Download QA34_6_PregnancyPrescribing

Medicines Q&As
Q&A 34.6
What should you think about when prescribing to pregnant
women?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 20th October 2014
In general, the use of medications in pregnancy should be avoided where possible, particularly in the
first trimester. The use of all medications in pregnancy should follow a careful risk versus benefit
assessment. A medication with the best safety record over time should be chosen over a new
medication, unless the safety of a new medication has been clearly established.
It is impossible to be sure that any drug is ‘safe’ in pregnancy because it is unethical to conduct the
randomised placebo-controlled trials that would be necessary to prove the point. It would involve not
treating the medical condition in the women in a placebo arm and intentionally exposing foetuses to a
potential teratogen in an active treatment arm. Hence the data available to support prescribing
decisions in pregnancy are usually of limited quantity and quality.
Medication in Pregnancy: General Principles
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Agents or factors that cross the placenta to cause congenital malformations are defined as
teratogens. This strict definition is often relaxed to include any agent that directly or indirectly,
causes structural or functional abnormalities in the foetus or child after birth when administered to
a pregnant woman. Teratogens do not cause abnormalities in all foetuses exposed at the critical
period. For example thalidomide, which is a highly teratogenic drug, caused abnormalities in less
than half of all foetuses exposed during the critical period.
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The incidence of major congenital malformations in the UK general population is estimated to be
between 2 - 3%. Over 75% of these malformations are of unknown aetiology; only 1 - 2% are
thought to be due to drugs.
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The embryo is most vulnerable to teratogens during the embryonic phase, from days 18 to 55,
when the cells differentiate and the major organs are formed. If differentiated cells are damaged
they are unlikely to be replaced resulting in permanent malformations.
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During the foetal period, from day 56 until birth, organs such as the cerebral cortex and the renal
glomeruli continue to develop and remain particularly susceptible to damage. Functional
abnormalities such as deafness may also occur.
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Teratogenicity is usually dose-dependent and there is normally a threshold dose below which a
drug does not exert any teratogenic effects. For example the incidence of neural tube defects with
sodium valproate may be dose-related.
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The risk of teratogenicity may be increased if the number of concomitant drugs is increased. This
has been studied especially in women with epilepsy: the incidence of malformations increases
with the number of anti-epileptic drugs taken.
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Although rodents are normally used to evaluate the safety of drugs in pregnancy, their physiology,
metabolism and development are very different to humans. It cannot be assumed that a drug that
does not cause embryotoxicity, foetotoxicity or teratogenicity in animal studies can be used
‘safely’ in human pregnancies. However if a drug does cause foetal toxicity in several animal
species, this is an indicator that the same effects may occur in man.
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Miscarriage is known to occur in approximately 20% of clinical pregnancies (1).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Drug Characteristics

A drug does not need to cross the placenta to cause foetal toxicity. For example, any drug that
causes vasoconstriction of the placental vasculature can harm the foetus.
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However, an estimated 99% of drugs do cross the placenta, mostly by simple diffusion. The
extent to which compounds will cross the placenta depends upon their molecular size, degree of
ionisation, protein binding and lipid solubility.
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Non-ionised, lipid-soluble drugs will cross in preference to polar, ionised, hydrophilic compounds
(e.g. the more lipid soluble labetalol will cross the placenta to a greater extent than the more
hydrophilic atenolol).
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Drugs with a high molecular weight tend not to cross the placenta (e.g. insulin, heparin).
Potential Adverse Effects
Although foetal malformations are the most obvious adverse pregnancy outcome that drugs can
cause, there are others. Drugs can cause any of the following:
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Spontaneous abortions (e.g. isotretinoin)
Intra-uterine growth retardation (IUGR) (e.g. many street drugs have been associated with IUGR
although other factors may be responsible)
Prematurity (e.g. warfarin)
Stillbirths (e.g. warfarin)
Obstetric complications (e.g. NSAIDs can cause excessive maternal bleeding)
Neonatal side effects (e.g. CNS depression due to sedatives)
Withdrawal reactions in the neonate (e.g. opioid or benzodiazepine withdrawal)
Mental impairment (e.g. phenytoin, sodium valproate)
Cancer (e.g. cervical adenocarcinoma caused by stilboestrol)
Other Considerations

Drug pharmacokinetics will change in the mother. For example increases in plasma volume
result in lower serum concentrations of drugs that are predominantly held in the plasma, that is
those with a low volume of distribution (e.g. aspirin, phenytoin). A reduction in serum albumin
concentrations may result in higher levels of the free fractions of some protein bound drugs (e.g.
phenytoin, diazepam). Increases in renal function may affect the clearance of drugs excreted by
the kidney (e.g. ampicillin, gentamicin).
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It is important to remember that some of these parameters will quickly revert back to their prepregnancy levels and that dose adjustments may be required soon after delivery. For example
the changes in drug metabolism that require lamotrigine doses to be significantly increased
during pregnancy rapidly return to normal postpartum, requiring close monitoring and prompt
dose reductions to avoid toxicity.
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All women should take folate supplements from the time pregnancy is planned and for the first 12
weeks of pregnancy to reduce the risks of neural tube defects in the foetus. Most women should
take 400 micrograms daily, with the exception of women taking antiepileptic medication, those on
proguanil for malaria prophylaxis and women who have previously had a child with neural tube
defects who should take 5mg daily.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As

Monitoring of any chronic condition should be intensified during pregnancy.
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Mothers may become poor compliers if they believe that there is a risk that medication may harm
their baby. It is important to explain the benefits and risks of drug treatment in a balanced way.
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When advising on a drug in pregnancy don’t forget maternal contraindications and precautions
(e.g. avoid recommending labetalol for hypertension in an asthmatic).
Ways to Reduce Risk
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Consider non-drug treatments and only prescribe drugs if essential.
Consider the period of gestation and, if possible, avoid all drugs during the first trimester.
Do not use drugs known to be human teratogens, unless absolutely unavoidable.
Avoid new drugs because usually there is little information on their effects in pregnancy.
Avoid polypharmacy.
Where appropriate, use the lowest effective dose for as short a period as possible.
References
(1) National Institute for Health and Care Excellence. NICE Clinical Guideline 154. Ectopic pregnancy
and miscarriage: Diagnosis and initial management in early pregnancy of ectopic pregnancy and
miscarriage. Published December 2012. Accessed via https://www.nice.org.uk/guidance/cg154 on
20th October 2014
Otherwise based on: Tutorial 4 – Drugs in Pregnancy in Badiani A & Wills S. UKMi Training
Workbook. Ashford Tailored Training Limited; 8th Edition 2014, p.4.1 - 4.12 (Original manuscript by Dr
Patricia McElhatton, consultant teratologist, National Teratology Information Service, Newcastle, UK
with subsequent updates by Angela Badiani)
Prepared by
Angela Badiani, Wessex Drug and Medicines Information Centre, University Hospital Southampton
NHS Foundation Trust.
Date Prepared
20th October 2014
Checked by
Nicola Watts (based on the Q&A previously checked by Sue Gough and Kate Pickett), Medicines
Information Pharmacist, Wessex Drug and Medicines Information Centre, University Hospital
Southampton NHS Foundation Trust.
Date of check
20th October 2014
Available through NICE Evidence Search at www.evidence.nhs.uk
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