohort study. Pregnancy outcomes in the MTX group were compared to outcomes in a group of disease‐matched women and a group of women without autoimmune diseases (neither group was exposed to MTX).
Results
The study sample included 324 MTX‐exposed pregnancies (188 exposed post‐conception, 136 exposed pre‐conception), 459 disease‐matched comparison women, and 1,107 comparison women without autoimmune diseases. In the post‐conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval 95% CI 29.2–58.7), which was significantly higher than the incidence of spontaneous abortion in either comparison group. The risk of major birth defects (7 of 106 6.6%) was elevated compared to both the cohort of women without autoimmune diseases (29 of 1,001 2.9%) (adjusted odds ratio OR 3.1 95% CI 1.03–9.5) and the disease‐matched cohort (14 of 393 3.6%) (adjusted OR 1.8 95% CI 0.6–5.7). None of the malformations were clearly consistent with MTX embryopathy. Neither the cumulative incidence of spontaneous abortion (14.4% 95% CI 8.0–25.3) nor the risk of major birth defects (4 of 114 3.5%) was increased in the pre‐conception cohort. Elective termination rates were increased in both of the MTX‐exposed cohorts. There were no other significant differences among groups in other study end points.
Conclusion
Post‐conception administration of MTX at dosages typically used in the treatment of rheumatic diseases was associated with an increased risk of major birth defects and spontaneous abortion. Such evidence was not found among women in our pre‐conception cohort.
Ondansetron is an effective antiemetic that is being widely used as a second‐line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ...ondansetron during pregnancy has—following publication of controversial and seemingly contradictory results—been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on “Fertility, pregnancy and lactation.” The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step—which has important clinical consequences—is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.
Aims
TNF‐α inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm ...birth and reduced birth weight after first trimester exposure to TNF‐α inhibitors.
Methods
Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational cohort study and compared with outcomes of a non‐exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services.
Results
In total, 495 exposed and 1532 comparison pregnancies were contributed from nine countries. The risk of major birth defects was increased in the exposed (5.0%) compared with the non‐exposed group (1.5%; adjusted odds ratio (ORadj) 2.2, 95% CI 1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but not the risk of spontaneous abortion (16.2%; adjusted hazard ratio HRadj 1.06, 95% CI 0.7, 1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non‐exposed cohort (P = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated.
Conclusions
TNF‐α inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF‐α inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs.
•TCZ does not seem to pose a major teratogenic risk, but experience is still too limited for a well-grounded risk assessment.•Larger studies are needed to ascertain safety of TCZ during pregnancy ...before its use can be recommended.•In case of inadvertent TCZ treatment in early pregnancy a detailed prenatal ultrasound should be offered and the patient reassured.
Tocilizumab (TCZ) is not recommended for use during pregnancy due to limited data, but pregnancies nevertheless occur and pregnant women need to be counseled about potential fetal risks. Participants of this study were recruited from the pool of callers who spontaneously contact the pharmacovigilance center “Embryotox” Berlin for risk assessment during pregnancy. Of 22 identified cases with TCZ exposure during pregnancy, 16 prospectively enrolled cases with maternal and two cases with paternal TCZ therapy could be completed. The outcomes of the 16 maternal cases were: four spontaneous abortions (SAB), one induced abortion for personal reasons and 11 live-born infants. Congenital malformations were not recorded, but one SAB at week 15+3 days was complicated by hydrops fetalis of unknown origin. An incidental continuation of TCZ into early pregnancy does not justify an elective termination. However, a detailed prenatal ultrasound should be offered.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• In recent years there has been concern regarding the possibility that selective serotonin reuptake inhibitors (SSRIs) cause an increased rate of congenital ...cardiovascular anomalies.
• As of today, there is still debate in the literature as to the possible effects of paroxetine and fluoxetine on the embryonic cardiovascular system.
WHAT THIS STUDY ADDS
• Based on prospective data from three Teratogen Information Services, we have demonstrated an increased rate of congenital cardiovascular anomalies among the offspring of fluoxetine‐ and paroxetine‐treated mothers.
AIMS
Recent studies have suggested a possible association between maternal use of selective serotonin reuptake inhibitors (SSRIs) in early pregnancy and cardiovascular anomalies. The aim of the present study was to evaluate the teratogenic risk of paroxetine and fluoxetine.
METHODS
This multicentre, prospective, controlled study evaluated the rate of major congenital anomalies after first‐trimester gestational exposure to paroxetine, fluoxetine or nonteratogens.
RESULTS
We followed up 410 paroxetine, 314 fluoxetine first‐trimester exposed pregnancies and 1467 controls. After exclusion of genetic and cytogenetic anomalies, there was a higher rate of major anomalies in the SSRI groups compared with the controls paroxetine 18/348 (5.2%), fluoxetine 12/253 (4.7%) and controls 34/1359 (2.5%). The main risk applied to cardiovascular anomalies paroxetine 7/348 (2.0%), crude odds ratio (OR) 3.47, 95% confidence interval (CI) 1.13, 10.58; fluoxetine 7/253 (2.8%), crude OR, 4.81 95% CI 1.56, 14.71; and controls 8/1359 (0.6%). On logistic regression analysis only cigarette smoking of ≥10 cigarettes day−1 and fluoxetine exposure were significant variables for cardiovascular anomalies. The adjusted ORs for paroxetine and fluoxetine were 2.66 (95% CI 0.80, 8.90) and 4.47 (95% CI 1.31, 15.27), respectively.
CONCLUSION
This study suggests a possible association between cardiovascular anomalies and first‐trimester exposure to fluoxetine.
Aims
Angiotensin‐II receptor 1 antagonists (AT1‐antagonists) may cause severe and even lethal fetopathy in late pregnancy. However, exposure still occurs in spite of warnings in package leaflets. ...This study aimed to assess the risk of fetopathy, the sensitive time window, and possible new symptoms in prospective as well as retrospective cases with AT1‐antagonist treatment during the second or third trimester of pregnancy.
Methods
Patients were enrolled by the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy between 1999 and 2011 through risk consultation. Symptoms defined as indicative of AT1‐antagonist fetopathy were: oligo‐/anhydramnios, renal insufficiency, lung hypoplasia, joint contractures, skull hypoplasia and fetal/neonatal death.
Results
In 5/29 (17%) prospectively enrolled cases with AT1‐antagonist exposure beyond the first trimester oligo‐/anhydramnios was diagnosed. Two infants showed additional symptoms of fetopathy. The risk is more than 30% if treatment continues beyond the 20th week of pregnancy. Oligo‐/anhydramnios was reversible after AT1‐antagonist withdrawal. Among 16 retrospective case reports, three infants presented with a thrombosis of the inferior vena cava in the vicinity of the renal veins. Four out of 13 live births did not survive.
Conclusions
Our survey suggests that the risk increases with duration of AT1‐antagonist treatment into late pregnancy and oligo‐/anhydramnios may be reversible after AT1‐antagonist discontinuation. Thrombosis of inferior vena cava may be a new feature of AT1‐antagonist fetopathy. AT1‐antagonist medication during pregnancy constitutes a considerable risk and must be discontinued immediately. In case of indicative diagnostic findings in either the fetus or newborn, previous maternal AT1‐antagonist exposure should be considered.
This prospective multicentre cohort study investigated pregnancy outcomes after fingolimod use for multiple sclerosis during pregnancy. Pregnancy outcomes of 63 fingolimod and 62 interferon-β-exposed ...pregnancies were compared. Rates of major congenital anomalies (MCA) were 4.8% (2/42) in the fingolimod group versus 2.3% (1/44) in the interferon-β group (odds ratio, 2.2; 95% confidence interval, 0.2–24.6). The adjusted hazard ratio for spontaneous abortion in fingolimod versus interferon-β-exposed pregnancies was 0.6 (95% confidence interval, 0.2–1.8). Further studies are needed to definitely rule out a moderately increased MCA risk after fingolimod exposure during pregnancy.
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