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

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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

Thalidomide

   No malformations if taken before the 34 th after last menstruation & usually no malformations if taken after the 50 th day 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 1 st birthday)

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suspected by Lenz (Germany) in November 1961 & endorsed by a letter by McBride to the Lancet in November 1961 Withdrawn in Germany at the end of Nov 1961  end of malformation ‘epidemic’ seen in July 1962 (as predicted) Thalidomide continued to be sold for several months in some countries e.g. Belgium, Brazil, Canada, Italy & Japan Finally withdrawn in Japan in Sept 1962  peak in epidemic occurred in Japan at a time when epidemic had ended in Germany

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

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

The problem

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

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

Causes of developmental disorders

• • • • • •

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%)

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

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 1 st 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

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

Some teratogenic drugs

ACE inhibitors Alcohol Aminoglycosides Androgens (e.g. danazol) Anti-cancer drugs Anti-thyroid drugs Carbamazepine Cocaine Diethylstilboestrol Lithium Phenytoin Retinoids Sodium valproate Thalidomide Warfarin Renal dysfunction and hypotension in the newborn, decreased skull ossification, hypocalvaria and renal tubular dysgenesis Fetal alcohol syndrome Deafness, vestibular damage Masculinisation of female fetus Multiple defects, abortion Fetal goitre Neural tube defects Cardiovascular, central nervous system defects Vaginal carcinoma after

in utero

exposure Cardiovascular defects (Ebstein’s anomaly) Fetal hydantoin syndrome Craniofacial, cardiac, central nervous system defects Neural tube defects Limb-shortening defects, renal malformations, congenital heart disease Fetal warfarin syndrome

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

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

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

Timing of drug exposure

 Exposure during the pre-embryonic period (until 14 days post-conception) effect’  the ‘all or nothing   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

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

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

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 9 th week developed vaginal or cervical cancer later in life

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

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

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

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.

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?

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%)

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)

Principles of prescribing in pregnancy

       Consider non-drug treatments Avoid all drugs in 1 st 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

Thank you

Any questions?

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