Fetotoxic risk of AT1 blockers exceeds that of angiotensin-converting enzyme inhibitors: an observational study.

OBJECTIVE: The fetotoxic potential of prenatal exposure to angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) has been known for many years. Symptoms range from transient oligohydramnios to neonatal anuria and permanent renal damage, joint contractures, hypocalvaria, lung hypoplasia and intrauterine or neonatal death. This study aims to investigate the critical gestational time for renin-angiotensin system inhibitor (RAS-I)-induced fetopathy, to quantify the fetopathy risk and to evaluate factors associated with the occurrence and severity of fetopathy. METHODS: Prospectively and retrospectively ascertained RAS-I exposed pregnancies from the databases of six teratology information services were analyzed. RESULTS: Eighty-nine pregnancies with ACE-I and 101 with ARB exposure beyond the first trimester were identified. Fifty-nine of these 190 pregnancies were classified as having evidence of RAS-I fetopathy. All pregnancies affected with fetopathy were exposed after 20 0/7 gestational weeks. Limited to prospectively enrolled cases with exposure at least 20 0/7 gestational weeks, the rate of fetopathy was 3.2% for ACE-I and 29.2% for ARB. The chance of recovery of amniotic fluid volume was higher with RAS-I discontinuation before 30 gestational weeks and with a longer exposure-free interval before delivery. CONCLUSION: Exposure to ARBs is associated with a higher fetopathy risk than exposure to ACE-Is. RAS-I should ideally be discontinued prior to pregnancy or immediately after recognition of pregnancy. Because symptoms may improve in cases of RAS-I-induced oligohydramnios, pregnancy should be maintained as long as there is fetal well being. Physicians and patients need to be alerted to the fetotoxic risks of RAS-I.

Neonatal effects of intrauterine metoprolol/bisoprolol exposure during the second and third trimester: a cohort study with two comparison groups.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Increased rate of birth defects after first trimester use of angiotensin converting enzyme inhibitors - Treatment or hypertension related? An observational cohort study.

OBJECTIVES: To analyze the risk of spontaneous abortions and major birth defects in pregnancies of women treated with angiotensin converting enzyme inhibitors (ACEIs) during the first trimester. STUDY DESIGN: Observational cohort study of prospectively ascertained pregnancies from the German Embryotox pharmacovigilance institute. Pregnancy outcomes after maternal exposure to ACEIs during the first trimester were compared with pregnancies without antihypertensive treatment. In a sensitivity analysis, ACEI exposed hypertensive women were compared with hypertensive women on methyldopa. RESULTS: The risk of spontaneous abortion among 329 ACEI exposed women was not increased compared to 654 women without antihypertensive treatment (adjusted hazard ratio 1.20, 95% confidence interval (CI) 0.74-1.92), whereas the risk for major birth defects (14/255; 5.5% vs. 19/567; 3.4%) was significantly increased (adjusted odds ratio 2.41, 95% CI 1.07-5.43). In contrast, birth defect rates were not significantly different between hypertensive women on ACEIs and hypertensive women on methyldopa. In addition, we did not observe a distinct pattern of birth defects among retrospectively ascertained pregnancies after ACEI exposure during the first trimester. CONCLUSIONS: Women with hypertension treated with ACEIs in early pregnancy are at higher risk for major birth defects, which may be explained by other factors associated with maternal hypertension. Women (inadvertently) exposed during early pregnancy may be reassured and treatment switched to antihypertensive drugs recommended for pregnancy.

Pregnancy outcome after first trimester exposure to bisoprolol: an observational cohort study.

OBJECTIVES: Beta-blockers are frequently used during pregnancy, with labetalol and metoprolol being considered as drugs of choice. As there are no prospective pregnancy studies for bisoprolol yet, our aim was to analyze pregnancy outcomes after bisoprolol exposure. METHODS: Pregnancies exposed to bisoprolol during the first trimester were retrieved from the German Embryotox pharmacovigilance database. Pregnancy outcomes of prospectively ascertained pregnancies were compared with women neither exposed to beta-blockers nor other antihypertensives. In addition, retrospective reports on adverse drug reactions were screened for patterns of birth defects. RESULTS: Inclusion criteria for the prospective study were met by 339 bisoprolol-treated women and 678 patients in the comparison cohort. Neither the risk for spontaneous abortions [adjusted hazard ratio (HRadj.) 1.06; 95% confidence interval (CI) 0.66-1.70] nor for major congenital malformations [adjusted odds ratio (ORadj.) 0.77; 95% CI 0.34-1.75] was increased after first trimester bisoprolol treatment. However, higher rates of preterm births [ORadj. 1.90; 95% CI 1.17-3.11] and reduced birthweights in singleton pregnancies (adjusted standard deviation score difference -0.48; 95% CI -0.62 to -0.34) were noted. Continued treatment with beta-blockers until birth was found to be associated with a higher risk for growth restriction than first trimester exposure only. A sensitivity analysis did not suggest higher rates of adverse pregnancy outcomes in hypertensive women on bisoprolol compared with nonhypertensive bisoprolol-exposed women. CONCLUSION: Our study supports the hypothesis that first trimester bisoprolol treatment does not increase the risk for spontaneous abortions or major birth defects. However, an influence of prolonged bisoprolol exposure on fetal growth cannot be ruled out.

Pregnancy outcome after first trimester use of angiotensin AT1 receptor blockers: an observational cohort study.

BACKGROUND: Ongoing discussion about the safety of renin-angiotensin inhibitors in the first trimester and limited data on pregnancy outcomes after exposure to angiotensin AT1 receptor blockers (ARBs). METHODS: Observational cohort study compares outcomes of 215 prospectively ascertained pregnancies with first trimester exposure to ARBs with 642 non-hypertensive pregnancies. RESULTS: The rate of major birth defects in the ARB cohort (9/168, 5.4%) was higher than in the comparison group (17/570, 3%), but not significantly increased (ORadj 1.9, 95% CI 0.7-4.9). There was no distinct pattern of anomalies among infants with birth defects. The risk of spontaneous abortions was not increased (HRadj 0.9, 95% CI 0.5-1.6), although the cumulative incidence was in the upper normal range (0.22, 95% CI 0.15-0.32). Higher rates of prematurity (ORadj 3.0; 95% CI 1.7-5.1) and a reduced birth weight after adjustment for sex and gestational age were observed. There was no evidence for an increased risk for major birth defects, spontaneous abortions, or preterm birth in a sensitivity analysis comparing ARB exposed hypertensive women to hypertensive women without ARB exposure during the first trimester. CONCLUSION: Our study supports the hypothesis that ARBs are not major teratogens. Patients inadvertently exposed to ARBs during the early pregnancy may be reassured. Nevertheless, women planning pregnancy should avoid ARBs. In selected cases, ARBs might be continued under careful monitoring of menstrual cycle and discontinued as soon as pregnancy is recognized.

Pregnancy outcome after anti-migraine triptan use: A prospective observational cohort study.

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.

Pregnancy Outcome After First Trimester Use of Methyldopa: A Prospective Cohort Study.

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. CLINICAL TRIAL REGISTRATION: URL: https://drks-neu.uniklinik-freiburg.de/drks_web/. Unique identifier: DRKS00010502.

Reversible oligohydramnios in the second trimester of pregnancy in two patients with long-term diclofenac exposure.

The use of non-steroidal anti-inflammatory drugs like diclofenac in the third trimester of pregnancy can cause severe side effects, in particular oligohydramnios, premature closure of ductus arteriosus, and fetal kidney damage. However, the treatment with non-steroidal anti-inflammatory drugs until gestational week 28 is accepted as relatively safe. Here we describe two retrospectively reported cases of early-onset oligohydramnios associated with long-term diclofenac exposure of at least 150mg per day. The pathological findings were detected at gestational weeks 22 and 23, respectively. Amniotic fluid turned to normal after discontinuation of diclofenac in both cases, suggesting causality. Although early-onset oligohydramnios is a rare complication, caution for long-term diclofenac use in high doses is recommended even before gestational week 28.

Angiotensin-II receptor 1 antagonist fetopathy--risk assessment, critical time period and vena cava thrombosis as a possible new feature.

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.