Prescribing in pregnancy

Psychotropic drugs reduce morbidity and mortality related tomaternal mental illness but may also cause harm to the foetus,the nature and magnitude of which is not completely understood.Up-to-date information should be shared as fully as possiblewith the pregnant woman and a treatment plan agreed jointly.

INTRODUCTION

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INTRODUCTION

The background risk of congenital malformations is acceptedas being 2–3%¹ and is known to be influenced by fixedmaternal risk factors such as increasing age, physical illnessand genetics, and modifiable risk factors such as the use of medicines during pregnancy. Medicines are commonly taken bypregnant women; in the UK-based Avon study, where data aboutthe use of medicines were collected prospectively for over14 000 pregnant women, over 80% reported taking medicationother than vitamin supplements and homoeopathic remedies during their pregnancy.² Medicines may be taken to alleviate minorself-limiting symptoms associated with pregnancy such as heartburn,nausea and constipation. They may also be taken to treat moreserious maternal illness such as hypertension, diabetes, depressionand psychosis, all of which, if left untreated, may negatively affect both the woman and her unborn child. With respect topsychotropic drugs, the potential benefits of continuing treatmentduring pregnancy include improved maternal self-care and thereforefoetal well-being, and better obstetric outcome and ultimatelychild development.

Types of drug-induced harm

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Types of drug-induced harm

Almost all drugs are transferred across the placenta to thedeveloping foetus, with the degree of foetal exposure determinedby the molecular size and lipid solubility of the drug. Foetalexposure is possible at all stages of pregnancy, includingvery early pregnancy when many women will not know that theyare pregnant.

Drugs generally cause most harm to the foetus in the first trimester,when the major organs and limbs are being formed. An associationbetween the use of a particular drug and foetal abnormalityis not always easy to detect, even when a drug commonly causesan abnormality that is rare in the general population. Themost extreme example of this is thalidomide, which caused majorlimb malformations in a third of those exposed in utero, yet many thousands of babies had been born before the associationwas recognised. Perhaps the most teratogenic drug used in currentpsychiatric practice is valproate. Around 7% of babies exposedto valproate in utero have congenital malformations–upto 1 in 20 has a neural tube defect.³ This has led to theadvice that valproate should be avoided in women of child-bearing age,⁴ yet many clinicians may be unaware of the magnitudeof the risk that it poses.⁵

Drugs may also cause intra-uterine growth retardation by reducingplacental blood flow and therefore the supply of nutrientsto the foetus. Problems during and immediately after deliveryare also possible; sedative drugs such as benzodiazepines cancause respiratory depression and drugs with a short half-lifecan cause withdrawal symptoms in the neonate.

Some agents may also affect the foetus in ways that are notapparent until much later in life. For example, valproate isassociated with developmental delay and diethylstilbestrolwith adenocarcinoma of the vagina in young women.

In this issue of the British Journal of Psychiatry, Newham et al⁶ present data that suggest an association between the useof second-generation antipsychotics in pregnancy and neonatesthat are large for their gestational age (defined as >90thpercentile). This association is biologically plausible. Somesecond-generation antipsychotics are associated with considerableweight gain,⁷ direct effects on insulin secretion⁸ and the development of gestational diabetes.⁴ This association isclinically important as a neonate that is large for its gestationalage places the mother and the unborn child at risk of birth complications, and in the longer-term, the child may be atincreased risk of obesity and, ultimately, diabetes.

Sources of information about drugs in pregnancy

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Sources of information about...

It is obviously unethical to include pregnant women in randomised controlled trials as this would involve the deliberate exposureof the foetus to a potential teratogen. In clinical practicehowever, women conceive while taking prescribed medicines andpregnant women develop medical conditions that require treatment.Although information from randomised controlled trials can beused to estimate the beneficial and harmful effects that theprescribed medicine may have on the mother, considerably lessrobust data from a number of sources are used to estimate potentialharm to the unborn child.

Studies in animals may provide some reassurance, but can neverguarantee safety in human pregnancy. Once a drug has been marketed,case reports start to appear in the literature; these usuallyhighlight negative outcomes and give no indication of the absoluteor relative risk of drug exposure, or even whether the outcomereported was due to the drug at all. Case reports can be usedto generate hypotheses that can be tested using prescriptiondatabase or case–control studies.

Prescribers also contact specialist centres such as the NationalTeratology Information Centre (NTIS) for advice. The advantageof NTIS data is that they are collected prospectively–thatis, before the outcome of the pregnancy is known. The disadvantagesare that it is not known whether the cases that doctors consultNTIS about are representative of women who take the drug in question during pregnancy and that there is no control groupthat allows assessment of the impact of other important variablessuch as the illness the drug was prescribed to treat or lifestyle.

The problems associated with interpreting NTIS data are highlightedby the literature pertaining to the safety of selective serotoninreuptake inhibitors (SSRIs) in pregnancy. A study based onthese data suggested an association between paroxetine andcardiac septal defects:⁹ of 330 paroxetine-exposed infants,5 had septal defects. This finding was not replicated by Alwanet al¹⁰ in a case–control study based on 1931 infantswith septal heart defects; however, in a further case–control study¹¹ based on 1161 children with septal defects, sertalinehas been implicated. In this issue of the Journal, Ramos et al¹² report on a case–control study that included dataonly for women who had received a diagnosis of a mood or anxietydisorder and had been prescribed antidepressant drugs in theyear prior to conception. This allowed the prevalence of antidepressantuse during pregnancy by the mothers of infants with and withoutcongenital malformations to be compared, relatively free of the confounding effects of maternal mental illness. Their datasuggest that the effects of maternal mental illness on obstetricoutcome may be considerable and the effects of SSRIs negligible.A second study in this issue,¹³ which also controlled forthe effects of maternal mental illness, reports that decreased gestational age and birth weight, and increased neonatal respiratorydistress, effects that have all previously been linked withSSRIs, were associated with the duration rather than the timingof in utero exposure. The severity of maternal illness partiallyaccounted for these outcomes.

Although these studies provide some reassurance regarding thesafety of SSRIs in pregnancy, the findings of Newham et al⁶in this issue raise new safety concerns about second-generationantipsychotics, specifically an increased risk of neonateswho are large for their gestational age. Their conclusionsare in contrast to those of McKenna et al,¹⁴ who reportedon data from the Canadian and Israeli teratology information services. Outcome data were available for 151 women who tooksecond-generation antipsychotics during pregnancy; babies bornto these women had a lower mean birth weight than babies bornto controls, despite the mean body mass index of the womentaking antipsychotics being higher than that of the controls.The data reported did not suggest an association between second-generation antipsychotics and neonates who were large for their gestationalage.

The paper by Newham et al⁶ was based on data for 86 womenwho were exposed to antipsychotics during pregnancy. Duringthe 10-year period that it took to accrue these cases, the averagebody mass index of the UK population was increasing, as wasthe use of second-generation antipsychotics–disentanglingthe weight-gaining effect of medication from the backgroundpopulation effect is impossible in the absence of a controlgroup. Other factors are also important. First- and second-generationantipsychotics are not distinct groups of drugs with clearly delineated receptor affinity or side-effect profiles: groupingdrugs in this way to determine an association with somethingas complex as effects on the foetus is fraught with difficulties.Newham et al also acknowledge that there is uncertainty overthe accuracy of their data on smoking, an important confoundingvariable when looking at birth weight as an outcome. Nevertheless,their recommendation that foetal size should be carefully monitoredin women who take olanzapine or clozapine during pregnancy is compelling.

Dilemma of prescribing in pregnancy

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Dilemma of prescribing in...

All standard psychopharmacology texts and evidence-based prescribing guidelines recommend that medicines should be prescribed forpregnant women only if the potential benefits to the motheroutweigh the potential risks to the unborn child. Given thatneither benefit nor harm are unidirectional and our understandingof the impact of drug treatment in both the short- and long-termis far from complete, the woman and her partner must be as fully involved as possible in the decision-making process. The UKNational Institute for Health and Clinical Excellence (NICE)evidence-based guideline on the management of antenatal andpostnatal mental health⁴ emphasises the importance of thisapproach and of acknowledging uncertainty over the nature andmagnitude of risk that drug treatment poses to the foetus. Communicatingthis constantly evolving information in a way that is easy to understand is clearly challenging.

REFERENCES

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