Upload
others
View
6
Download
0
Embed Size (px)
Citation preview
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
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)