The medic's guide to prescribing: Prescribing in pregnancy

Pregnancy may be the trickiest situation in which doctors prescribe. Sarah Thomas and colleagues offer valuable advice in the last article of the series

When a baby is born with a congenital defect, parents and professionals look for a cause. As most women use over the counter or prescription drugs at some stage of their pregnancy, drugs are often indicted as the probable culprit-guilt by association.

Studies that look at causality are less impressive-teratogens (drugs or chemicals that cause abnormal development in cells and tissues) are thought to contribute to a minority (2.5%) of all congenital malformations.^w1 Nevertheless the thalidomide tragedy of the 1960s, when thousands of babies were born with short or absent limbs after their mothers had taken thalidomide as a treatment for morning sickness, still colours the perception of patients and doctors.

Prescribing practice is shaped by anecdotal reports, retrospective series, and extrapolations from animal studies, especially as randomised placebo controlled trials in pregnancy are exceedingly rare. Prescribing in this emotionally charged setting without the backup of strong scientific evidence is a daunting challenge. But women will continue to have babies and perfect health cannot be guaranteed for everyone during their nine months of pregnancy, so it is advisable to have an approach to prescribing for pregnant women. Here we use a fictitious case study to highlight some important points to consider.

Ms P, a 26 year old woman, was admitted to hospital after a generalised seizure. She is known to have epilepsy and had been seizure-free for the past five years while taking lamotrigine. On admission her examination was unremarkable, but she had a positive pregnancy test. At that time Mrs P was nine weeks pregnant, and on closer questioning admitted to having discontinued her drugs three weeks earlier because of concerns of harming her baby.

Compliance and concordance

Drugs are unlikely to work if not taken, but only about half of pregnant women take their prescribed treatment.^w2 Expectant mothers cite concerns of harming their unborn child as the main reason for not taking drugs, so it is important that pregnant women have access to balanced information that allows them to make an informed choice.

We need to put into perspective the risks associated with taking the drugs. Even drugs that are known to be potential teratogens do not always cause anatomical defects-for instance, taking lamotrigine in pregnancy increases the risk of a serious congenital malformation in the baby by about 1.5-fold to less than 4%.^w3 This risk must be balanced against the harms associated with not taking the drug. An untreated medical condition may not only endanger the mother's health but also may also jeopardise the baby-five or more generalised tonic-clonic seizures in the mother are associated with a lower verbal IQ in the child.^w4

Prepregnancy prescribing

When prescribing drugs for pregnant women they should be counselled about the possible harm of taking the drugs and the risks of not taking the drugs to ensure that any decisions are made in concordance (in agreement with the patient and the doctor). Ideally these discussions should take place before pregnancy. This will allow drugs to be discontinued in a controlled fashion or the patient to be established on a different drug regimen before conception if this is deemed desirable.

The timing is important as much of the structural development of the fetus is complete by the time the woman has her first antenatal appointment at the end of the first trimester (figure). A prepregnancy consultation would also offer an opportunity for advice on folic acid supplementation, healthy diet, and stopping drinking alcohol and smoking. Such preconception care improves pregnancy outcome, and women are more likely to adhere to prescriptions if they are informed about the risks.^w5

Critical periods in human development (adapted with permission^w9)

Ms P was reviewed in a joint antenatal clinic by an obstetrician and neurologist who counselled her about antiepileptic treatment and about uncontrolled seizures during pregnancy. Lamotrigine was restarted and folic acid supplementation added to reduce the risk of a neural tube defect.

Prescribing during pregnancy

Prescribing drugs to pregnant women also unnerves many doctors whose prescribing is governed by a premise to "do no harm." The absolute safety of a drug can never be guaranteed, and lists of drugs that are not known to harm the fetus are painfully short.

Guidance is often vague, with a reminder not to use a drug unless "benefit outweighs risk"-without specifying either. To help the prescriber many countries have developed risk classification systems (see table A on student.bmj.com). These also highlight some drugs that may be in common use in general practice but should largely be avoided in pregnancy (table).

*Can cause neonatal dependence and respiratory depression but is preferable to non-steroidal anti-inflammatory drugs.

In addition to consulting references, knowledge of some basic embryology is useful because it highlights the critical periods of organ formation when the embryo is particularly vulnerable (figure). Because drug effects are not limited to causing anatomical malformations, however, it is important to also consider their potential effect on growth or neurological development; whether they will influence how well the baby will adapt to life outside the womb; and whether the baby is likely to suffer from neonatal drug withdrawal.

Some factors determine the susceptibility of a fetus to the development of congenital defects and other side effects of drugs. These include the genotype of the mother and fetus; the time, dose, and duration of exposure; and variation in maternal metabolism and placental transfer. Although the mechanism of teratogenicity differs with various drugs the untoward effects may be caused by excessive or reduced apoptosis, reduced biosynthesis, impeded morphogenetic movements, or mechanical disruption of tissues.^w1

To tackle such complex issues satisfactorily, pregnant women with medical conditions are ideally looked after by multidisciplinary teams. This allows experts to deliver care in a unified approach and to monitor both mother and baby.

When patients self medicate

In addition to the health professionals' efforts many women self medicate with over the counter preparations and herbal or Chinese remedies in a belief that these are inherently safer.^w6 Mild analgesics top the list. Although paracetamol is considered safe in pregnancy, use of non-steroidal anti-inflammatory drugs such as ibuprofen can interfere with implantation of the pregnancy, reduce the fetus's kidney function, precipitate premature closure of the ductus arteriosus, and impede labour.

It is important to recognise that just because drugs are sold on supermarket shelves they are not necessarily appropriate or safe for pregnant women and many contain more than one active ingredient. Less is known about the effect of many complementary medicines but women need to be made aware that active ingredients may harm their baby.

When Ms P was seen in the antenatal clinic three weeks later she had experienced two further seizures. Although she assured her doctors that she was now taking her medication, lamotrigine concentrations measured in her blood were low. Reassuringly a single fetus of appropriate size for her gestation was seen on ultrasound scan.

Pharmacokinetics

During pregnancy a woman's body undergoes many changes that may influence the pharmacokinetics of drugs. These physiological changes can alter how the body handles drug absorption, distribution, metabolism, or elimination.^w7 Remember that these changes are not uniform, and handling of a specific drug will fluctuate during pregnancy. Thus alteration to doses may need to be made throughout the pregnancy and depend on the specific drug itself.

Absorption-Systemically acting oral drugs require absorption from the gastrointestinal tract. Drugs are commonly prescribed to be taken in the morning, a time when morning sickness tends to be at its worst. Women may therefore not take their drugs at all or vomit at least part of them up. Changing the time of day when the drug is taken may be a simple solution. The patient may also need to be prescribed an antiemetic. Other physiological changes in pregnancy, such as reduced gastric acid secretion and slowed gastrointestinal motility, can theoretically alter drug absorption, although this is rarely clinically relevant.

Distribution-Total body water increases by about 8 l in pregnancy, effectively diluting any given dose of drug and lowering its concentration in the body compared with the non-pregnant state. As serum albumin concentrations also decrease considerably in pregnancy, the proportion of drug bound to albumin decreases leaving proportionally more free drug. Because it is the free drug that is pharmacologically active, therapeutic and toxic effects may increase initially but as it is also the free drug that is cleared (metabolised or excreted) the effect will be shorter lived.

Metabolism-The activity of many metabolising liver enzymes is affected by circulating sex hormones. For instance the UDP-glucuronosyltransferase enzyme that inactivates lamotrigine is induced by sex hormones, so doses need to be increased to achieve the same serum concentrations as before pregnancy.

Excretion-The higher cardiac output of pregnancy increases glomerular filtration rate by about 50%. This results in more clearance, especially of drugs that are excreted unchanged in the urine, such as penicillins. So the physiological changes of pregnancy have the potential to alter drug pharmacokinetics at several steps, but this is usually only clinically relevant in drugs with a narrow therapeutic index, such as antiepileptic drugs. When in doubt, concentrations should be monitored.

After an increase in the lamotrigine dose, Ms P remained seizure-free and delivered a healthy baby boy at 39 weeks' gestation. The lamotrigine was rapidly decreased to the prepregnancy dose after delivery. Before discharge from hospital Ms P wanted to know whether it was safe to breast feed while taking lamotrigine.

Breastfeeding

A woman's physiology returns close to within normal parameters within days of delivery, and drug doses are usually returned to baseline within the first three days after childbirth. Breast feeding provides many short and long term benefits to mother and baby. Even though many drugs pass into breast milk, few are present in sufficient quantity to cause any adverse effects.

Some drugs are actively secreted and concentrated into breast milk (for example, phenobarbital), however. Some drugs have undesirable pharmacodynamic effects on the baby (for example, iodine in amiodarone may cause neonatal hypothyroidism, and cytotoxics may cause bone marrow suppression), and the immature neonatal liver may be unable to breakdown drugs. Drug accumulation can have undesirable effects in the baby (for example, benzodiazepines can lead to drowsiness).

When starting out as a newly qualified doctor it is natural to feel anxious about writing your first prescription, let alone prescribing to a pregnant woman. As for all aspects of prescribing it is important to seek additional information if you're unsure. Do not be disheartened; the ability to weigh up benefits and harms comes with experience and may require input from a number of specialties.

1. Finnell,RH. Teratology: General considerations and principles. J Allergy Clin Immunol 1999;103:S337-42
2. Butters L, Howie CA. Awareness among pregnant women of the effect on the fetus of commonly used drugs. Midwifery 1990;6(3):146-54.
3. Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77(2):193-8.
4. Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004;75(11):1575-83.
5. Chambers K. Asthma education and outcomes for women of childbearing age. Case Manager 2003;14(6):58-61.
6. Conover EA. Herbal agents and over-the-counter medications in pregnancy. Best Pract Res Clin Endocrinol Metab 2003;17(2):237-51.
7. Dawes M, Chowienczyk PJ. Drugs in pregnancy. Pharmacokinetics in pregnancy. Best Pract Res Clin Obstet Gynaecol 2001;15(6):819-26.
8. Briggs G, Freeman R, Yaffe S. Drugs in Pregnancy and Lactation. 7th ed: Lippincott, Williams & Wilkins, 2005.
9. Rodier PM. Correlations between prenatally-induced alterations in CNS cell populations and postnatal function. Teratology 1977;16(2):235-46.

   

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