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© National Poisons Information Service
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.
© NPIS and UKTIS 2012
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
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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.’
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© NPIS and UKTIS 2012
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
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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
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© NPIS and UKTIS 2012
First trimester antidepressant use
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Percentage of pregnancies exposed to prescription medicines with potential for harm
Daw et al, Pharmacoepidemiology and Drug Safety, 2011; 20: 895–902
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Mother
Benefits Risks
Fetus
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
Anim
al studies
Obser-
vational
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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
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Sertraline in pregnancy
Sit et al, J Clin Psychiatr 2008
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Factors affecting placental transfer
• Plasma protein binding• Lipid solubility / ionisation
(Fetal trapping of weak bases)• Molecular weight (< 1,000 D)• Transporter activityPlacental
transfer
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Missed period
Week (LMP) 4 10 18 40
Conception
Congenital malformations
Growth and development,
direct fetotoxicity
Neonatal problem
s
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Known first trimester teratogens
Maternal exposure
• Androgens Virilisation of female fetus
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Known first trimester teratogens
Maternal exposure
• Androgens
• Diethylstilboestrol Uterine lesions, vaginal carcinoma
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Known first trimester teratogens
Maternal exposure
• Androgens • Diethylstilboestrol
• Lithium Cardiovascular defects
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Known first trimester teratogens
Maternal exposure
• Androgens • Diethylstilboestrol• Lithium
• Thalidomide Limb reduction defects /other abnos.
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Known first trimester teratogens
Maternal exposure
• Androgens • Diethylstilboestrol• Lithium• Thalidomide
• Cytotoxic drugs Multiple defects, abortion, growth retardation, stillbirth
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Known first trimester teratogens
Maternal exposure
• Androgens • Diethylstilboestrol• Lithium• Thalidomide• Cytotoxic drugs
• Retinoids Craniofacial, cardiac, CNS defects
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Known first trimester teratogens
Maternal exposure
• Androgens • Diethylstilboestrol• Lithium• Thalidomide• Cytotoxic drugs• Retinoids
• Warfarin Nasal hypoplasia, skeletal defects
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Known first trimester teratogens
Maternal exposure
• Androgens • Diethylstilboestrol• Lithium• Thalidomide
• Cytotoxic drugs• Retinoids• Warfarin• Streptomycin Deafness, vestibular damage
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Known first trimester teratogens
Maternal exposure
• Androgens • Diethylstilboestrol• Lithium• Thalidomide• Cytotoxic drugs• Retinoids• Warfarin• Streptomycin
• Sodium valproate Facial defects, mental retardation, neural tube defects
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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
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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
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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
care
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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
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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
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• 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.
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ENTIS
• 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
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ENTIS data: Exposure to H2 blockers in pregnancy
Garbis et al, Reproductive Toxicology 2005
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Population-based registries
Since Population coverage
Births/y(1,000s)
Notes
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
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Record linkage
Birth registries
Congenital malformation
registriesPrescription
data
GP data
Uniqueidentifier
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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
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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
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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
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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
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Acknowledgements
Dr Pat McElhattonTeratologist1948 – 2011