Abstract Objectives Analyze the cumulative evidence for pregnancy outcomes after maternal exposure to tocilizumab, an anti-interleukin-6-receptor monoclonal antibody used for the treatment of ...rheumatoid arthritis and juvenile idiopathic arthritis. At present, published experience on tocilizumab use during pregnancy is very limited. Methods We have analyzed all pregnancy-related reports documented in the Roche Global Safety Database until December 31, 2014 ( n = 501). Results After exclusion of ongoing pregnancies, duplicates, and cases retrieved from the literature, 399 women were found to have been exposed to tocilizumab shortly before or during pregnancy, with pregnancy outcomes being reported in 288 pregnancies (72.2%). Of these 288 pregnancies, 180 were prospectively reported resulting in 109 live births (60.6%), 39 spontaneous abortions (21.7%), 31 elective terminations of pregnancy (17.2%), and 1 stillbirth. The rate of malformations was 4.5%. Co-medications included methotrexate in 21.1% of the prospectively ascertained cases. Compared to the general population, an increased rate of preterm birth (31.2%) was observed. Retrospectively reported pregnancies ( n = 108) resulted in 55 live births (50.9%), 31 spontaneous abortions (28.7%), and 22 elective terminations (20.4%). Three infants/fetuses with congenital anomalies were reported in this group. No increased risks for adverse pregnancy outcomes were observed after paternal exposure in 13 pregnancies with known outcome. Conclusions No indication for a substantially increased malformation risk was observed. Considering the limitations of global safety databases, the data do not yet prove safety, but provide information for physicians and patients to make informed decisions. This is particularly important after inadvertent exposure to tocilizumab, shortly before or during early pregnancy.
Abstract
Background
Non-steroidal anti-inflammatory drugs (NSAID) are frequently used to treat pain, fever and inflammatory conditions. Due to evidenced fetotoxicity, treatment with NSAID and ...metamizole should be avoided in the 3rd trimester of pregnancy. There is an ongoing debate on fetotoxic risk of 2nd trimester use which is why we have conducted this study.
Methods
In this observational cohort study outcome of pregnancies with NSAID and/or metamizole exposure in the 2nd and/or 3rd trimester (study cohort
n
= 1092) was compared with pregnancies exposed to NSAID and/or metamizole in the 1st trimester only (comparison cohort,
n
= 1154). The WHO-UMC system was used to assess causality between study medication and study endpoints. Prenatal study endpoints were constriction of ductus arteriosus Botalli, oligohydramnios, late spontaneous abortion (SAB) or stillbirth. Postnatal study endpoints were patent ductus arteriosus (PDA), anomalies of the right heart ventricle, primary pulmonary hypertension (PPHT), and neonatal impairment of kidney function.
Results
Ductus arteriosus constriction was diagnosed in 5/1092 (0.5%) in the study cohort versus 0/1154 pregnancies in the comparison cohort. In one fetus, ductus arteriosus constriction and oligohydramnios occurred already in the late 2nd trimester after long-term NSAID exposure. Oligohydramnios was diagnosed in 41/1092 (3.8%) in the study cohort versus 29/1154 (2.5%) cases in the comparison cohort RR, 1.5 (95% CI 0.9–2.4). Limited to 2nd trimester, oligohydramnios occurred in 8/904 (0.9%) versus 2/1154 (0.2%) pregnancies RR, 5.1 (95% CI 1.1–24.0). At least in four of the 2nd trimester exposed pregnancies NSAID exposure lasted several weeks. Late SAB or stillbirth occurred in 14/1092 (1.3%) versus 17/1154 (1.5%). Postnatal cardiovascular or renal pathology did not differ between the cohorts.
Conclusions
NSAID use in the 2nd trimester limited to a few days does not appear to pose a relevant risk. Use for longer periods in the advanced 2nd trimester, however, may cause oligohydramnios and ductus arteriosus constriction similar to effects observed after 3rd trimester use.
•Observational cohort studies based on TIS data are an important source for risk characterization of drugs during pregnancy.•Study participants are predominantly recruited from women who voluntarily ...contact the service.•Therefore it is unknown whether these women differ from the general population.•Medium- and high-level educated women tend to be overrepresented among TIS enquirers.•Observational cohort studies should involve an unexposed comparison cohort using the same population of women.
All women of reproductive age should have access to Teratology Information Services (TIS). Observational cohort studies based on TIS data are one of the most important sources for risk characterization of drugs during pregnancy. A selection in TIS populations towards higher socioeconomic level would compromise the TIS’ goal of health prevention and the quality of research. The aim of this study is to investigate in which respect Berlin TIS enquirers are different from the general female population of reproductive age in Germany. 5,239 women aged between 20 and 39 were compared with the general female population of reproductive age in Germany. Medium- and high-level educated women tend to be overrepresented among TIS enquirers. TIS should strive towards reaching subpopulations with poor access to health care. TIS-based observational studies require appropriate comparison cohorts from the same data pool with similar procedures of ascertainment to reduce the risk of selection bias.
•Pregnant women with Wilson disease should continue chelation therapy.•Dose reduction of chelators about 25–50% should be considered in pregnancy.•Our case series did not show major birth defects ...after maternal chelation exposure.•The teratogenic risk seems to be very low after well controlled maternal chelator therapy.
Continuation of treatment is recommended for pregnant women with Wilson disease. Therapy options include the copper chelating agents d-penicillamine and trientine. However, there are still uncertainties concerning a possible teratogenic risk. In this case series, we report on the outcome of 20 pregnancies with maternal chelator exposure at least during the first trimester. Of these 20 pregnancies documented by the German Embryotox Project, 14 were prospectively ascertained and 6 were retrospective. No major birth defects were observed. Three of the 14 prospective cases resulted in a spontaneous abortion, and one pregnancy was electively terminated. Our results do not support the hypothesis of teratogenicity based on earlier case reports of congenital anomalies. Therefore our study may contribute to reassure women needing chelation therapy during pregnancy. However, it must be taken into account that the sample size of this case series is too limited to make final conclusions on teratogenic effects.
Our aim was to evaluate the effects of beta-blockers during the second and third trimester on fetal growth, length of gestation and postnatal symptoms in exposed infants.
The current prospective ...observational cohort study compares 294 neonates of hypertensive mothers on metoprolol or bisoprolol during the second and/or third trimester with 225 methyldopa-exposed infants and 588 infants of nonhypertensive mothers. The risks for reduced birth weight, prematurity, neonatal bradycardia, hypoglycaemia and respiratory disorders were analysed.
The rate of small-for-gestational-age children was significantly higher in long-term beta-blocker exposed infants (24.1%) compared with the methyldopa cohort 10.2%, odds ratio (OR)adj 2.5, 95% confidence interval (CI) 1.2-5.2 and the nonhypertensive cohort (9.9%, ORadj 4.3, 95% CI 2.6-7.1). The risk for preterm birth was significantly increased compared with nonhypertensive pregnancies (ORadj 2.2, 95% CI 1.3-3.8) but not compared with the methyldopa cohort. Neonatal adverse outcomes occurred more frequently in the study cohort (11.5%) compared with the nonhypertensive comparison group (6.5%) and the methyldopa cohort (8.4%), but without statistical significance (ORadj 1.5, 95% CI 0.7-3.0 and ORadj 1.5, 95% CI 0.7-3.3, respectively).
Long-term intrauterine exposure to metoprolol or bisoprolol may increase the risk of being born small-for-gestational-age. It is still a matter of debate to which extent maternal hypertension contributes to the lower birth weight. Serious neonatal symptoms are rare. Altogether, metoprolol and bisoprolol are well tolerated treatment options, but a case-by-case decision on close neonatal monitoring is recommended.
Objective
The objective of our study is to assess the impact of triptan exposure on pregnancy outcome.
Methods
We performed a prospective observational cohort study with 432 pregnant women exposed to ...triptans and enrolled by the German Embryotox system. Pregnancy outcomes were compared with a migraine and a non-migraine comparison cohort. Primary objectives were major birth defects and spontaneous abortion; secondary endpoints were preterm delivery, birth weight, pregnancy complications and the rate of electively terminated pregnancies.
Results
Compared to a non-migraine cohort the rates of major birth defects (ORadj 0.84; 95% CI 0.4–1.9), spontaneous abortions (ORadj 1.20; 95% CI 0.9–1.7), preterm delivery (ORadj 1.01; 95% CI 0.7–1.5), and preeclampsia (ORadj 1.33; 95% CI 0.7–2.5) were not increased in triptan-exposed pregnancies.
Conclusions
Our findings support the evidence that triptans are not major teratogens. When compellingly needed during pregnancy, sumatriptan as the best studied triptan appears an acceptable treatment option. A detailed fetal ultrasound should be offered in cases of first trimester exposure to less well-studied triptans.
Trial registration number in German Clinical Trials Register: DRKS00007660
•largest monocentric cohort study on metformin safety during the first trimester.•336 pregnancies with metformin exposure and 1011 matched controls.•no increase in major birth defects and spontaneous ...abortions.•no distinct pattern of major birth defects.
The aim of this study was to evaluate the risk of major birth defects and spontaneous abortion after metformin use during the first trimester of pregnancy. We conducted an observational cohort study comparing pregnancies with metformin treatment during the first trimester with non-exposed women matched for BMI and year of enrolment. Pregnancies were prospectively ascertained in the German Embryotox pharmacovigilance database between 2004 and 2014. The study sample included 336 pregnancies with metformin exposure for PCOS and fertility disorders (56.8%), diabetes (25.9%) and insulin resistance (14.9%) and 1011 matched controls. Independent of the treatment indication, neither the rate of major birth defects (OR adjusted 0.58, 95% CI 0.3–1.3) nor of spontaneous abortions (HR adjusted 0.95, 95% CI 0.6–1.5) was significantly increased among metformin exposed. Our study supports the evidence that metformin does not carry a developmental risk for the fetus when used during the first trimester.
Purpose
Ivabradine has been approved for the treatment of chronic heart failure and chronic stable angina pectoris in Europe. Based on adverse outcomes of reproductive animal studies and the lack of ...human data, ivabradine is considered contraindicated during pregnancy. The aim of this observational study is to analyse ivabradine use before and during pregnancy.
Methods
We evaluated all ivabradine-related requests to the German Embryotox Institute from 2007 to 2019. Exposed pregnancies were analysed as to their outcome.
Results
Off-label use for supraventricular tachycardia was frequent in women of childbearing age. Of 38 prospectively ascertained pregnancies with ivabradine exposure and completed follow-up, 32 resulted in live births, 3 in spontaneous abortions, and 3 were electively terminated. One neonate presented with major birth defects (atrial septal defect and cleft palate). In 33/38 patients, ivabradine was discontinued after confirmation of pregnancy without cardiac deterioration and 5/38 women continued ivabradine throughout pregnancy. In addition, there were 3 retrospectively reported pregnancies including one major birth defect (tracheal atresia).
Conclusion
This case series represents the largest cohort of ivabradine-exposed pregnancies, published so far. According to our findings, ivabradine appears not to be a major teratogen. However, established drugs of choice with strong evidence of low risk for the unborn should be preferred in women planning pregnancy. After inadvertent exposure during pregnancy or lack of treatment alternatives, fetal ultrasound for structural anomalies and growth restriction is recommended. In addition, close monitoring is necessary in pregnant women with supraventricular arrhythmias or cardiac disease.
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