•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.
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.
Effects of valproate (VPA) dose and treatment discontinuation during the first trimester of pregnancy on the risks of spontaneous abortions (SAB) and major birth defects were analyzed. Pregnancies ...with first trimester VPA exposure (n = 484) prospectively recorded by the German Embryotox center in 1997-2016 were compared with a randomly selected, non-exposed cohort (n = 1446). The SAB risk was not significantly increased in the VPA cohort HR
1.31 (95% CI 0.85-2.02) but major birth defects were significantly more frequent 8.7% vs. 3.4%; OR
2.61 (95% CI 1.51-4.50). Risk was even higher in pregnancies with no VPA discontinuation in first trimester OR
3.66 (95% CI 2.04-6.54). Significant ORs were found for nervous system defects in general OR
5.69 (95% CI 1.73-18.78), severe microcephaly OR
6.65 (95% CI 1.17-37.68), hypospadias OR
19.49 (95% CI 1.80-211) and urinary system defects OR
6.51 (95% CI 1.48-28.67). VPA dose had a stronger effect than antiepileptic poly- versus monotherapy; for VPA dose ≥ 1500 mg/day the OR
was 5.41 (95% CI 2.32-12.66). A daily dose increase of 100 mg was calculated to raise the risk for major birth defects by 15% OR 1.15 (95% CI 1.08-1.23). Overall, maternal first trimester treatment regimen had a relevant impact on birth defect risk.
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.
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.
Spontaneous abortion rates are of general interest when investigating pregnancy outcome. In most studies observations are left truncated as pregnant women enter with a delay of several weeks after ...conception. Apart from spontaneous abortion pregnancy may end in induced abortion or live birth. These outcomes are considered as competing events (risks). Although statistical methods for handling this setting are available since more than 10 years, studies on pregnancy outcome after drug exposure usually report crude rates of spontaneous abortions, ignoring left truncation and competing risks.
The authors propose simple methods which remove bias inherent to crude rates. The probability of spontaneous abortion is estimated using an event-history based approach for the subdistribution of competing risks that handles left truncation appropriately. Variance estimation enables the construction of approximate confidence intervals and of a simple test-statistic for comparing rates between different cohorts. The proposed methods are applied to a comparative prospective study on the association of spontaneous abortion and exposure to coumarin derivatives.
The naive analysis using crude rates gives substantially different results than those based on the proposed methods, with up to a twofold change. Correctly incorporating left truncation into the analysis may increase the variance of the estimators, relative to an ideal sample where all pregnancies are followed from the time of conception. The consequences of such truncation for study design are discussed.
Combining corrections for left truncation and competing risks offers a powerful method for analyzing miscarriage risk.
ABSTRACT
Even though from preclinical testing to drug risk labeling, the situation with drugs in pregnancy has improved substantially since the thalidomide scandal, there is still an increasing need ...to provide healthcare professionals and patients with updated individualized risk information for clinical decision making. For the majority of drugs, clinical experience is still insufficient with respect to their safety in pregnancy. There is often uncertainty in how to interpret the available scientific data. Based on 20 years of experience with Teratology Information Services (TIS) cooperating in the European Network of Teratology Information Services (ENTIS) methods of risk interpretation, follow‐up of exposed pregnancies through the consultation process and their evaluation is discussed. Vitamin K antagonists, isotretinoin and angiotensin (AT) II‐receptor‐antagonists are presented as examples of misinterpretation of drug risks and subjects of research based on observational clinical data recorded in TIS. As many TIS are poorly funded, advocacy is necessary by establishing contacts with decision makers in health politics and administration, informing them of the high return in terms of health outcomes and cost savings provided by TIS as reference institutions in clinical teratology.
Allopurinol is a purine analogue that inhibits xanthine oxidase. It is mainly used for the treatment of hyperuricemia in patients with gout or tumor lysis syndrome. Experience with allopurinol in ...pregnancy is scarce. In 2011, Kozenko et al. reported on a child with multiple malformations after maternal treatment with allopurinol throughout pregnancy. Possible teratogenicity of allopurinol was proposed due to the similarity of the pattern of malformations in children with mycophenolate embryopathy. A possible common mechanism of both drugs, i.e. disruption of purine synthesis, was discussed. We report on the outcome of 31 prospectively ascertained pregnancies with allopurinol exposure at least during first trimester. Pregnancy outcomes were 2 spontaneous abortions, 2 elective terminations of pregnancy and 27 live born children. The overall rate of major malformations (3.7%) and of spontaneous abortions (cumulative incidence 11%, 95%-CI 3-40) were both within the normal range. However, there was one child with severe malformations including microphthalmia, cleft lip and palate, renal hypoplasia, low-set ears, hearing deficit, bilateral cryptorchidism, and micropenis. The striking similarity of the anomalies in this child and the case described by Kozenko et al. might be considered as a signal for teratogenicity. Thus, we would recommend caution with allopurinol treatment in the first trimester, until further data are available.
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.
Drug safety in pregnancy is of utmost importance because prenatal exposure to the unborn child may result in side effects with life-long consequences. Data on their risks in pregnancy are scarce for ...many drugs. Furthermore, there is often uncertainty how to translate risk data into practice.This article aims to identify tools to improve data ascertainment on exposed pregnancies and their outcome. Using the example of the German Embryotox institute, it is demonstrated how to disseminate drug safety knowledge to healthcare professionals and patients for clinical decision-making.Observational data are the most important basis for drug risk assessment in pregnancy. Such data are collected by Embryotox through the risk consultation process. Prospective cohort studies with comparison cohorts allow to estimate relative risks for birth defects, pregnancy loss, and other developmental anomalies. Retrospectively ascertained adverse drug reactions contribute to identification of distinct pattern of congenital anomalies.Drugs in pregnancy counselling require risk characterization dependent on the individual clinical setting: recommendation of treatment of choice (comparative risk assessment between effective drugs), individual risk estimation after (inadvertent) exposure, and assessment of causal relationship in cases of congenital anomalies. Combining counselling and protocols of pregnancy outcome after drug exposure is optimal to cost-efficiently ascertain data of high quality.Using acetaminophen, valproic acid, AT1-receptor blockers and retinoids as examples, recent discussions on drug risks in pregnancy and their clinical implications are presented.
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