thomas, simon fetal toxicity associated with maternal ...€¦ · • fetal death • teratogenic...

Fetal toxicity associated with maternal exposure to drugs

Simon ThomasDirectorUK Teratology Information ServiceNewcastle upon Tyne Hospitals NHS TrustWolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle NE2 4HH, UK.

The problem

• Women need appropriate drug treatment during pregnancy– chronic illness– intercurrent illness– conditions associated with pregnancy

• Limited information on risks (if any) associated with any individual treatment

SmPC for Salmeterol

‘As yet, experience of the use of salmeterol during pregnancy is limited. As with any medicine, use during pregnancy should be considered only if the expected benefit to the mother is greater than any possible risk to the foetus.’

Prescribing in pregnancy -background

• 650,000 maternities in England and Wales annually

• 500,000 women pregnant at any one time

• 20-50% pregnancies unplanned

• Delay before recognition of pregnancy

Drug use in pregnancy

• Medications taken by almost 96-98% women during pregnancy

• 60-80% use prescribed medications

• Use increases with age

• Multiple drug use increasing

• 1-4% prescribed ‘contraindicated’ medicines

First trimester antidepressant use

Percentage of pregnancies exposed to prescription medicines with potential for harm

Daw et al, Pharmacoepidemiology and Drug Safety, 2011; 20: 895–902

Mother

Benefits Risks

Maternal need for treatment • Acute intercurrent illness• Pregnancy-associated conditions• Chronic conditions

• Fetal death• Teratogenic effects• Growth and development• Neonatal effects

Limited information available

Effects of pregnancy on risk of ADR

Fetal benefits from good maternal health, e.g. diabetes, epilepsy, influenza, fever

Altered physiology and pharmacology

Placental transfer

al studies

Obser-

vational

Pregnancy and pharmacokinetics

• Absorption–Delayed gastric emptying–Increased gastric pH

• Distribution–Increased total body water–Increased fat stores–Inceased cardiac output–Reduced plasma albumin

• Metabolism–Reduced hepatic blood flow–Variable effects on metabolism

•Excretion–Increased GFR

IncreasedCYP2A6CYP2C9CYP2D6CYP3A4UGT

ReducedCYP1A2CYP2C19

Depends on stage of pregnancy

Sertraline in pregnancy

Sit et al, J Clin Psychiatr 2008

Factors affecting placental transfer

• Plasma protein binding• Lipid solubility / ionisation

(Fetal trapping of weak bases)• Molecular weight (< 1,000 D)• Transporter activityPlacental

transfer

Missed period

Week (LMP) 4 10 18 40

Conception

Congenital malformations

Growth and development,

direct fetotoxicity

Neonatal problem

Known first trimester teratogens

Maternal exposure

• Androgens Virilisation of female fetus

Maternal exposure

• Androgens

• Diethylstilboestrol Uterine lesions, vaginal carcinoma

Maternal exposure

• Androgens • Diethylstilboestrol

• Lithium Cardiovascular defects

Maternal exposure

• Androgens • Diethylstilboestrol• Lithium

• Thalidomide Limb reduction defects /other abnos.

Maternal exposure

• Androgens • Diethylstilboestrol• Lithium• Thalidomide

• Cytotoxic drugs Multiple defects, abortion, growth retardation, stillbirth

Maternal exposure

• Androgens • Diethylstilboestrol• Lithium• Thalidomide• Cytotoxic drugs

• Retinoids Craniofacial, cardiac, CNS defects

Maternal exposure

• Androgens • Diethylstilboestrol• Lithium• Thalidomide• Cytotoxic drugs• Retinoids

• Warfarin Nasal hypoplasia, skeletal defects

Maternal exposure

• Androgens • Diethylstilboestrol• Lithium• Thalidomide

• Cytotoxic drugs• Retinoids• Warfarin• Streptomycin Deafness, vestibular damage

Maternal exposure

• Androgens • Diethylstilboestrol• Lithium• Thalidomide• Cytotoxic drugs• Retinoids• Warfarin• Streptomycin

• Sodium valproate Facial defects, mental retardation, neural tube defects

Substances associated with adverse outcomes after late pregnancy exposure

Drug Possible effect on the infant

Warfarin Fetal haemorrhage; CNS abnormalitiesNSAID & salicylates Prolongation of gestation & labour, premature

closure of ductus arteriosus, neonatal pulmonary hypertensionSulphonamides Hyperbilirubinaemia, kernicterusTetracyclines Staining of teeth, impaired bone growthAminoglycosides Deafness, vestibular damageNarcotics Neonatal respiratory depression & withdrawal beta-blockers Growth retardation? neonatal bradycardia,

hypoglycaemiaACE inhibitors & A2s Oligohydramnios, growth retardation, lung &

kidney hypoplasia, Lithium Hypocalvaria, neonatal convulsions, hypotension, anuriaPhenothiazines Neonatal hypotonia, hyporeflexia, reduced sucklingBenzodiazepines Neonatal respiratory depression, withdrawal

Identifying teratogens -problems

Species differences render animal studies of limited use

Most malformations occur rarely (2-3% overall risk)

Large numbers of infants exposed in utero are needed to prove or disprove teratogenicity, unless risks very high

Risk depends on intensity, duration and timing of exposure

Confounding factors

Malformation Rate /1000 births

Club foot 5.7Cardiovascular 4.2Anencephaly 2.0Hypospadias 1.8Hydrocephalus 1.4Spina bifida 1.4Polydactyly 1.1Cleft palate / lip 1.0Syndactyly 0.7Limb reduction 0.6OVERALL 20.8

Leck et al,Teratology 1968

Drug use in pregnancy -confounding factors

• INDICATION• Demographic differences• Use of other medicinal drugs• Substance use

– smoking, alcohol, caffeine, recreational drugs

• Chronic illness• Obstetric history• Infections, e.g. STD, HIV• Fever• Nutritional status• Quality of antenatal

Observational data

• Case reports and spontaneous reporting systems (e.g. yellow card scheme)

• Case-control studies• Cohort studies

– Pregnancy registries– Congenital malformation registries– Teratology Information Service follow up data– Computerised data sets

Pregnancy registriesCharacteristics• Specific drugs or diseases

– e.g. Epilepsy, HIV, Migraine, depression, HSV, H1N1v

• Direct enrolment or via health professional • Data collection at enrolment and after delivery• Validation of outcome

Problems• Limited enrolment• Incomplete follow up• Selection bias• Drug company sponsorship

Morrow et al, J Neurol Neurosurg Psych 2006

UK Epilepsy and pregnancy register

• Started in 1979.• More than 1.5

million births surveyed per year in Europe.

• 43 registries in 20 countries.

• 29% of European birth population covered.

• Founded 1990• Objectives

– to coordinate and collaborate the activities of the different Teratology Information Services

– to collect and evaluate data in order to contribute to the primary prevention of birth defects and developmental disorders.

• Access may be– Limited to health professionals– Open to the public

ENTIS data: Exposure to H2 blockers in pregnancy

Garbis et al, Reproductive Toxicology 2005

Population-based registries

Since Population coverage

Births/y(1,000s)

Swedish Medical Birth Register 1994 90% 85-120 Medical records available via personal identifiers

Norwegian Medical Birth Register 1967 100% 60Finnish Medical Birth Register 1987 100 58Danish National Registry of Patients 1963 100 50Saskatchewan Population Registries

1970 93 11.4

UK General Practice Research Database

1986 5% 59

Kaiser Permanente, USA 1995 30 San Francisco Bay area

Tennessee Medicaid 1985 38United Healthcare 1990 27

Record linkage

Birth registries

Congenital malformation

registriesPrescription

GP data

Uniqueidentifier

Cardiac malformations and SSRI exposure in pregnancy

• Swedish data (1995-2004) from

– Swedish Medical Birth Register

– Register of Congenital Malformations

– Hospital Discharge Register

•6,481 SSRI exposures

Direct data collection from women

• Internet-based data collection• Linked to information on medicines safety in pregnancy

designed for the public• Women recruited at booking, via social medial or when

they seek information• Data collected throughout pregnancy including

demographic info, medical history, confounding factors• Pregnancy outcome provided when known• Possibility of longer-term outcome data

Prescribing in pregnancy

Obtain and share accurate and balanced information

Only prescribe if clear indication / need (especially T1)

Use drugs where there is previous experience, avoiding newer drugs if possible, using lowest effective dose for minimum time

Avoid polypharmacy when possible Use folate supplementation Appropriate screening when important

exposures have occurred

Conclusions

• Prescribing during pregnancy is common and is increasing for some drug classes

• Most drugs cross the placenta• Pharmacokinetics altered during pregnancy• Inadequate information on safety of many drugs during pregnancy and lactation

– Observational data, inadequate power, confounding etc.• Better epidemiological methods required for more complete data collection

– Pharmacovigilance planning– Pregnancy registers– Record linkage

• Information on-line and via telephone from Teratology Information Services

Acknowledgements

Dr Pat McElhattonTeratologist1948 – 2011

thomas, simon fetal toxicity associated with maternal ...€¦ · • fetal death • teratogenic...

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