Stephanie Padberg

Observational Cohort Study of Pregnancy Outcome after First-Trimester Exposure to Fluoroquinolones

ABSTRACT 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 [ORadj], 0.91; 95% confidence interval [CI], 0.6 to 1.5) nor the risk of spontaneous abortion (adjusted hazard ratio [HRadj], 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 [ORcrude], 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 (HRadj, 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.

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.

Does the average drug exposure in pregnant women affect pregnancy outcome? A comparison of two approaches to estimate the baseline risks of adverse pregnancy outcome

The results of observational cohort studies on drug effects on pregnancy outcome may depend among others on suitable comparison cohorts. The aim of this investigation was to compare two distinct definitions of maternal exposure status for comparison cohorts.

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.

Transient congenital dilated cardiomyopathy after maternal R-CHOP chemotherapy during pregnancy

Pregnancy-associated diffuse large B-cell lymphoma (DLBCL) is a rare event. Experience regarding fetal effects of maternal treatment during pregnancy is limited. Cardiotoxicity is a known adverse effect of some antineoplastic agents especially of doxorubicin. We report a case of pregnancy-associated DLBCL, which was treated between gestational week 26 and 33 with three cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone combined with rituximab). At gestational age 34 2/7 she delivered a male infant who was admitted to neonatal care due to cardiomyopathy. In the absence of other explanations it was interpreted as a direct toxic effect of maternal chemotherapy. At age 6 months the boys cardiac output had normalized. This case report is the first presenting congenital cardiomyopathy after maternal R-CHOP during pregnancy. Since especially anthracyclines are known to cause acute and chronic cardiotoxicity in treated patients, the most probable explanation for neonatal cardiomyopathy in this case is doxorubicin.

Pregnancy Outcome After First Trimester Use of Methyldopa

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.

Pregnancy Outcome After First Trimester Use of MethyldopaNovelty and Significance: 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.

Antiinfektiva während der Schwangerschaft und im Wochenbett

Bakterielle Infektionen konnen nicht nur die Mutter gefahrden, sondern auch den Verlauf der Schwangerschaft komplizieren. Falls bei einer Schwangeren eine medikamentose antiinfektive Behandlung erforderlich ist, richtet sich diese primar nach der Empfindlichkeit der zu erwartenden Keime. Nach heutigem Kenntnisstand hat sich keines der langer eingefuhrten Antiinfektiva als ernsthaft entwicklungstoxisch fur den Embryo oder Feten gezeigt. Zwar wurden von einzelnen Autoren Signale erortert, die z. B. auf eine leicht erhohte Rate von Herzseptumdefekten und Pylorusstenosen nach Behandlung der Mutter mit Erythromycin im 1. Trimenon hindeuteten, doch konnte ein solcher Verdacht bisher nicht erhartet werden. Wie bei anderen Erkrankungen auch sollten nicht nur wahrend einer Graviditat, sondern auch wegen einer haufig ungeplant entstehenden Schwangerschaft generell im gebarfahigen Alter ausreichend erprobte Arzneimittel bevorzugt werden. Neue Medikamente sind den alteren oft keineswegs uberlegen und ihre Vertraglichkeit fur das Ungeborene ist nicht zu beurteilen. Antibiotika der ersten Wahl sind in allen Phasen der Schwangerschaft Penicilline und Cephalosporine. Als Alternative, z. B. bei Allergie, stehen Makrolide zur Verfugung. Im Fall von vital bedrohlichen Infektionen, insbesondere mit Problemkeimen, kann eine Therapie mit schlechter erprobten oder fur die Schwangerschaft suspekten Antibiotika erforderlich werden. Dabei uberwiegt der therapeutische Nutzen in den meisten Fallen das potenzielle Risiko fur das ungeborene Kind.