Principles of drug use in pregnancy

1. Principles of drug use in pregnancy Swansea NHS Trust Scott Pegler Clinical & Information Pharmacist Swansea NHS Trust

2. History • Thalidomide: probably the most notorious human teratogen • Marketed as a sedative in late 1950’s • Associated with up to 12,000 birth defects, primarily phocomelias • Other effects included: • facial hemangiomata, oesophageal & duodenal atresia, teratology of Fallot, renal agenesis & anomalies of the external ear

3. Thalidomide • No malformations if taken before the 34th day after last menstruation & usually no malformations if taken after the 50th day • Sensitive time period: day 35 to day 49 • Day 35 – 37: absence of ears & deafness • Day 39 – 41: absence of arms • Day 43 – 44: phocomelia with three fingers • Day 46 – 48: thumbs with three joints • If taken throughout the sensitive period: severe defects of the ears, arms & legs & internal malformations often leading to early death (40% died before their 1st birthday)

4. Thalidomide • Association between thalidomide and human teratogenicity suspected by Lenz (Germany) in November 1961 & endorsed by a letter by McBride to the Lancet in November 1961 • Withdrawn in Germany at the end of Nov 1961 • end of malformation ‘epidemic’ seen in July 1962 (as predicted) • Thalidomide continued to be sold for several months in some countries e.g. Belgium, Brazil, Canada, Italy & Japan • Finally withdrawn in Japan in Sept 1962 • peak in epidemic occurred in Japan at a time when epidemic had ended in Germany

5. Thalidomide • 20% of pregnancies exposed during this period resulted in anomalies • Administration to female rabbits did not show any adverse effects on fertility • There was an increase in early pregnancy loss (equivalent to miscarriage) • There were no thalidomide-associated malformations in surviving foetuses

6. Overview • All drugs should be avoided in pregnancy unless they are ‘essential’ • In practice, it may not be easy to know what treatment is really necessary or whether a particular medicine is an appropriate choice • Requires a balanced approach: • Being over-cautious may deny a beneficial therapy • Lack of due caution might harm babies as a consequence of drug exposure • Benefits of treatment need to be weighed against the risks of giving no medication • Note: while the benefits of Tx may be clear, the risks may be largely unknown or unquantifiable • For minor conditions, the risks almost always outweigh the (often trivial) benefits

7. The problem • 80% of women use prescribed or OTC drugs during pregnancy • 3 – 8 different drugs (partly prescribed and partly self-medication) • The risks of drug use in pregnancy has lagged far behind advances in other areas of pharmacotherapy • Main reasons: epidemiological difficulties in establishing causality and ethical barriers to prospective RCTs

8. Teratogenicity and drugs • In the UK, the spontaneous malformation rate at birth is 2-3% i.e. approximately 1 in 40 babies will be born with a malformation • The incidence of malformations increases to approximately 5% by 4-5 years of age • Drugs are thought to cause less than 1% of malformations • Therapeutic drugs do not appear to be a significant cause of birth defects • However, most birth defects have no known cause and exposure to drugs may play a part in some of these

9. Causes ofdevelopmentaldisorders • Unknown:- Spontaneous development disorders; multigenetic conditions; combination and interactions of exogenic and endogenic factors (65%) • Genetic diseases:- (20%) • Chromosomal disorders:- (5%) • Anatomical factors:- Uterus anomalies; twin pregnancy; oligohydramy (2%) • Maternal conditions:- Diabetes mellitus; hypothyroidism; phenylketonuria; cytomegaly; listeriosis; lues; rubella; toxoplasmosis; Varicella (4%) • Chemical and physical agents:- Medicinal products; drugs of abuse (especially alcohol); ionizing radiation; hyperthermia; environmental chemicals (4%)

10. Evaluating drug safety in pregnancy • Most birth defects are rare & so an increased risk posed by a teratogen may not be easily identified • Most suspected teratogens cause only a relatively small increase in baseline risk of malformations • Epileptic women treated with anticonvulsant drugs have a 2-3 fold increased risk of malformations, i.e. a 10% risk of having an abnormal baby. • …or at least a 90% chance of having a normal baby

11. Evaluating drug safety in pregnancy • Epidemiological studies of drug exposure in pregnancy require large numbers of exposed infants to prove or disprove the teratogenic potential of a drug – few have the statistical power as they cannot include sufficient patients • e.g. 1,600 live births following 1st trimester exposure to aciclovir would need to be monitored to detect a 5-fold increase in the risk of a specific defect which occurs as frequently as 1 per 1000 live births, with an 80% power • For these reasons, no drug is safe beyond all doubt in early pregnancy

12. Evaluating drug safety in pregnancy • Animal studies are required before new drugs are licensed, but it is difficult to extrapolate findings to human pregnancy • Drugs which produce defects in animals can be relatively safe in humans e.g. corticosteroids • Of over 2,000 drugs, chemicals & environmental agents shown to be teratogenic in animals, less than 50 are proven human teratogens

13. Some teratogenic drugs

14. Embryo/fetotoxic risk assessment • Generally accepted that the predictive value of animal studies for predicting safety in humans is less than adequate • With the exception of androgens, several antimitotic drugs, sodium valproate and vitamin A derivatives, all human teratogens were discovered earlier in man than in animals • Most were case studies from alert clinicians rather than epidemiological studies

15. Drugs and the fetus • Nearly all drugs, except those with a very high molecular weight e.g. insulin and heparin, cross the placenta to the fetus • Lipid-soluble un-ionised drugs cross the placenta more rapidly than polar drugs • In practice, all drugs should be regarded as having the potential to affect the unborn child • The effect of drug exposure will depend upon: • Timing of exposure • Dosage • Concomitant maternal disease • Genetic susceptibility

16. Drugs and the fetus • However, it should be remembered that: • Teratogens do not cause defects in all fetuses exposed at the critical period of gestation • A drug that harms a baby in one pregnancy may have no effect in a subsequent pregnancy in the same woman

17. Timing of drug exposure • Exposure during the pre-embryonic period (until 14 days post-conception)  the ‘all or nothing effect’ • Damage to all or most cells  death • If only a few cells are injured  normal development • Women with a history of drug use in the month following their last menstrual period can often be reassured • Limitations • Drug must be completely eliminated before this time (not useful for drugs with long half-life) • Dates of conception uncertain

18. Timing of drug exposure • Fetus most vulnerable to teratogens from week 3 to week 8 after conception (embryonic phase) when major organ systems formed • For some drugs there is a period of greatest risk • Exposure to sodium valproate at the time the neural tube closes (between day 17 & 30 post-conception) may result in spina bifida • Cleft palate develops at about 36 days post-conception & so a drug exposure outside this period is unlikely to be implicated in any a/e

19. Timing of drug exposure • During the fetal period (week 9  birth) the fetus is less susceptible to toxic insults, although some organs (cerebellum & urogenital structures) continue to be formed • Exposure is more likely to cause growth retardation or interfere with functional development within specific organ systems • Danazol can cause virilisation of a female fetus after 8 weeks gestation • Warfarin may cause intracranial haemorrhage in the second & third trimesters

20. Timing of drug exposure • Drugs taken close to term cause predictable pharmacological effects • Beta-blockers can cause neonatal hypoglycaemia • SSRIs can cause withdrawal effects after regular in utero exposure • Rarely, exposure can have delayed effects • Diethylstilboestrol – synthetic oestrogen used for threatened spontaneous abortion • Many female fetuses exposed before the 9th week developed vaginal or cervical cancer later in life

21. Dose & polypharmacy • In general teratogenicity is dose dependent • Neural tube defects & sodium valproate have shown a correlation with: • Total daily dose • Dose per administration • Peak level achieved • Dose is only a relative risk factor • Normal babies have been born to women who have received high doses of valproate & vice versa

22. Dose & polypharmacy • Risk of malformations increases with exposure to multiple drugs • e.g. anti-epileptics • 4% incidence of defects for 1 drug • 23% incidence for 4+ drugs • Potential for confounding with disease severity can be discounted as epilepsy is not thought to be associated with an increase in malformation rate • Avoid polypharmacy whenever possible

23. Genetic factors • Increasing evidence (mainly from anti-epileptic drugs) that genetic factors are important determinants of teratogenic effects • Malformation rates may be correlated with high levels of epoxide metabolites of phenytoin in individuals with low activity of epoxide hydrolase

24. Risk communication • Clear distinction must be made: • Prospective query – choice of therapy in pregnancy (or planned pregnancy) • is Tx really necessary? • Retrospective – communicating the (un)safety of drugs when exposure during pregnancy has already occurred • Detailed risk assessment • Health & well-being of mother (maternal history etc.) • Drug(s) taken (when?), dose & duration • Reason for query e.g. for reassurance vs. help with interpretation of an abnormal scan etc.

25. Pregnancy resources • Summary of Product Characteristics • Often very general, outdated or misleading thus preventing clinician making an individualised decision with their patient • Commonly written to protect the manufacturer from potential liability • “Contraindicated in pregnancy” • Is the drug embryo- or fetotoxic or did the clinical trials simply exclude pregnant women?

26. Pregnancy resources • Individual risk vs. population risk • Consider a drug with a relative risk of causing a malformation of 1.2 • The risk for an individual is very small • To a drug company, the same risk implies an extra 400 malformed children per 100,000 exposed pregnancies (with a background rate of 2%)

27. Pregnancy resources • BNF • Appendix provides brief information on drugs which may have harmful effects, together with trimester of risk • Drugs not listed cannot be assumed to be safe! • UK Medicines Information Centres • Access numerous independent resources, specialist textbooks & databases e.g. ReproTox • UKMi Centres also have links with NTIS (National Teratology Information Service) which in turn has links with NPIS (National Poisons Information Service) & ENTIS (European Network of Teratology Information Services)

35. Principles of prescribing in pregnancy • Consider non-drug treatments • Avoid all drugs in 1st trimester if possible • Avoid drugs known to have harmful effects • Avoid new drugs where possible • More experience with ‘older drugs’ – greater evidence of safety, but can’t assume they are necessarily safe • Avoid polypharmacy • Use the lowest effective dose for the shortest duration possible & review regularly • Consider the need for dosing changes & TDM due to the effect of pregnancy on drug handling • Changes in serum albumin & total body water

36. Thank you Any questions?