How to advise about medicines use in pregnancy 42nd UKMi Practice Development Seminar

27 Sept 2016, Birmingham

Dr Laura M. Yates

UK Teratology Information Service (UKTIS), Institute of Genetic Medicine,

Newcastle University

Laura.Yates@nuth.nhs.uk

Overview

1. Exposure susceptibility during fetal

development & current thinking on the ‘all or

nothing’ period

2. Lack of guidelines regarding the ‘drug of

choice’ in pregnancy – what therapy is

advised?

3. Communicating information to women

4. Clinical interpretation of new associations in

the media eg. paracetamol and autism

5. What can be done to improve medicine use in

pregnancy?

Human fetal development

Thalidomide Embryopathy

• Limb defect sensitive period week

39th-41st day Absence of arms

43rd-44th day Phocomelia with three fingers

46th-48th day Thumbs with three joint

•

CS12

Week 7

Week 9

UKTIS (uktis.org) Hosted by NUTH, commissioned by PHE

Conceptualised in 1983 following Thalidomide

• Provide evidence based up-to-date information and advice to UK HCPs on the fetal effects drugs and chemicals in concert with the UK NPIS

- national telephone advice line 0344 892 0909

- online scientific written reviews (‘monographs’) of animal

and human pregnancy data www.toxbase.org

- Patient information at bumps www.medicinesinpregnancy.org

• Surveillance of known and emerging teratogens - Follow up of poisoning in pregnancy enquiries to NPIS/UKTIS

- National database of pregnancy outcomes

• Research - enhanced surveillance, funded studies

Mycophenolate Embryopathy

Main features

• microtia, atresia of external auditory canal (EACA)

• cleft lip and/or palate

• congenital heart defect

• coloboma / eye anomalies

Less frequent malformations

• Brachydactyly, nail hypoplasia

• tracheo-esophageal anomalies

• agenesis of corpus callosum

• diaphragmatic hernia

• kidney anomalies

Overlap with known genetic syndromes e.g. CHARGE, 22q11

Perez-Aytes et al 2007

Abnormal neural crest cell migration

Abnormal neural crest cell migration

Isotretinoin Embryopathy

• Microcephaly (small head and brain)

• ear and eye defetcts,

• cleft palate

• cardiac defects

• Intellectual disabilities (60%)

Pachajoa, Arch Argent Paediatr 2012;110(3)

Santagati & Rijli Nature Reviews Neuroscience 4,

806-818 ( 2003)

Human fetal development

ACE-I Fetopathy (type 1 AE) (exposure in T2/T3)

Inhibition of the fetal RAS

amniotic fluid

• ‘Potter’s face’ – flattened nose, exaggerated infraorbital grooves, low set crumpled ears

• loose wrinkly skin

• limb contractures

• delayed development of the calvarial bones

• pulmonary and renal hypoplasia

• intrauterine growth retardation

“OLIGOHYDRAMNIOS SEQUENCE”

Human fetal development

•embryonic gene sequence and copy number tempero-spatial expression

•environment (uterine shape, size, perfusion – nutrients e.g. folate, oxygen)

Weeks 0 -2 post conception,

preimplantation • extensive epigenetic reprogramming

and modification,

activation of the nascent human

embryonic genome

• drug concentration in uterine

secretions or fallopian tube fluid

may exceed maternal plasma

concentrations e.g azithromycin

Barker hypothesis

http://www.embryology.ch/anglais/evorimpl

antation/furchung05.html

Diethylstilbestrol (DES) • Synthetic hormone (1940’s)

• “Daughter’s of DES”

Clear Cell Ca Vagina, ?Breast cancer

- reproductive failure

- ?Grandaughters (Ca)

• Sons and grandsons of DES

- hypospadius

• “Endocrine disruptor “

- high unbound maternal fraction (SHBG and AFP bind estradiol preferentially)

- reactive intermediates

Risk to fetus of exposure by

stage of pregnancy

• Pre-implantation -probably low risk of CM*, SA

(week 0-2pc) -risk of long term effects unknown

• Post-implantation

(week 2-10pc) - main risk period for major

structural malformation, SA

(week 10-40pc) - functional effects (some reversible,

may extend into neonatal period)

- “minor” malformation, SA or IUD

Long term and transgenerational effects?

NB. * Unless exposure has a long half-life

What is the treatment of choice

in pregnancy?

Risk benefit analysis CMACE Report – Confidential Enquiry into Maternal Deaths (UK)

2011

• young woman with brittle asthma advised to discontinue prednisolone in

early pregnancy due to concerns about potential adverse fetal effects.

• underlying maternal conditions (pre-existing or new),in many cases

deemed preventable or treatable, leading cause of maternal death in the

UK.

2014

• sudden unexplained death in epilepsy remains the leading cause of

mortality among pregnant women or recently delivered women with

epilepsy

• all the women who died had concerns about the risk to their baby of

taking antiepileptic medication in pregnancy

• none of these women had been prescribed valproate, the only

antiepileptic that is a confirmed major teratogen

Prescribing in pregnancy ……. Risks and benefits for two patients

Risks to the mother

• Risks from the underlying illness/condition

• Risks from the treatment (including a/e unrelated to pregnancy)

• Risks from delayed / suboptimal treatment

Risks to the fetus

• Risks from the maternal illness

• Risks from the treatment

• Risks from failing to adequately treat the mother

Conflict between unknown risk/guidance and need to treat patient

WHAT HAS HAPPENED TO

THE UKTIS GUIDELINES on:

1. Treatment of depression in pregnancy

? TCAs no longer first choice despite no

suggestion of fetal risk

? Paroxetine vs other SSRIs

recognition of the maternal risks associated with

TCAs vs SSRIs

working group with perinatal psychiatrists and patient

representatives

2. Nausea and vomiting in pregnancy

?evidence for efficacy, a/e risks, NIHR review

‘What is the treatment of choice

for xx in pregnancy?’

….Often no one drug – need to consider risk to

the fetus as well as

1. natural history of the condition during

pregnancy

2. anticipated efficacy of treatment

3. maternal risk from adverse effects

4. health economics

Guideline development challenging and

complex

RCOG 2016 GTG on NVP

Advising on drug use in

pregnancy

1. Is pharmacological treatment necessary?

(natural history of condition, severity, non-

pharmacological options)

2. Is a specialist review indicated?

3. Are pregnancy specific guidelines available?

4. If no, consult non-pregnancy guidelines for

therapeutic options e.g. ‘pain ladder’

Consider stage of pregnancy

available human pregnancy safety data

past therapies, any contra-indications

Prescribing in pregnancy cont.

5. Evidence based discussion of risk benefit

analysis, involving patient (even if guidelines!)

6. If medication indicated, lowest effective dose

only for as long as needed

7. Consider need for additional fetomaternal

monitoring (antenatal and of neonate)

8. Inform patient of registers or UKTIS

surveillance (section 251 NHS Act 2006)

Shared decision making ‘Translating’ the scientific data for the patient

Dealing with uncertainty – the unknown

• Animal data not necessarily predictive of human risk

• New knowledge & techniques emerging rapidly

• Contribution of underlying maternal illness on outcome

• Inter-individual variability in drug metabolism, adverse

effect susceptibility

Are exposures in utero one of a multitude of risk factors that

may cumulatively adversely outcome???

Shared decision making ‘Translating’ the scientific data for the patient

Be clear as to whether increased risk of an adverse

outcome is:

• Purely theoretical e.g a new folic acid antagonist

• Uncertain at present e.g. conflicting data, single study

• Suspected e.g. multiple studies with similar findings

• Confirmed (causal association with drug established)

Quantify the risk (if possible), use absolute rather than

relative risk

Contextualise the risk – background risks

Quantify the risk (if possible), use absolute

figures rather than relative risk

Contextualise the risk – background risk,

other exposures

Shared decision making ‘Translating’ the scientific data for the patient

Terminology

• Appropriate to patient’s level of understanding

• Avoid use of ‘safe’ – ‘not thought to be harmful but not a

enough information yet to be certain….not all possible

effects on pregnancy studied’

• Use phrases like ‘developmental delay’ cautiously as

implies potential for catch-up

• Be clear about whether a suggested intervention has

confirmed or theoretical benefit e.g. high dose folic acid

with valproate therapy or divided dosing, glycaemic

control in diabetics

The challenges • Medicine use in pregnancy common

• Poor understanding of background risks and risk from

disease, other exposures (alcohol, smoking)

• Human pregnancy ‘safety’ data generally limited,

especially for longer term outcomes, even if long

history of use in pregnant women.

• Recent increase in studies, new methodologies and

media - keeping up with the data

- clinical relevance of possible ‘signals’

- an association does not prove causality

Paracetamol and ADHD, ASD

• Increasing use of electronic health record

databases (EHRDs) for pharmacovigilance

- Exposure often assumed

- Associations investigated may reflect

frequency of exposure or outcome, not a

scientific hypothesis (?....fishing)

- ADHD and ASD complex in aetiology

Risk use of therapies with greater risks

untreated pyrexia (NTDs)

Clinical relevance of

publications reporting a ‘signal ’

1. Assess each publication to determine clinical relevance

2. Consider limitations in the methodology

3. Contextualise findings by considering what is already

known about the exposure and the outcome

4. Consider whether existing studies reflect outdated study

methodology or clinical knowledge e.g. miscarriage risk

calculations, modern diagnostic techniques such as echo

5. How does risk compare to that for other therapeutic

options?

best use of medicines

in pregnancy

(www.medicinesinpregnancy.org)

Improving use of meds in pregnancy What needs to be done

• Encourage reporting to pregnancy registries (especially

for new, uncommonly used meds) e.g. UKEPR, UKTIS

to enable follow up of prospectively recorded exposures

* patient identifiers required*

• Improve collection of non-CM outcomes

• Standardise information available to women

NB. Local hospital PILs often outdated, often available

online (e.g. ref to ‘Fetal Anticonvulsant Syndrome’)

Acknowledgements

Thank you

• Invitation

• Enquirers to

UKTIS

• Patients and

families

• Colleagues at

UKTIS & NPIS

Causes of congenital malformation

Genetic

20%

Maternal Illness

2%

Multifactoral

20%Unknown

Reasons

50%

Teratogenic

8%

• Background risk:

• ~700,000 live births per year in England and Wales

• 2-3% ‘major’ malformation

• 5-7% ‘major’ or ‘minor’ malformation

• 14,000 to 21,0000 live births per year with congenital malformations

• 8% due to teratogenic exposure:

• ~ 1120 to 1680 infants per year

• Medication exposure accounts for 2-3% of total malformed infants:

• ~280 to 630 infants per year

Teratogenic effects

may be unpredictable

JACPOC 1992 Vol 27.

Num1 pp. 3

Most still not fully understood

Prescribing in pregnancy Consider effects of pregnancy on maternal pharmacology

Absorption

• may be affected by the increase in gastric pH

• slower gastric emptying may delay peak drug concentrations after oral ingestion.

Distribution

• accelerated distribution due to increased cardiac output

• increased total body water and plasma volume affect distribution volumes and steady state plasma concentrations of water soluble drugs

• decreased plasma albumin concentration and binding affinity may result in toxicity at lower total drug concentrations of albumin bound drugs due to an increased free drug : total drug ratio

Metabolism

• may be unpredictable due to altered hepatic blood flow and variable effects of pregnancy on hepatic enzyme activity

Excretion

• increased clearance of renally-excreted drugs and active drug metabolites

• renal tubular secretion of drugs via p-glycoprotein (P-gp) increased in late pregnancy

……and fetal metabolism may also be different

Take home messages for teens Shared decision making requires accurate up-to-date information

• 50% pregnancies unplanned

Contraception, contraception, contraception

• Planned pregnancy enables

- review of meds

- discussion of known or unknown risks of medicines to

fetus (including LT neurodevelopment)

vs.

mum and fetus of stopping / changing meds

- time to optimise health for mum and baby

(Lifestyle factors – weight, smoking, alcohol, folate)