Whats neW in prescribing in pregnancy

Whats new in prescribing in pregnancy

sally stephens Ken hodson simon hL thomas

Most drugs can cross the placenta and some of these have adverse foetal effects. Organogenesis occurs between 18 days and 10 weeks of gestation and this is the highest risk period for teratogenic effects. however, later exposure may cause growth or developmental effects while exposure near term may be associated with neonatal toxicity or withdrawal syndromes. this article provides an update on prescribing during pregnancy, concentrating on the management of hypertension, hypercholesterolaemia, diabetes, epilepsy and depression, as well as treatments for autoimmune disease and organ transplantation.
Keywords autoimmune disease; depression; diabetes; epilepsy; hypertension; pregnancy; therapeutics; transplantation
Most drugs have a molecular weight of less than 600 Daltons, and so are able to cross the placenta freely. Some have teratogenic properties, i.e. cause congenital structural or functional abnormality in the offspring after in utero exposure. In the UK the background risk for all congenital abnormalities is between 2 and 3%. Of these, it is estimated that 25% are secondary to drug or toxin exposure. Factors contributing to the risk of teratogenicity include dose, duration of exposure and genetic susceptibility. Timing of exposure is critical: most congenital malformations are likely to arise if exposure occurs between 18 days and 10 weeks of gestation, the period of organogenesis. Prior to this, exposure is likely to either have no effect or to cause foetal death (the all or nothing effect). Congenital abnormalities are unlikely from later exposure,

Whats new?
there is increasing evidence that ace inhibitors and statins can cause congenital malformations and, if possible, these drugs should be avoided during pregnancy n women with gestational diabetes, metformin appears as effective as insulin and is i better tolerated. glyburide also has similar efficacy to insulin ssri antidepressant use in pregnancy has recently been linked with anencephaly, craniosynostosis and omphalocele, while use in late pregnancy may provoke persistent pulmonary hypertension of the neonate. paroxetine has been associated with congenital cardiac malformations Older antiepileptic drugs, especially sodium valproate, can cause neural tube defects and other malformations, especially when used in combination. Lamotrigine monotherapy may be safer, but there are inadequate data available for assessing the safety in pregnancy of newer antiepileptic drugs Methotrexate and mycophenolate mofetil are teratogenic, but no increased risk of foetal malformations has been found with azathioprine or tacrolimus. there is inadequate information available on the safety of biological disease-modifying therapies when used during pregnancy

but there may be effects on foetal growth and neurological development.

Sally Stephens PhD is Assistant Head of Teratology at the United Kingdom Teratology Information Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK. Competing interests: none declared. Ken Hodson MBChB MRCP is a Specialist Registrar in Medicine and Clinical Pharmacology and Therapeutics at the UK Teratology Information Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK. Competing interests: none declared. Simon HL Thomas MD FRCP FRCPE is Medical Director of the UK Teratology Information Service, Newcastle upon Tyne Hospitals NHS Foundation Trust,and Professor of Clinical Pharmacology and Therapeutics at the Institute of Cellular Medicine, Newcastle University, UK. Competing interests: none declared.

Therapeutics in pregnancy
Medicines should only be prescribed in pregnancy when absolutely necessary, weighing the benefits against possible risks. Risks of discontinuation of long-term therapy to the mother and foetus should also be considered. In some conditions, for example epilepsy or asthma, the risks associated with uncontrolled disease may outweigh the risk of in utero exposure.

MeDicine 37:9

500

2009 elsevier Ltd. all rights reserved.

Whats neW in prescribing in pregnancy

Drugs contraindicated during pregnancy

Absolute Cytotoxic drugs busulphan cyclophosphamide Methotrexate Vitamin A analogues etretinate, isotretinoin Thalidomide Relative Psychotropic drugs Lithium

Anticoagulants Warfarin Anticonvulsants carbamazepine phenytoin sodium valproate Cardiovascular drugs beta-blockers Minoxidil Antibiotics tetracycline ciprofloxacin aminoglycosides chloramphenicol nitrofurantoin Vancomycin Anti-inflammatory drugs colchicine Endocrinological drugs carbimazole propylthiouracil

Cardiovascular drugs angiotensin-converting enzyme inhibitors angiotensin ii inhibitors spironolactone Antifungal drugs griseofulvin Ketoconazole triazoles fluconazole, itraconazole (in high doses) terbinafine

been shown to be teratogenic, causing congenital renal dysfunction (e.g. oligohydramnios, neonatal anuria), pulmonary hypoplasia, intrauterine growth restriction (IUGR) and increased foetal death. Skeletal abnormalities such as hypocalvaria (failure of skull bone formation) have also been reported. There is also evidence of an increased risk of cardiovascular and central nervous system (CNS) anomalies after first-trimester exposure. Angiotensin II blockers have a similar teratogenic profile in animal studies, and case reports in humans have also described renal and CNS anomalies. Beta-blockers, especially atenolol, have been associated with intrauterine growth restriction, respiratory depression, neonatal bradycardia, hypoglycaemia and hypothermia, effects predictable from their pharmacological properties. However, significant teratogenic effects have not been identified. There is conflicting evidence as to whether labetolol may have similar effects and it is commonly used as a second-line agent. Screening for IUGR is appropriate in pregnant patients treated with these agents. Hypercholesterolaemia Along with the incidence of obesity and diabetes, the proportion of young women treated with statins is increasing. Cholesterol is an essential component for growth and development, including cell membrane formation and steroid synthesis. Drugs that interfere with cholesterol metabolism could therefore have teratogenic potential. Animal toxicity studies have shown inconsistent results. Simvastatin and atorvastatin have not been associated with increased teratogenicity but skeletal malformations were reported after exposure to lovastatin, cerivastatin or fluvastatin. In humans, there have been case reports of severe CNS malformations and unilateral limb deficiencies with statin exposure and of vertebral-analcardiac-tracheal-oesophageal-renal-limb (VACTERL) wmalformation after lovastatin exposure. However, data from two observational studies involving 513 women did not detect an increased risk of abnormalities.1,2 In view of the uncertainty about safety in pregnancy and the low absolute risk associated with untreated hypercholesterolaemia for the duration of pregnancy, it

Anti-inflammatory drugs nsaiDs (third trimester) Endocrinological drugs radioactive iodine sex hormones Octreotide Antihelminthic drugs Mebendazole Others Misoprostol Mefloquine biphosphonates

Others Dapsone (third trimester)

adapted from shehata, ha and nelson-piercy c. Drugs to avoid in pregnancy: Curr Obstet Gynaecol 2000; 10: 4452.

Table 1

Frequently used drugs that are contraindicated or should be used with caution in pregnancy are shown in Table 1 and treatment of common disorders is outlined in Table 2. Prescribing information and advice can be obtained from the National Teratology Information Service and other sources (see Table 3). Hypertension The antihypertensive agent most appropriate for use in pregnancy is methyldopa,

since there is considerable experience of its use. Labetolol and long-acting nifedipine preparations are also commonly used. National Institute for Health and Clinical Excellence (NICE) guidelines recommend angiotensin-converting enzyme (ACE) inhibitors or beta blockers as first-line treatment in younger non-black females who are not planning pregnancy, but these are associated with problems if used in pregnancy. ACE inhibitors have
501

MeDicine 37:9

2009 elsevier Ltd. all rights reserved.

Whats neW in prescribing in pregnancy

Common therapeutic problems in pregnancy

Therapeutic problem pain 1st line paracetamol 2nd line codeine 3rd line nsaiD - usually ibuprofen - until 28 weeks only Comments nsaiDs are not recommended after 28 weeks due to the risk of premature closure of the ductus arteriosus chronic use of opiates, or high-dose regimens may cause maternal constipation and respiratory depression in the foetus/neonate saline laxatives, i.e. magnesium, sodium and potassium salts, are not recommended due to electrolyte disturbances Lubricant laxatives (liquid paraffin) can interfere with absorption of fat-soluble vitamins

constipation

stool-bulking agent (ispaghula)

Lactulose or glycerin suppositories

senna (possible effect on uterine contractions) or docusate sodium in low doses

heartburn and dyspepsia nausea and vomiting

antacids (aluminium/ magnesium hydroxide) cyclizine or promethazine

h2 receptor antagonists ranitidine is preferred Metoclopramide or prochlorperazine

proton pump inhibitor omeprazole is preferred Ondansetron limited data; suitable for treatment of resistant symptoms only Metoclopramide is commonly associated with dystonias in younger adults and is therefore not usually considered for firstline therapy Fluconazole in high-dose chronic therapy (>400mg/day) is not recommended Massaging and stretching the effective muscles may bring relief

candidiasis

topical imidazole clotrimazole all drug treatment should be avoided

Fluconazole single 150mg dose only

Leg cramps

nsaiD, non-steroidal anti-inflammatory drug.

Table 2

is recommended that statins are not prescribed during pregnancy. Diabetes Diabetes in pregnancy is associated with increased risks of miscarriage, congenital abnormality, foetal macrosomia, neonatal complications and stillbirth. Because improved glycaemic control is associated with a better neonatal outcome, targets for glycaemic control have become more stringent and the number of women requiring treatment has increased. Insulin is safe in pregnancy, but must be administered parentally, so there is increasing interest in using oral hypoglycaemic agents instead in women with type 2 or gestational diabetes. Metformin

and glyburide are the most extensively researched drugs. Neither have been shown to be teratogenic in animals. There are considerable data available on metformin as it is used to improve fertility in polycystic ovary syndrome. First-trimester use is not associated with increased malformation rates. Use throughout pregnancy reduced rates of miscarriage and gestational diabetes with similar rates of perinatal mortality and pre-eclampsia as in healthy controls. The Metformin in Gestational Diabetes trial, a randomized control trial comparing metformin with insulin in 751 women with gestational diabetes, showed similar neonatal outcomes, but metformin was better tolerated by patients and there was no
502

difference in malformation rates between the two groups.3 A randomized controlled trial comparing glyburide with insulin in 404 women showed similar efficacy in terms of glycaemic control and similar rates of macrosomia, respiratory distress, neonatal hypoglycaemia, admissions to neonatal intensive care and foetal anomaly.4 Interestingly, glyburide was not found in cord blood samples at birth, despite therapeutic concentrations in maternal blood. The drug may not reach the foetal circulation because of its strong plasma protein binding, short half-life or because of active pumping of the drug back into the maternal circulation by placental transport proteins.

MeDicine 37:9

2009 elsevier Ltd. all rights reserved.

Whats neW in prescribing in pregnancy

Additional resources
UK national teratology information service provides information and guidance on drugs in pregnancy (tel: 0844 892 0909) tOXbase includes information on safety of drugs in pregnancy and lactation in addition to poisoning information (http://www.toxbase.org) UK Drugs in Lactation advisory service provides information on drug safety for breast-feeding mothers (http://www.ukmicentral.nhs. uk/drugpreg/guide.htm) Drugs During Pregnancy and Lactation, edited by schaefer, peters and Miller (elsevier, 2007), offers treatment options and risk assessment with recommendations Motherisk is the canadian teratology service and provides useful information via its website (http://www.motherisk.org) the british national Formulary contains sections on prescribing in pregnancy and lactation (http://www.bnf.org) Drugs in Pregnancy and Lactation, edited by briggs, Freeman and yaffe (Lippincott, Williams and Wilkins, 2008), is a comprehensive reference source cochrane pregnancy and childbirth group as part of the cochrane collaboration provide reviews on a range of drugs in pregnancy (http:// www.cochrane.org) Table 3

Depression There is a lot of experience of tricyclic antidepressants (TCA) such as amitriptyline and imipramine for the treatment of depression in pregnancy and these remain drug treatments of choice. However, TCAs cause maternal and foetal toxicity in overdose and should be avoided if possible in women at risk of self-harm. There are conflicting data on the effects of selective serotonin reuptake inhibitor (SSRI) exposure on rates of congenital malformations. Most studies have shown no or little increase in risk, particularly after correcting for confounding variables. However, a large recent study demonstrated a two- to three-fold increase in anencephaly, craniosynostosis and omphalocele after SSRI exposure.5 The increase in absolute risk appeared modest and the findings could be due to chance, as other studies with similarly-sized populations have not confirmed these associations.6 There may be a particular problem with paroxetine. In 2005, the US Food and Drug Administration issued a warning about this drug following subgroup analyses in two trials indicating an increased risk of congenital cardiac malformation, specifically atrio- and ventriculoseptal defects.6,7 A recent meta-analysis also suggested a small increased risk of congenital heart defects (odds ratio: 1.7), but women on SSRIs also had more antenatal scans and neonatal echocardiograms, hence detection bias may contribute.8 There are concerns that SSRI therapy late in pregnancy may provoke persistent pulmonary hypertension of the neonate (PPHN) by promoting hypertrophy of pulmonary vascular smooth muscle. PPHN

affects 12 infants per 1,000 births and presents with respiratory failure soon after delivery. It results from the failure of the neonatal pulmonary vascular resistance to fall at birth, resulting in right-to-left shunting. Two studies have demonstrated an association with SSRI use, with an estimated three- to six-fold increased relative risk if exposed during late pregnancy (after 20 weeks).9,10 PPHN is strongly associated with preterm birth, particularly before 28 weeks' gestation. SSRI use has not been shown to cause premature delivery, but nevertheless exposed neonates born at term have increased rates of PPHN. This association is a relatively new finding and further work is required to quantify the absolute risks involved. Epilepsy Antiepileptic drug therapy is associated with congenital abnormalities, but the adverse foetal effects of drug treatment need to be weighed against the risks associated with uncontrolled seizures. The older antiepileptic drugs (AEDs) valproate, carbamazepine, phenytoin and phenobarbital have all been associated with a two- to three-fold increase in risk of major congenital malformations, especially when used in combination. These malformations include neural tube defects, facial dysmorphism (e.g. depressed nasal bridge, low-set ears, low hairline, small jaw), cleft lip and palate, hypospadias, cardiac defects and limb abnormalities. There is also some evidence of long-term neurodevelopmental delay. The risk of neural tube defects may be reduced by high-dose (5 mg/day) folic acid prophylaxis in the first trimester, which should be encouraged.
503

In light of the teratogenic potential of the older AEDs, data regarding the newer AEDs has been sought actively in the hope that these may present lower risks. A large number of pregnancy outcomes have been collected after exposure to lamotrigine. In registry studies, the frequency of malformations associated with monotherapy has been 2.53.2%. Preliminary findings from the North American Antiepileptic Drug Pregnancy Register suggested an elevated prevalence of isolated non-syndromic oral clefts in infants after first-trimester exposure.11 However, the EUROCAT congential anomalies register12 and the UK Epilepsy and Pregnancy Registry13 have both reported no increase in risk. There are limited data available on the use of topiramate in pregnancy but the small number of published studies has not suggested an increased malformation rate following monotherapy. The manufacturers report an increased risk of hypospadias, but this observation has not been replicated in two recent prospective studies.14,15 Pregnancy outcome data after exposure to levetiracetam are scarce. To date, it has been shown not to increase the risk of congenital malformations but there is some inconsistent evidence that levetiracetam may be associated with low birth weight. Data from pregnancy registries do not indicate a substantial foetotoxic risk from gabapentin monotherapy when used for the treatment of epilepsy, but safety in pregnancy has not been established. Autoimmune diseases Women of childbearing age with autoimmune disease may need to continue with their treatment throughout pregnancy to

MeDicine 37:9

2009 elsevier Ltd. all rights reserved.

Whats neW in prescribing in pregnancy

control the maternal disease. Since systemic autoimmune maternal disease is also associated with adverse foetal effects irrespective of drug treatment, including IUGR and premature delivery, the underlying maternal illness as well as concurrent use of other medications may confound the interpretation of pregnancy outcomes. Methotrexate is a proven teratogen, causing malformations of the CNS, limbs and palate as well as cranial ossification and growth retardation; malformations have been reported with the lower doses (520 mg weekly) used to treat autoimmune disease. Methotrexate is therefore contraindicated in pregnancy and must be withdrawn 3 months prior to a planned pregnancy. Leflunomide is also contraindicated in pregnancy due to the limited data currently available. Preliminary data involving a small number of cases have shown no increase in spontaneous abortion or malformations, but a slight increase in the rate of prematurity. Several hundred documented pregnancies have indicated that azathioprine does not increase malformation rates. Low birth weight has been reported. Low birth weight and prematurity have also been associated with cyclosporine use during pregnancy. However, these findings could be due to underlying maternal disease or concomitant therapy with corticosteroids. If maternal illness necessitates treatment then both azathioprine and cyclosporine may be considered for use during pregnancy. Tacrolimus has been used successfully in pregnant women after organ transplants. Studies have not demonstrated an increased teratogenic risk but there may be an increased risk of IUGR and prematurity; again, underlying illness and/or concurrent medication may be contributory. Tacrolimus should not be withheld in pregnancy if there is an appropriate indication. Recent data on mycophenolate mofetil show an increased risk of anomalies of the distal limbs, heart, oesophagus, kidney and ear (microtia, anotia), dysmorphia and cleft lip and palate, as well as spontaneous abortion. It should not be prescribed in pregnancy and should be discontinued at least 6 weeks before a planned pregnancy. Data for all reported pregnancy outcomes after maternal treatment with infliximab show no increased risk of spontaneous abortions, prematurity or

congenital malformations compared with non-exposed women. However, the largest study of infliximab-exposed pregnancies to date reported 3 infants out of 125 with similar complex malformations.16 Information on etanercept is scarce, but data from 72 pregnancies, the majority with exposure in the first trimester, do not indicate a causal association with congenital malformations. There is inadequate information on adalimumab use in pregnancy. The number of exposures to tumour necrosis factor (TNF) -inhibitors is too limited to say whether there is any increased risk of foetal toxicity after in utero exposure. There is some debate over whether TNF -inhibitors should be stopped during pregnancy and the severity of the maternal illness may dictate the necessity to use these treatments throughout pregnancy.

Conclusions
When prescribing to young women, appropriate contraceptive advice and counselling with regard to the timing of pregnancy should be given. Particular caution should be practised in women who are already pregnant or breastfeeding. Careful explanation of the benefits and risks are essential in order for an informed decision to be made. Specialist advice and guidance are available and should be sought if there are concerns. Investment in infrastructure to collect and share data is required to ensure adequate surveillance of potential adverse foetal effects from in utero exposure to the pharmacological innovations of the future.

REfEREnCEs 1 pollack ps, shields Ke, burnett DM, et al. pregnancy outcomes after maternal exposure to simvastatin and lovastatin. Birth Defects Res A Clin Mol Teratol 2005; 73: 88896. 2 Ofori b, rey e, brard a. risk of congenital anomalies in pregnant users of statin drugs. Br J Clin Pharmacol 2007; 64: 496509. 3 rowan Ja, hague WM, gao W, battin Mr, Moore Mp. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358: 200315. 4 Langer O, conway DL, berkus MD, Xenakis eM, gonzales O. a comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000; 343: 11348.

5 alwan s, reefhuis J, rasmussen sa, Olney rs, Friedman JM. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007; 356: 268492. 6 Kallen ba, Otterblad Olausson p. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol 2007; 79: 3018. 7 berard a, ramos e, rey e, et al. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol 2007; 80: 1827. 8 bar-Oz b, einarson t, einarson a, et al. paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther 2007; 29: 91826. 9 chambers cD, hernandez-Diaz s, Van Marter LJ, et al. selective serotoninreuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006; 354: 57987. 10 Kallen b, Olausson pO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf 2008; 17: 8016. 11 holmes Lb, baldwin eJ, smith cr, et al. increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 2008; 70: 21528. 12 Dolk h, Jentink J, Loane M, Morris J, de Jong-van den berg LtW, on behalf of the eUrOcat antiepileptic Drug Working group. Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? Neurology 2008; 71: 71422. 13 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 Psychiatr 2006; 77: 19398. 14 Ornoy a, Zvi n, arnon J, et al. the outcome of pregnancy following topiramate treatment: a study on 52 pregnancies. Reprod Toxicol 2008; 25: 3889. 15 hunt s, russell a, smithson Wh, et al. topiramate in pregnancy: preliminary experience from the UK epilepsy and pregnancy register. Neurology 2008; 71: 2726. 16 pye sM, cortes J, ault p, et al. the effects of imatinib on pregnancy outcome. Blood 2008; 111: 55058.

MeDicine 37:9

504

2009 elsevier Ltd. all rights reserved.

Whats neW in prescribing in pregnancy

Practice points
Medicines should be prescribed in pregnancy only when absolutely necessary, weighing the benefits against possible risks. patients should be fully informed and involved in the decision When prescribing during pregnancy, up-to-date information should be obtained from appropriate sources (table 3), e.g. the UK teratology information service the risks to the foetus of uncontrolled maternal disease may be greater under some circumstances that those of the medicines required for treating the mother When treatments potentially hazardous to the foetus cannot be avoided, these should be used in the lowest possible dose, avoiding the period of highest risk when this is possible

MeDicine 37:9

505

2009 elsevier Ltd. all rights reserved.