Patricia R. McElhatton

The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS)

The European Network of the Teratology Information Services (ENTIS) has collected and evaluated data on 689 pregnancies in which exposure to tricyclic and nontricyclic antidepressants occurred. Data were collected prospectively from the time of in utero exposure and all the cases were followed up to the first few weeks of postnatal life using standardized procedures. In most cases, no longer term follow-up data were available. Approximately two-thirds of the mothers were on multidrug therapy, and of those, half took a benzodiazepine. About 95% of the patients were exposed during the first trimester. The most striking feature of the pregnancy outcomes is that 97% of live-born babies were morphologically normal. The incidence of spontaneous abortion and late fetal/neonatal deaths were within the normal range. Fourteen live-born babies and one fetus had either major or minor malformations, and six had minor anomalies. However, there was no increase in either a particular type of malformation or a specific pattern of defects. Another 31 infants without malformations had neonatal problems; these were usually associated with chronic multidrug therapy, especially near term. Elective termination of pregnancy occurred more frequently in the multidrug groups (86 out of 488) than in the monotherapy groups (20 out of 201), but data concerning the condition of the fetus are not available in the majority of the cases. Overall, no causal relationship could be established between in utero exposure to antidepressants and adverse pregnancy outcome.

The effects of benzodiazepine use during pregnancy and lactation

Although there are a number of studies and individual case reports concerning the use of benzodiazepines in human pregnancy, the data concerning teratogenicity and effects on postnatal development and behaviour are inconsistent. There is evidence from studies in the 1970s that first trimester exposure to benzodiazepines in utero has resulted in the birth of some infants with facial clefts, cardiac malformations, and other multiple malformations, but no syndrome of defects. Diazepam and chlordiazepoxide are amongst the drugs most frequently implicated in the earlier studies. However, data from later studies provide no clear evidence of significant increase in either the overall incidence of malformations or of any particular type of defect. Many of the women included in these studies has psychiatric illnesses, epilepsy, or diabetes all of which have an intrinsic risk in pregnancy, and some were on multidrug therapy. Medical-obstetric histories and family history of malformations were not always presented in the publications, which makes assessment of risk associated with benzodiazepine use per se difficult. Nevertheless, in most of the studies involving first trimester use of benzodiazepines, the majority of infants were normal at birth and had normal postnatal development. Late third trimester use and exposure during labour seems to be associated with much greater risks to the fetus/neonate. Some, but by no means all infants exposed at this time, exhibit either the floppy infant syndrome, or marked neonatal withdrawal symptoms. Symptoms vary from mild sedation, hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms have been reported to persist for periods from hours to months after birth. This correlates well with the pharmacokinetic and placental transfer of the benzodiazepines and their disposition in the neonate. However, there has been no significant increase in the incidence of neonatal jaundice and kernicterus in term infants. The prolonged use of benzodiazepines throughout pregnancy raised the concern that there may be altered transmitter synthesis and function, leading to neurobehavioural problems in the children. In approximately 550 children who were followed up for various times up to four years of age, there is no increase in either the malformation rate or adverse effects on neurobehavioural development and IQ. Although some of the data indicate that a small number of children were slower to develop during the first year or so, they did exhibit catch up growth and most had developed normally by four years of age. Where developmental deficits persisted, it was not possible to prove a cause-effect relationship with benzodiazepine exposure. These children were often from families where there was maternal illness requiring prolonged drug therapy or where there were social problems. It is important to consider poor environmental and social factors when assessing the possible prenatal influence of the benzodiazepines on the postnatal health and development of the child. There is evidence that clonazepam, clorazepate, diazepam, lorazepam, midazolam, nitrazepam, and oxazepam are excreted into breast milk. The published data indicate that the levels detected in breast milk are low; therefore, the suckling infant is unlikely to ingest significant amounts of the drug in this way. Problems may arise if the infant is premature or has been exposed to high concentrations of drug either during pregnancy or at delivery.

Congenital anomalies after prenatal ecstasy exposure

Prospective follow-up of 136 babies exposed to ecstasy in utero indicated that the drug may be associated with a significantly increased risk of congenital defects (15.4% [95% CI 8.2-25.4]). Cardiovascular anomalies (26 per 1000 livebirths [3.0-90.0]) and musculoskeletal anomalies (38 per 1000 [8.0-109.0]) were predominant.

Birth weight of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study

BACKGROUND The effects of in utero exposure to atypical antipsychotics on infant birth weight are unknown. AIMS To determine whether atypical and typical antipsychotics differ in their effects on birth weight after maternal exposure during pregnancy. METHOD Prospective data on gestational age and birth weight collected by the National Teratology Information Service for infants exposed to typical (n=45) and atypical (n=25) antipsychotics was compared with data for a reference group of infants (n=38). RESULTS Infants exposed to atypical antipsychotics had a significantly higher incidence of large for gestational age (LGA) than both comparison groups and a mean birth weight significantly heavier than those exposed to typical antipsychotics. In contrast those exposed to typical antipsychotics had a significantly lower mean birth weight and a higher incidence of small for gestational age infants than the reference group. CONCLUSIONS In utero exposure to atypical antipsychotic drugs may increase infant birth weight and risk of LGA.

Paracetamol overdose in pregnancy analysis of the outcomes of 300 cases referred to the teratology information service

A prospective study was carried out to investigate the outcome of pregnancy in 300 women who had self-administered an overdose of paracetamol, either alone, or as part of a combined preparation. Exposure occurred in all trimesters. The most striking feature of this study is that the majority of the pregnancies had normal outcomes. Over half of the mothers (160 = 53%) required treatment for the overdose, and 49 of these had specific antidotes (33 mothers had acetylcysteine and 16 mothers had methionine). The rest of the mothers were given nonspecific treatments including ipecacuanha (52), gastric lavage (42), and charcoal (16). None of the mothers died. There were 219 liveborn infants with no malformations, 61 of whom had been exposed in the first trimester. Eleven liveborn infants had malformations; none was exposed in the first trimester. On other infant exposed at 18 weeks had a diaphragmatic hernia; this pregnancy was terminated at 22 weeks. In none of these 12 infants can the malformations be directly associated with paracetamol exposure. There were no apparent differences either in the sex ratio or the body weights of term infants. There were seven full-term infants with neonatal problems that seem unrelated to paracetamol exposure. Six premature infants also had neonatal problems, which were more likely to be related to their degree of prematurity rather than paracetamol exposure. There was no obvious relationship between the time of exposure and the time of delivery. The overall conclusion is that paracetamol overdose per se is not an indication for termination of pregnancy.

A case control study to examine the pharmacological factors underlying ventricular septal defects in the North of England

Background: Amphetamine exposure is associated with congenital cardiac abnormalities in animals. We previously reported an association between recreational use of 2,4-methylenedioxymethamphetamine (ecstasy, MDMA) and ventricular septal defect in babies born to users. We have carried out a case control study to investigate risks in the occurrence of ventricular septal defect in a cohort of babies born in the North East of England. Methods: Cases were identified from paediatric cardiology units in Newcastle upon Tyne and Leeds, and controls were recruited from the mothers of babies born in the same hospital as the index case. Research nurses carried out interviews using a structured questionnaire. Results: A total of 296 case control pairs were studied. There was insufficient exposure to ecstasy to test the primary hypothesis. Increased risk of ventricular septal defect was found to be associated with consumption of cough and cold remedies [pre-conception OR 2.2, 95% CI 1.41, 3.51; pregnancy OR 5.1, 95% CI 2.56, 11.27; exposure in either OR 2.83, 95% CI 1.85, 4.45; P<0.005] and in the case of non-steroidals for exposures in pregnancy (OR 4.2, 95% CI 1.54, 14.26; P<0.005). Conclusions: These findings suggest that ventricular septal defect is associated with consuming the medications identified. They are also compatible with the hypothesis that sympathomimetics (pseudoephedrine, phenylephrine and phenylpropanolamine) present in cough mixtures cause the increased risk, and with our original hypothesis that sympathomimetics and amphetamines are potentially cardiotoxic in utero.