Elsevier

Reproductive Toxicology

Volume 19, Issue 4, March–April 2005, Pages 453-458
Reproductive Toxicology

Pregnancy outcome after exposure to ranitidine and other H2-blockers: A collaborative study of the European Network of Teratology Information Services

https://doi.org/10.1016/j.reprotox.2004.09.002Get rights and content

Abstract

Background:

Published data on pregnancy outcome after exposure to H2-blockers is scarce. The aim of the present study was to evaluate the data collected by the memberships of the European Network of Teratology Information Services (ENTIS).

Methods:

The patients were pregnant women who or whose doctor or midwife did contact a Teratology Information Service for risk assessment after the use of a H2-blocker in pregnancy. The data were prospectively collected, i.e. before the outcome of pregnancy was known. Standardized procedures for data collection were used by each centre. The data of the exposed women were compared to those of a control group exposed to non-teratogenic substances.

Results:

Data on the outcome of 553 pregnancies with exposure to an H2-blocker were evaluated (ranitidine n = 335; cimetidine n = 113, famotidine n = 75; nizatidine n = 15, roxatidine n = 15). Most of them had been exposed at least in the first trimester. The incidence of premature deliveries was higher in the exposed group compared to the control group. There was no increase in the incidence of major malformations. Two pregnancies with maternal use of famotidine in early pregnancy were terminated after the prenatal diagnosis of a neural tube defect.

Conclusion:

There is no indication for an increased risk of major malformations after the use of H2-blockers during pregnancy.

Introduction

H2-receptor antagonists inhibit gastric secretion and are used in the treatment of peptic ulcer diseases and gastroesophageal reflux diseases which are common disorders also in pregnancy.

H2-blockers cross the placenta by passive diffusion and umbilical cord concentrations are equal to or lower than the maternal serum concentration. Fetal clearance is similar to maternal clearance. Ranitidine has been found to accumulate in amniotic fluid [1], [2], [3], [4], [5].

Several authors have reported on pregnancy outcomes after the use of H2-receptor antagonists. The information concerns mainly exposures in the first trimester [6], [7], [8], [9], [10] or near delivery [1], [3], [11], [12], [13], [14]. Published data on the effects after the first trimester is scarce. Most data concern exposure to ranitidine and cimetidine and data on famotidine, nizatidine or roxatidine are few.

Teratology Information Services have been established in most European countries and have collaborated within the European Network of Teratology Information Services (ENTIS) since 1990. One of the goals of ENTIS is to collect and to evaluate data on pregnancy outcome after exposure to drugs or other exogenous agents. The insufficient data on H2-blockers in the early 1990s prompted ENTIS to evaluate the data collected by the different memberships. The results are reported here.

Section snippets

Materials and methods

This is a controlled prospective study. Major malformations were defined as structural anomalies having surgical, medical or cosmetic relevance. Prematurity is defined as gestational age less than 37 weeks.

The patients in the experimental group were pregnant women who or whose doctor or midwife did contact a Teratology Information Service for risk assessment after the use of an H2-blocker in pregnancy, mainly in the first trimester.

Data on the experimental group were collected between 1990 and

Results

Eighteen Teratology Information Services of the European Network participated in the study. Data were recorded on 635 pregnancies exposed to H2-blockers of which 82 were lost to follow-up for the following reasons: follow-up form was not returned, patient or doctor had moved, patient withdrew from control visits to her gynecologist or midwife, and other. The outcome of 553 pregnancies was evaluated (ranitidine n = 335; cimetidine n = 113; famotidine n = 75; nizatidine n = 15 and roxatidine n = 15).

Of the

Discussion

Our prospective cohort study confirms earlier data that the use of H2-blockers during pregnancy does not significantly increase the risk of major congenital malformations or other pregnancy complications.

Only two cases of adverse pregnancy outcome are reported in the literature, one of a MURCS association (Müllerian duct, renal and cervical vertebral defects) after prenatal exposure to cimetidine [16] and one of transient liver impairment in an infant born to a mother receiving cimetidine in

References (23)

  • B. Källén

    Delivery outcome after the use of acid-suppressing drugs in early pregnancy with special reference to omeprazole

    Br. J. Obstet. Gynaecol.

    (1998)
  • Cited by (56)

    • A survey on the incidence of common musculoskeletal side effects among the patients taking long-term anti-ulcerant therapies in Bangladesh

      2022, Toxicology Reports
      Citation Excerpt :

      During this survey, respondents have chosen between PPIs and H2-blockers users for several GI problems where most of them were PPIs users (95 %). This large usage difference between these two antiulcerants might be due to the good treatment success with greater inhibition of gastric acid secretion properties of PPIs at low doses while safety concerns for the H2-blocker use in some cases [6–8] and the recent report of the presence of unacceptable level of N-Nitrosodimethylamine, hepatotoxic and carcinogenic agents, in H2-Blockers, might also decrease the number of H2-blockers prescriptions nowadays [9,10]. The study computed several influencing factors such as age, gender, BMI, dietary intake, cigarette smoking and alcohol status and a few other parameters, but we didn’t observe any significant differences between these parameters that can affect the study outcomes (Table 1 and Table 2).

    • Ethical approval for multicenter cohort studies on drug exposure during pregnancy: A survey among members of the European Network of Teratology Information Services (ENTIS)

      2018, Reproductive Toxicology
      Citation Excerpt :

      Furthermore, TIS staff collects patient data both during initial contact and after a follow-up period covering pregnancy outcome. Using these data from individual TIS databases, ENTIS has been successful in performing collaborative research leading to a significant number of scientific contributions regarding a variety of drugs during pregnancy [1–19]. This research activity is an important mainstay for one of the primary ENTIS goals, which is “to contribute to the primary prevention of birth defects and developmental disorders”.

    • The Effect of Diabetes and Hypertension on the Placental Permeation of the Hydrophilic Drug, Ranitidine

      2016, Placenta
      Citation Excerpt :

      Previous studies have shown that ranitidine does cross placenta and that umbilical cord levels are equal or lower than the maternal serum concentrations. It is also found to accumulate in amniotic fluid and that its clearance in fetus is similar to its maternal clearance [4,5]. One of ranitidine's side effects is the subsequent increase in gastric pH in neonates, as bacterial overgrowth and infections become a serious possibility [6,7].

    • Towards in vitro DT/DNT testing: Assaying chemical susceptibility in early differentiating NT2 cells

      2015, Toxicology
      Citation Excerpt :

      Due to very little literature on the β adrenoceptor antagonist timolol, the 5-HT serotonin receptor modulators cinanserin and fluperlapine, the potassium channel-blocking class III antiarrhythmic drug nifekalant and the nicotinic acetylcholine receptor agonist 1.1-dimethyl-4-phenylpeperazinium iodide, potential developmental adverse effects were assessed indirectly via congeneric molecules and have been reported for beta blocking agents (Altoama et al., 2015; Finn et al., 2012; Sun et al., 2014), modulators of the 5-HT serotonin receptor system, which is generally considered a target for neuroteratogens (Aldridge et al., 2005), potassium channel-blocking class III antiarrhythmic drugs (Jomaa et al., 2014; Mikovic et al., 2010; Yamamoto et al., 2006) and nicotinic acetylcholine receptor agonists (Rasoulpour et al., 2012; Slotkin and Seidler, 2015). For the histamine H2 receptor antagonist roxatidine older studies report no indication for an increased risk (Garbis et al., 2005) or conclude that H2 receptor antagonist can be used safely in pregnancy (Gill et al., 2009), whereas recent research suggest additional studies – especially for H2 blockers – to be conducted before an assessment of safety with respect to birth defect risk could be made (Gilboa et al., 2014). For anastrozole, an aromatase inhibitor supporting ovulation and pregnancy in polycystic ovary syndrome and infertility, high-quality evidence on adverse effects including DT/DNT is missing.

    • Gastro-intestinal medications, hypolipidemic agents and spasmolytics

      2015, Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment: Third Edition
    • Chronic Urticaria in Pregnancy: Physiologic and Hormonal Background for an Immune Skin Disease

      2024, Journal of South Asian Federation of Obstetrics and Gynaecology
    View all citing articles on Scopus
    View full text