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.
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.
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 analysis focuses on effects of naproxen and not on NSAIDs as a group.•Naproxen does not appear to have a significant teratogenic effect.•No signal for specific birth defects after first ...trimester exposure to naproxen.
In contrast to other non-steroidal anti-inflammatory drugs (NSAIDs), naproxen use during pregnancy is not well studied. The objective of this analysis was to assess negative effects on pregnancy outcomes following naproxen exposure in the first trimester of pregnancy. Out of 121 exposed pregnancies prospectively recorded by two German teratology information services (TIS) 15 ended as spontaneous abortion and ten were electively terminated; in one case for prenatal diagnosis of anencephaly. Four pregnancies were stillborn, in these cases naproxen was discontinued more than two months before the event. Of 95 live-born infants, including three pairs of twins, two were born with major birth defects: one with dysmelia of the left hand and foot and another with a complex congenital heart defect, esophageal atresia with tracheoesophageal fistula, and choanal stenosis. The results of this case series do not suggest that naproxen has a significant teratogenic effect. However, due to the limited cohort size and lack of comparable reference group results should be interpreted with caution and better studied NSAIDs such as ibuprofen should be preferred in the first and second trimester of pregnancy. This work was supported by the German Federal Institute for Drugs and Medical Devices (BfArM).
Fluoroquinolones are avoided during pregnancy due to developmental toxicity in animals. The aim of this study was to assess the fetal risk after intrauterine fluoroquinolone exposure. We performed an ...observational study of a prospectively ascertained cohort of pregnant women exposed to a fluoroquinolone during the first trimester. Pregnancy outcomes were compared to those of a cohort exposed to neither fluoroquinolones nor teratogenic or fetotoxic drugs. The outcomes evaluated were major birth defects (structural abnormalities of medical, surgical, or cosmetic relevance), spontaneous abortion, and elective termination of pregnancy. Pregnancy outcomes of 949 women with fluoroquinolone treatment were compared with those of 3,796 nonexposed controls. Neither the rate of major birth defects (2.4%; adjusted odds ratio OR(adj), 0.91; 95% confidence interval CI, 0.6 to 1.5) nor the risk of spontaneous abortion (adjusted hazard ratio HR(adj), 1.01; 95% CI, 0.8 to 1.3) was increased. However, there was a nonsignificant increase in major birth defects after exposure to moxifloxacin (6/93, 6.5%; crude odds ratio OR(crude), 2.40; 95% CI, 0.8 to 5.6). Neither a critical exposure time window within the first trimester nor a specific pattern of birth defects was demonstrated for any of the fluoroquinolones. The rate of electively terminated pregnancies was increased among the fluoroquinolone-exposed women (HR(adj), 1.32; 95% CI, 1.03 to 1.7). The gestational ages at delivery and birth weights did not differ between groups. Our study did not detect an increased risk of spontaneous abortion or major birth defects. These reassuring findings support the recommendation to allow fluoroquinolone use in early pregnancy in selected cases. After the use of moxifloxacin, a detailed fetal ultrasound examination should be considered.
The aim of this observational cohort study was to specify the risk of the vitamin K antagonist (VKA) phenprocoumon during first trimester of pregnancy, in particular to estimate the risk of birth ...defects and spontaneous fetal loss. Four hundred eight pregnancies with phenprocoumon exposure were compared to 1,642 pregnancies neither exposed to VKA nor to other major teratogens or fetotoxicants. There was no typical warfarin embryopathy in our exposed cohort. However, the overall rate of major birth defects was significantly increased (7.4 % vs 2.3 %; adjusted odds ratio OR
2.14; 95 % confidence interval CI 1.4-3.4). With early cessation until five completed gestational weeks the birth defect risk was similar to the comparison cohort (2.4 % vs 2.3 %; OR
1.07; 95 % CI 0.2-3.6). With treatment duration exceeding seven gestational weeks the rate of major birth defects increased up to five-fold (10.8 % vs 2.3 %; OR
5.18; 95 % CI 2.0-11.6). The overall risk of spontaneous abortion (SAB) was 38.0 % vs 17.5 % in the comparison cohort (adjusted hazard ratio HR
2.9; 95 % CI 2.2-3.9). The treatment duration had a significant effect on the hazard of SAB (HR
1.12; 95 % CI 1.01-1.25 per each additional exposure week). Phenprocoumon and other VKA carry an embryotoxic risk. This risk seems to be time-dependent with a steep risk increase for birth defects and also for fetal loss after week 5. If maternal disease permits, VKA therapy should be switched to safer alternatives such as heparins immediately after early recognition of pregnancy.
Published experience on first trimester exposure to methyldopa is still limited, although it is recommended as first-line treatment for hypertensive disorders in pregnancy in most countries. The ...primary aim of this prospective observational cohort study was to analyze the rate of major birth defects and spontaneous abortions in women with methyldopa therapy for chronic hypertension. Outcomes of 261 pregnancies with first trimester exposure to methyldopa and 526 comparison pregnancies without chronic hypertension reported to the German Embryotox pharmacovigilance institute were evaluated. The rate of major birth defects in the exposed cohort was not significantly increased compared with the comparison cohort (3.7% versus 2.5%; adjusted odds ratio, 1.24; 95% confidence interval, 0.4-4.0). There was a tendency toward a higher rate of spontaneous abortions in exposed women. The risk of preterm birth was significantly higher, and adjusted birth weight scores were significantly lower in the methyldopa group. Head circumferences were significantly reduced in exposed boys only. There was neither evidence for an increased risk for birth defects or increase in early pregnancy loss nor evidence for growth restriction or a reduced head circumference in a sensitivity analysis comparing monotherapies with methyldopa to metoprolol. However, the significantly increased risk of preterm birth in methyldopa-treated pregnancies was confirmed. In conclusion, our study does not indicate a teratogenic risk of methyldopa. Further studies are needed to confirm its safety in the first trimester and clarify the influence of hypertension and methyldopa on preterm birth and intrauterine growth.
URL: https://drks-neu.uniklinik-freiburg.de/drks_web/. Unique identifier: DRKS00010502.
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