Review

Drug-prescribing challenges during pregnancy

Anette M Freyer

Abstract
Most women take either prescribed or over-the-counter medication during pregnancy. Pregnant women often make independent decisions about their treatment and require careful counselling that allows them to balance the risk of taking a drug against the risk of not taking a drug and leaving a medical condition untreated. Advice needs to be tailored to the individual and is hampered by the lack of safety data on drugs in pregnancy and the puerperium. Prescribing is further complicated by both the mothers and the foetus changing physiologies as riskbenefit assessments alter throughout pregnancy. Treatment decisions may require the input of multi-disciplinary teams that consider the severity of the mothers condition, maternal physiology, a drugs pharmacokinetic, pharmacodynamic and safety profile and the developmental stage of the foetus.

Keywords concordance; drug safety; pharmacokinetics; pregnancy;

prescribing; teratogen

Introduction
Almost all women use medication at some point during their pregnancy. Around one-third of women receive prescription drugs and many more use over-the-counter preparations. The ubiquitous advice on medicine bottles and package inserts to consult your doctor before using the medication should direct a flurry of inquiries to general practitioners, obstetricians and medical specialists. Yet many of us are not well equipped to weigh up the risks and benefits of taking or not taking various treatments. There can never be a generic definitive formula on prescribing for pregnant women (or those that are planning to conceive) but this article will highlight some of the important points to consider.

Challenge 1: preconception counselling

During pregnancy treatment is sought for three separate groups of conditions: pre-existing medical conditions, co-incidental illnesses and pregnancy-induced conditions. Pre-pregnancy counselling has the most obvious potential benefit in the first instance but should be offered to all women as part of routine medical

care. It is a good opportunity to address the use of medication and supplements in the run up to pregnancy and after conception. It is well recognised that preconception health has an important bearing on pregnancy outcome a pre-conception visit to offer general health advice and a review of any pre-existing conditions of the mother is, therefore, a good investment. Although there are some general guiding principles, specific advice will depend both on the underlying medical condition as well as the individual circumstances of the prospective mother. The overall aim is for the women to take the lowest effective dose of the least toxic drug for the shortest period to keep her condition under control and achieve the best possible pregnancy outcome. Not only are women more likely to conceive if their disease is controlled, but they also tend to have fewer flares during pregnancy if they are well controlled when they become pregnant. This is especially true for inflammatory conditions such as inflammatory bowel disease and systemic lupus. Rarely medication will be increased prior to pregnancy for the reasons mentioned above or to achieve tight glycaemic control in diabetic patients. Tight diabetic control before and around the time of conception reduces the risk of congenital malformations and warrants intensified insulin regimens. More commonly treatment regimens are reduced for instance statins for hypercholesterolaemia are usually discontinued and non-lifesaving medication cut back where possible (e.g. antihistamines for allergic rhinitis, beta-blockers or tricyclic antidepressants for migraine prophylaxis). At other times switching to alternate drug regimens may be advisable (e.g. substituting lamotrigine for sodium valproate in certain forms of epilepsy, changing from an angiotensin-converting enzyme inhibitor to methyldopa in the treatment of hypertension, or switching from paroxetine to another selective serotonin uptake inhibitor in the treatment of depression) because of the better safety profile in pregnancy of the alternate drug (Table 1). Changing prescriptions prior to conception has the advantage that medication can be discontinued in a controlled fashion (e.g. it is not desirable to stop anticonvulsants or antidepressants suddenly) and the effectiveness of the new treatment can be evaluated outside of pregnancy. Importantly, the woman will not be taking the potentially more teratogenic medication during the early period of organogenesis when the foetus is most vulnerable and the woman may not know that she is pregnant (Figure 1). Despite the apparent advantages of pre-pregnancy intervention, several significant challenges prevail, not least in that even in women with medical conditions the timing of pregnancy is unplanned in around 40% of cases. Furthermore, it is unreasonable to assume that any one healthcare professional could competently weigh up riskbenefit ratios for all conditions and treatments and costly multi-professional specialist teams are often required to discuss the options with the prospective mother.

Challenge 2: compliance and concordance

Involving women in the discussions about their treatment is even more important when prescribing in pregnancy than outside it. Around one-third of pregnant women receive prescriptions for medicines other than vitamins, yet only around half of these women take their prescribed treatment and most of the others do not inform their doctors about their decision not to take the
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Anette M Freyer MBBCh PhD is a Clinical Lecturer in Therapeutics at the Division of Therapeutics and Molecular Medicine, University of Nottingham Medical School, Queens Medical Centre, Nottingham, UK.

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Drugs known or suspected to cause developmental defects and safer alternatives

Drug class Drugs that should be avoided in pregnancy NSAiDs Trimethoprim (1st trimester) Aminoglycosides warfarin (1st and 3rd trimester) Sodium valproate Phenytoin ACe inhibitors Amiodarone Sulfonylureas Problems associated with these drugs Drugs considered safer alternatives Paracetamol Opiates* Penicillins Cephalosporins erythromycin Heparin Lamotrigine Carbamazepine Methyldopa Digoxin insulin

Analgesics Antibiotics

Anticoagulants Anticonvulsants

Cardiovascular drugs Hypoglycaemics

Other

Cytotoxics Retinoids Statins Thalidomide

implantation failure, cardiac defects, renal dysfunction Folate inhibitor therefore causes structural defects such as cleft palate Nephrotoxicity and ototoxicity embryopathy, central nervous system defects, neonatal haemorrhage Neural tube defects, hepatotoxicity, learning difficulties Foetal hydantoin syndrome, facial anomalies Stillbirth, renal agenesis Cardiac arrhythmias and growth restriction Multiple organ malformations including central nervous system, gastrointestinal and cardiovascular. Congenital defects Spontaneous abortion, central nervous system, heart and facial anomalies Spontaneous abortion Limb defects, major organs and central nervous system malformations

NSAiDs, non-steroidal anti-inflammatory drugs; ACe, angiotensin-converting enzyme. *For moderate-severe pain.

Table 1

medication. Expectant mothers cite concerns over harming their unborn child as the main reason for not taking the drugs, so it is important that they have access to balanced information that allows them to make an informed choice. Women are more likely to adhere to prescriptions if they are informed about the risks. Pregnant women are usually primarily concerned with the risks of taking medication, and it is important to highlight the risks of not taking the medication. An untreated medical condition may not only endanger the mothers health but also jeopardise the baby. For example, repeated generalised tonic-clonic seizures in the mother put the mother at risk of injury and sudden death and are also associated with a lower verbal intelligence quotient (IQ) in the child. On the other hand, even drugs that are known to be potential teratogens do not always cause anatomical defects: taking lamotrigine during pregnancy increases the risk of a major congenital malformation in the baby by about 1.5-fold to less than 4%. When prescribing drugs for pregnant women it is, therefore, important to counsel women about the possible harm of taking the medication and the risk of not taking the medication. Despite the anxieties over harmful side-effects of prescription drugs the use of over-the-counter medication and herbal remedies during pregnancy is increasing, possibly because women assume that these are inherently safer. Mild analgesics top the list; and although paracetamol is considered safe in pregnancy, use of nonsteroidal anti-inflammatory drugs such as ibuprofen can interfere with implantation, reduce the foetus kidney function and amniotic
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fluid volume, precipitate premature closure of the ductus arteriosus, and impede labour. It is important to recognise that because drugs are sold on supermarket shelves they are not necessarily appropriate or safe for pregnant women. Less is known about the effect of many complimentary medicines but women need to be made aware that active ingredients may harm their baby.

Challenge 3: limited evidence on drug safety

The best intentions of counselling women about the inherent risks of drugs are frustrated by the lack of clear safety data of most compounds in pregnancy. Prospective randomised trials involving pregnant or lactating mothers are exceedingly rare and extrapolations from marketing studies often with predominantly male patients and pregnancy as an exclusion criterion do not form a reliable base from which to extrapolate safety findings. So on what do we base our current knowledge? Animal studies, observational case reports or epidemiological series. As part of all new drug licensing applications manufacturers have to submit detailed animal toxicology reports including reproductive studies. Although the drug licensing requirements were less stringent in the 1960s, the manufacturers of thalidomide did present reproductive animal data that failed to alert them or the licensing boards to the risk of phocomelia. It was the compilation of case reports that led to the realisation that the mothers of babies born with short or absent limbs had taken thalidomide as a treatment

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Age of embryo (weeks) 1 2 3 4 5 6 Teeth Eye Heart Eye Palate Ear 7 8 Period of dividing zygote, implantation CNS and bilaminar embryo Heart Indicates common site of teratogen

Fetal period (weeks) 9 Brain 16 2036

Full term 38

Limbs

Ear

External genitalia Central nervous system Heart Upper limbs Eyes Lower limbs Teeth Palate

Not susceptible to teratogens Prenatal death Major congenital abnormalities (red)

External genitalia Ear functional defects and minor congenital anomalies (yellow)

Red indicates highly sensitive periods when teratogens may induce major anomalies

Figure 1 Critical periods in human development. Reproduced with permission from: Moore KL, Persaud TvN. The Developing Human: Clinically Oriented Embryology. 6th edn. Philadelphia: wB Saunders Company, 1998: 548.

for morning sickness. Safety data for pregnancy and lactation, therefore, often only become available once the drug is in widespread use and women (inadvertently) take it during pregnancy. These publications are more likely to report unfavourable findings than uncomplicated pregnancy outcomes and, therefore, serve to highlight adverse drug events rather than drug safety an inherently more difficult endpoint. When a pregnancy does not result in the delivery of a healthy infant, the search for a possible cause is desperate. Because of the high prevalence of medication use, drugs are often indicted as the probable culprit in such instances guilty by association! Studies looking at causality are less commanding: for instance, teratogens are thought to contribute to a minority (2.5%) of all congenital malformations and only about 30 drugs or drug groups are probable or definite teratogens. Nevertheless, potentially drug-induced events are often seen as avoidable, which makes it even more difficult to balance the risks of a drug against the risks of an untreated medical condition. It is easier to weighup the risks of various treatments for the same condition. In order to assist the prescriber many national drug licensing authorities provide a risk classification system such as the United States Food and Drug Administration pregnancy safety categories (Table 2). Their chief limitations lie in their categorical brevity and the fact that they leave the prescriber to balance the drugs potential benefit. However, they do serve to highlight some drugs that may be in common use in general practice but
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should largely be avoided during pregnancy (Table 1). Prescribers need to be aware that risk classifications are subjective: only a quarter of 236 common drugs were placed into the same risk category in the US and Sweden. Furthermore, the classifications are broad: the safety benefit of carbamazepine over sodium valproate is widely accepted, yet both are classified as D positive evidence of foetal risk. Classifications serve as a useful reference but provide insufficient data on which to base safe prescribing choices. More detailed information is available from the manufacturer, published literature or additional resources listed below.

Challenge 4: the biology of the foetus

Assigning strict safety ratings to drugs is further limited by the mothers and foetus genotype and changing biology. Only a small number of foetuses who are exposed to a known or suspected teratogen display any adverse effects. For instance, less than 10% of infants exposed to phenytoin have structural malformations. It is thought that the genetically encoded activity of enzymes involved in phenytoin metabolism is important in determining this risk. Infants with the lowest levels of epoxide hydroxylase activity are at highest risk of developing foetal hydantoin syndrome. It is thought that the low levels of the enzyme result in higher concentrations of reactive oxide metabolites, which can adversely affect DNA repair or RNA stability.

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United States Food and Drug Administration foetal risk categories

Category A Description Adequate, well-controlled studies in pregnant women have not shown any risk to the foetus in the first 3 months of pregnancy. There is no evidence of risk later either. There have been no adequate, well-controlled studies in women but studies using animals have not shown any risk or animal studies that have found risk, this was not confirmed by adequate studies with pregnant women. No adequate, well-controlled studies have been performed in pregnant women but studies in animals have shown harmful effect to the foetus, or there have not been any studies done with either animals or women. CAUTiON iS ADviSeD but the benefits of this medication still may outweigh the risks. Clear evidence of RiSK TO HUMAN FOeTUS. Benefits may still outweigh the risks if the woman has a serious condition that cannot be treated effectively by a safer drug. Clear evidence that the medication CAUSeS ABNORMALiTieS iN THe FOeTUS. Risks outweigh the benefits for women who are or may become pregnant. Examples Doxylamine Folic acid

Diclofenac Penicillin

Salbutamol Ramapril Prednisolone Trimethoprim

Diazapam Phenytoin Atenolol

Methotrexate Thalidomide Simvastatin

Table 2

A plethora of proteins is involved in controlling cell division, cell migration, programmed cell death, DNA repair and transcription, RNA translation and degradation, protein homeostasis and ion channel activity. Theoretically the genetic setup underlying any of these processes alters the foetus susceptibility to a drugs potential teratogenic effects. Practically very few have been identified. As is true for biological systems in general, developing organisms are more vulnerable than mature fully developed organisms and similar insults at various stages of development have varying effects. Prior to implantation, an insult is thought to have an allor- nothing effect: either the zygote or blastocyst survives without any recognisable untoward effect or it dies. Beyond this, during the critical periods of organ formation (Figure 1), the embryo is particularly vulnerable to the
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teratogenic effects of drugs. The specialised needs of differentiating cells make them especially sensitive to insults or deprivation. Under certain circumstances it may be possible and prudent to delay the use of non-lifesaving medication beyond the first trimester. When this is not feasible we need to consider specific risks. For example, we know that the use of folate antagonists (such as phenytoin and carbamazepine which impair folate absorption; trimethoprim a dihydrofolate reductase inhibitor; and many cancer chemotherapeutic agents that inhibit thymidylate synthase) in early pregnancy increases the risk of neural tube defects. However, we also recognise that this particular risk is only of concern up to the end of the 4th week of gestation (6th week since last menstrual period) as the neural tube closes by then. Therefore, we ought to consider alternative treatments or institute additional folic acid supplementation during this time. Knowledge about specific vulnerable periods in development also underpins anticoagulation regimens. Women are often switched from their pre-pregnancy maintenance dose of warfarin to a heparin at the beginning of pregnancy. Once the critical period for developing coumarin syndrome passes, women often choose to return to their tablet rather than injection form of therapy and warfarin is restarted after 12 weeks gestation. Because it is not generally deemed desirable to deliver whilst on warfarin because of the increased risk of haemorrhagic complications in mother and neonate, women are then often swapped back onto heparin in the last trimester. However, these generalised protocols are not universally applicable: it is important to consider additional factors such as the indication for warfarin and the risk of thrombotic or haemorrhagic complications. For instance certain mitral valve replacements are at high risk of clotting a potentially fatal problem and in this case the possibility of coumarin syndrome may pose an overall more acceptable risk than a potential valve thrombosis. Early on in pregnancy the most striking untoward effects on the foetus are structural malformations. However, organs continue to develop and mature throughout pregnancy and later adverse effects are, therefore, more likely to be functional. These side-effects are often more subtle and may only become apparent once the child is older, such as the increased requirement for special needs education in children whose mothers took sodium valproate during pregnancy. Furthermore, drugs may influence how well the baby will adapt to life outside the womb. Some of these effects can be extrapolated from the mode of action of the drug, others are less intuitive: for example, the use of beta-blockers in the last trimester has been linked not only with neonatal bradycardia but also with neonatal hypothermia and hypoglycaemia. Other drugs may predispose babies to neonatal drug withdrawal syndromes: the babies born to mothers on regular opiates or antidepressants effectively go cold turkey after their placental drug supply is cut off. Interestingly, supplying an ongoing low dose of the drug by breastfeeding may actually ameliorate the symptoms. Many of these complications are not insurmountable but it would be prudent to inform the paediatricians and invite them to the delivery suite to try and immediately address any problems that may arise. Ongoing surveillance is, therefore, important as the relative risks and benefits to mother and baby may change throughout pregnancy.

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Challenge 5: the mothers changing physiology

A womans body undergoes numerous changes during pregnancy that may influence the pharmacokinetics (how the body handles the drug) and pharmacodynamics (how the body responds to the drug) of medication. These physiological changes may influence drug absorption, distribution, metabolism and/or elimination, as well as a drugs therapeutic and toxic effects. Absorption Systemically acting oral medication requires absorption from the gastrointestinal tract. Medication is commonly prescribed to be taken in the morning, a time when morning sickness as the name implies tends to be at its worst. Women may, therefore, not take their medicine at all or vomit at least part of it up. Changing the time of day when the medicine is taken may be a simple solution to this problem. In some cases, the patient will also need to be prescribed an anti-emetic. Other physiological changes of pregnancy are seldom relevant clinically, although it is well recognised that progesterone directly inhibits gastric acid secretion and slows gastrointestinal motility. Theoretically this can slow drug absorption and lead to lower peak drug concentrations. This tends to be more of a problem with single doses, especially anti-emetics or analgesics, which rely on peak concentration for their effect and where patients appreciate a rapid onset of action. Distribution Total body water increases by around 8 litres during 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 significantly during pregnancy, and some drug is displaced from its protein carrier by the higher concentration of steroid hormones, the proportion of bound drug is lower, leaving proportionally more free drug. As it is the free drug that is pharmacologically active both therapeutic and toxic effects may be enhanced initially but as it is also the free drug that is cleared (metabolised or excreted) the effect will be shorter lived. Caution needs to exercised when interpreting assays for drugs such as phenytoin as laboratories tend to report total drug (not free drug) concentrations the higher free concentrations are not reflected in the total drug concentration result and drugs should not be increased on the basis of these levels alone. Total body fat also increases during pregnancy but this usually has no demonstrable clinical effect on drug pharmacokinetics. Changes in distribution tend to be larger with hydrophilic drugs (such as most antibiotics) than with lipophilic drugs (such as antipsychotics or antidepressants). Metabolism Drug metabolism involves two kinds of biochemical reactions: catabolic phase I reactions (oxidation, reduction or hydrolysis) and anabolic phase II reactions, which involve conjugation to an inactive compound. The effect of pregnancy on drug metabolism is complex and can affect the cytochrome P450 (CYP) enzymes of phase I reactions, as well as the transferase enzymes of phase II reactions. Some enzymes of the CYP family are induced by steroid hormones, others inhibited (Table 3).
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Effect of pregnancy on cytochrome P450 isoenzymes

Enzyme CYP1A2 Effect of pregnancy inhibited, especially in the 3rd trimester Probably inhibited Example of substrates Amitryptiline, Caffeine, Haloperidol, Olanzapine, Ondansetron, Theophylline Citalopram, Propanolol, Proton pump inhibitors, Thalidomide NSAiDs Amitryptiline, Clomipramine, Chlorpheniramine, Codeine, Fluoxetine, Haloperidol, Metoclopramide, Propanolol Calcium channel blockers, Carbamazepine, Chlorpheniramine, erythromycin, Hiv protease inhibitors, Midazolam, Tacrolimus

CYP2C19

CYP2C9 CYP2D6

induced induced

CYP3A4

induced

NSAiDs, non-steroidal anti-inflammatory drugs.

Table 3

Clinically, one of the most relevant alterations of a phase II reaction is the induction of UDP-glucoronosyltransferase, which inactivates lamotrigine, so doses of this antiepileptic commonly 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 around 50%. This results in enhanced clearance, especially of drugs that are excreted unchanged in the urine (such as penicillins and digoxin). Hepatic blood flow is also increased and may thus lead to increased hepatic clearance, though this is counteracted in part by the physiological cholestasis of pregnancy. The effect on hepatically cleared drugs such as theophylline can, therefore, be unpredictable. Pharmacodynamics Alterations in pharmacodynamics effects are primarily due to the changes in the underlying physiology. For instance, beta-blockers are less likely to cause bradycardia in the presence of the relative tachycardia of pregnancy and calcium channel blockers are less likely to further decrease total peripheral resistance in the already vasodilated blood vessels. Angiotensin-converting enzyme inhibitors (which are contra-indicated in pregnancy) are also less effective in reducing blood pressure, because pregnant women are less sensitive to the renal and vascular effects of angiotensin II. Thus, the physiological changes of pregnancy have the potential to alter drug pharmacokinetics and pharmacodynamics at several steps but this is usually only clinically relevant in drugs with a narrow therapeutic index, such as anti-epileptic medication. When in doubt, free drug levels should be monitored.

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Challenge 6: the role of the placenta in foetal drug exposure

Historically the foetus was thought to exist in a safe haven protected from environmental and infective insults. We now know that this is not true but can we rely on placental drug transporters to limit foetal drug exposure? Most drugs that enter the maternal circulation can cross the placenta. This occurs mainly by diffusion and is easier for lipophilic substances in this case the rate limiting factor is placental blood flow. Polar hydrophilic substances (which include many nutrients and waste products) diffuse only slowly, a process limited by membrane permeability. Although this means that drugs diffuse slowly from mother to foetus, the reverse is also true, and drugs and their metabolites may become trapped in the foetal system. This process may be encouraged by the lower pH in the foetal circulation, where hydrophilic substances become ionised and more polar. Drugs may also accumulate in amniotic fluid where concentrations as much as four times the maternal serum concentration have been recorded for labetalol. These processes are counteracted by efflux transporters. P- glycoprotein is situated on the maternal side of the trophoblast, has broad selectivity, and uni-directionally pumps out potentially toxic compounds back towards the maternal circulation. P-glycoprotein thereby limits foetal drug exposure. Multidrug resistance-associated proteins do a similar job for polar compounds, less is known about the selectivity of breast cancer resistance protein, although its function appears to be similar to that of P-glycoprotein. Other placental transporters can pump in both directions and are important in maintaining homeostasis, although less little is known about their role in modulating foetal drug exposure. Influx transporters that actively pump substances into the foetal compartment have been identified but their role in drug translocation has not as yet been studied. Several CYPs isoenzymes are also known to be expressed in placental tissue but they are not thought to have a major effect on metabolising drugs to inactive metabolites. Overall, the mechanical and physiological properties of the placenta appear to work together to minimise foetal drug exposure, although in some instances toxic metabolites may accumulate.

Very few medical conditions are contra-indications to breastfeeding. Many women are aware of the benefits of breastfeeding and we should try to support them if they would like to do so by choosing drugs that pose minimal risk to the nursing infant. Unfortunately, safety data for drugs in lactation are even scarcer and vaguer than those in pregnancy. Even though many drugs pass into breast milk, few are present in sufficient quantity to cause any adverse effects. However, some drugs are actively secreted and concentrated into breast milk (e.g. phenobarbital), others have undesirable pharmacodynamic effects on the baby (e.g. iodine in amiodarone may cause neonatal hypothyroidism, cytotoxics may cause bone marrow suppression), and the immature neonatal liver may be unable to break down drugs drug accumulation can then have undesirable effects in the baby (e.g. benzodiazepines can lead to drowsiness). Consulting neonatologists is often helpful in this situation not only because they have experience in dealing with adverse drug reactions in babies, but also because of their detailed understanding of neonatal physiology.

Conclusion
Prescribing in the emotionally charged setting of pregnancy without the back-up of strong scientific evidence is a daunting challenge. But as women will continue to have babies, and as perfect health cannot be guaranteed for all during their 9 months of confinement, it is important to be aware of potential prescribing issues. Individual solutions are often derived by multi-disciplinary teams in consultation with the prospective mother.

Challenge 7: prescribing in the postpartum period

Prescribing challenges do not disappear after delivery as we face two main predicaments: how quickly does the maternal physiology return to baseline and are the medicines safe for a breastfed infant? The rate at which physiology normalises varies widely between individuals and physiological systems. Fluid shifts briskly in the first 48 hours after delivery. Renal physiology has generally reverted to pre-pregnancy levels by 6 weeks postpartum, whereas the cardiovascular system may require 3 months. Adjusting prescriptions is easier if we know the pre-pregnancy drug doses: women usually resume their pre-pregnancy insulin regimen the day after delivery. Anti-epileptic medication is generally weaned to pre-pregnancy doses by the end of the first week postpartum. However, these are rough guidelines and we need to exercise great care during this period of rapid flux. Which parameters (e.g. blood pressure, urine output and blood sugar levels) require intensive monitoring will be dictated by the underlying condition.
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FUrThEr rEADIng Adab N, Kini U, vinten J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004; 75: 15751583. Briggs G, Freeman R, Yaffe S. Drugs in pregnancy and lactation, 7th edn. London: Lippincott, williams & wilkins, 2005. Butters L, Howie CA. Awareness among pregnant women of the effect on the fetus of commonly used drugs. Midwifery 1990; 6: 146154. Chambers K. Asthma education and outcomes for women of childbearing age. Case Manager 2003; 14: 5861. Conover eA. Herbal agents and over-the-counter medications in pregnancy. Best Pract Res Clin Endocrinol Metab 2003; 17: 237251. Dawes M, Chowienczyk PJ. Drugs in pregnancy. Pharmacokinetics in pregnancy. Best Pract Res Clin Obstet Gynaecol 2001; 15: 819826. Finnell RH. Teratology: general considerations and principles. J Allergy Clin Immunol 1999; 103: S337342. Moore KL, Persaud TvN. The developing human: clinically oriented embryology, 6th edn. Philadelphia: wB Saunders Company, 1998. Morrow J, Russell A, Guthrie e, 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: 193198. Rodier PM. Correlations between prenatally-induced alterations in CNS cell populations and postnatal function. Teratology 1977; 16: 235246. Unadkat JD, Dahlin A, vijay S. Placental drug transporters. Curr Drug Metab 2004; 5: 125131. weiner CP, Buhimschi C, Swaan P. Drug-prescribing challenges during pregnancy. Curr Obstet Gynaecol 2005; 15: 157165.

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Practice points
All women of childbearing age are potentially pregnant check before you prescribe women will have their own views on medications and the risks they pose to their babies discuss these, if possible, prior to conception Balance the risk of taking a drug with the risks of not taking a drug: sick mums are more likely to have sick babies Prescribe the lowest dose of the most appropriate drug for the shortest possible time The altered physiological state of pregnancy may affect a drugs pharmacokinetics doses may need to be altered check levels if you are concerned Many women require multi-disciplinary teams to manage their illnesses during pregnancy consult your colleagues A foetus susceptibility to toxic effects changes throughout gestation

Additional resources
British National Formulary ontains appendices with guidance on prescribing in pregnancy and for breastfeeding mothers Toxbase includes information about safety of drugs in pregnancy and lactation: www.toxbase.org National Teratology Information Service offers information on drugs and pregnancy for routine enquiries (Tel: 0191 232 1525) and in emergencies (Tel: 0191 223 1307) Drugs in Pregnancy and Lactation edited by Briggs, Freeman and Yaffe (Lippincott, williams & wilkins 2005) provides a comprehensive reference source, including results from animal studies and is available for PDAs and pocket PCs Cochrane Database Group as part of the Cochrane Collaboration provide reviews on a range of drug therapies in pregnancy: www.cochrane/org

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