Medicines Q&As
Q&A 34.5
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: 23rd May 2012
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 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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Exposure to a drug during the pre-embryonic phase of pregnancy, which lasts until the 17th day
after conception, will either result in survival of the intact embryo or death. This is sometimes
referred to as the ‘all or nothing principle’. If most cells are affected the pregnancy is
spontaneously miscarried. If only a few cells are damaged the embryo is normally unaffected.
Most women will have not have missed their first period and not even realise they are pregnant.
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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.

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.
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As

Genetic factors may play some part in determining teratogenic risk. Further studies are under
way.
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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.

Miscarriage is known to occur in 10-20% of clinical pregnancies (1).
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.

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.

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).

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)
Cancer (e.g. cervical adenocarcinoma caused by stilboestrol)
Other Considerations

Drug pharmacokinetics will change in the mother. The volume of distribution increases, proteinbinding decreases, and renal function increases gradually.

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 anti-epileptic medication and
women who have previously had a child with neural tube defects who should take 5mg daily.
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As

Monitoring of any chronic condition should be intensified during pregnancy.

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 contra-indications 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) Hinshaw K, Fayyad A, Munjuluri P. Royal College of Obstetricians & Gynaecologists Clinical
Green Top Guidelines: The Management of Early Pregnancy Loss (25) - Oct 2006.
Accessed via http://www.rcog.org.uk/files/rcog-corp/uploadedfiles/GT25ManagementofEarlyPregnancyLoss2006.pdf on 23rd May 2012.
Otherwise based on: Tutorial 4 – Drugs in Pregnancy in Badiani A & Wills S. UKMi Training
Workbook. Ashford Tailored Training Limited; 7th Edition 2011, p.4.1 - 4.12 (with advice from Dr
Patricia McElhatton, consultant teratologist, National Teratology Information Service, Newcastle, UK)
Prepared by
Angela Badiani, Wessex Drug & Medicines Information Centre, University Hospital Southampton NHS
Foundation Trust.
Date Prepared
23rd May 2012
Checked by
Sue Gough (based on Q&A previously checked by Kate Pickett), Critical Evaluation Pharmacist,
Wessex Drug & Medicines Information Centre, University Hospital Southampton NHS Foundation
Trust.
Date of check
23rd May 2012
From the NHS Evidence website www.evidence.nhs.uk
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