The topic of "drug safety in pregnancy"
embraces the effect of drugs on the pregnancy, foetus or neonate, and
the effects of the pregnancy on drug disposition. Almost all drugs cross the placenta
to some extent and may pose risk to the developing foetus. A few exceptions
exist (eg. insulin, heparin) which are very large molecules that do not cross
biological membranes readily.
The effect of drugs on the pregnancy, foetus or neonate
First-trimester drug exposure has the largest risk of
malformations and ideally all drug therapy should be stopped before attempting
conception. Accidental drug exposure is a frequent occurrence because
approximately half of all pregnancies are unplanned. Major malformations are
thought to affect 2 – 4% of all live births. In the majority of cases, the
cause of the abnormalities cannot be identified. Exogenous factors such as drugs
are thought to cause only 1 – 5% of all malformations (ie affecting < 0.2%
of all live births) [1-3]. The percentage of pregnancies affected by
drugs is small but largely preventable.
It is difficult to predict which pregnancies exposed to
teratogens will result in a malformation. This is because most known teratogens
only cause problems in a small percentage of exposed pregnancies (Table 1).
Accurate timing of the exposure can help in assessment of foetal risk as some
drugs only cause specific abnormalities at a certain time period in the
pregnancy. For example, folic acid antagonists (eg. carbamazepine) will not
cause neural tube defects if exposure to the drug occurred after the fourth week
post-conception, by which time neural tube closure has occurred [2,4]. However, folic acid antagonists may cause other types of malformations beyond
Pregnancy can be divided into pre-embryonic, embryonic and
(days 0 – 17 post-conception): drug exposure during this time
is not usually considered to pose risk of malformations. An ‘all
or nothing response’ is said to occur ie. there is early abortion or
no adverse effect on foetal development [2,5]. However, the
half-life of the drug must be considered because many drugs remain in
the maternal circulation for a long period after discontinuation.
(days 18 – 56 post-conception): This is the most important
time in terms of risk of foetal malformations (Table 1) [2,5].
I: Drugs considered to be human teratogens (not exhaustive) [1,2,6]
vitamin A &
derivatives eg. isotretinoin
Foetal period (days 56 – term): The risk of malformations is lower,
but some abnormalities may still occur because development of organs/tissues
such as the central nervous system, teeth and genitalia continues. For example,
ethanol exposure may affect central nervous system development, and
tetracyclines may adversely discolour deciduous teeth and suppress bone growth
In general, these can be predicted based on the
mechanism of action of the drug. For example, excessive dosing with antihypertensives may reduce
placental blood flow and cause foetal hypoxia. Some drugs (eg. antidepressants,
opioids, benzodiazepines) may cause withdrawal reactions in the foetus or
neonate with abrupt maternal cessation or delivery, respectively. Excessive
clinical effects following in utero exposure may also occur in the
neonate. The risk of these perinatal complications may be reduced by gradually
reducing the maternal dose towards the end of the third trimester. However, the
possibility of disease relapse or withdrawal symptoms in the mother must also be
considered and, under some circumstances, this may pose greater foetal risk.
Sometimes a drug may be administered to the neonate (eg. following opioid
exposure) to prevent or treat withdrawal. Some drugs may affect pregnancy
maintenance. For example, NSAIDs and ß2-agonists
have been used to retard labour.
Table II: Examples of pharmacological
Renal dysfunction, oligohydramnios, intrauterine growth
Foetal hypoxia with excessive treatment due to
decreased placental perfusion
Withdrawal reactions, ‘floppy infant syndrome’
Premature closure of the ductus arteriosis, renal
effects of pregnancy on drug disposition (pharmacokinetics)
The physiological changes that
occur with pregnancy may affect
pharmacokinetics. These effects vary with the drug and with the individual, are
generally difficult to predict and frequently poorly studied.
Gastrointestinal motility may be reduced during pregnancy and this may result in delayed absorption of orally
administered drugs. However, in the vast majority of cases this is unlikely to
be of clinical significance as the total amount of drug that is systemically
available will not change appreciably .
Maternal water and fat content
increases in pregnancy and may increase the volume of distribution of drugs.
This should only impact on those drugs that are initiated with a loading
dose, when higher doses may be required.
Plasma albumin concentrations decrease in pregnancy and may
result in reduced protein binding of some drugs . For most drugs
these changes should not impact on drug dosing because the unbound (active)
concentration should not change. However, problems may arise when drug
concentrations are used to tailor drug therapy (eg. anticonvulsants). Routine
measured drug concentrations are usually the total concentrations ie. bound plus
unbound (free). Total drug concentrations may decline in pregnancy so for drugs
such as phenytoin it is important to measure unbound concentrations just prior
to and during pregnancy. Total phenytoin concentrations must not be used to make
dosage adjustments in pregnant women. Interpretation of phenytoin concentrations
during pregnancy is very complicated and specialist consultation is usually
Maternal drug clearance often increases because of changes that include increased renal and hepatic blood
flow and enzyme induction. This generally means that increased maintenance
doses of both metabolised and renally eliminated drugs may be required in
pregnancy. For example, drugs that are extensively renally eliminated (eg.
penicillins) will have enhanced clearance in pregnancy because of increased
glomerular filtration rates. Increased hepatic metabolism of drugs is
variable  but can be expected to result in increased dosage
requirements in the third trimester for agents such as phenytoin and
Herbal and other complementary therapies are often perceived by the lay
public as 'safe'. Unfortunately, data on many of these products are very
limited and insufficient to determine their safety in pregnancy. In general,
herbal remedies should be avoided during pregnancy.
If drug therapy is needed, select drugs with the most established safety
record. For example, amitriptyline (or nortriptyline) or fluoxetine should be selected over
moclobemide or nefazodone for depression.
Use the lowest effective dose for the shortest possible time. Note: poor
control of some maternal disease states may carry significant risk to the
development of the foetus. In addition, the severity or frequency of some
maternal diseases (eg. migraines) may improve in pregnancy allowing a reduction
in the dosage of some drugs, or cessation of treatment.
Schardein JL. Chemically induced birth defects. Marcel Dekker:New York (2nd
Theis JWG, Koren G. Maternal and fetal clinical pharmacology. In: Speight
TM, Holford NHG (eds). Avery’s Drug Treatment, Adis International
Limited:Auckland (4th ed), 1997.
McCombs J, Cramer MK. Pregnancy and lactation: therapeutic considerations.
In: DiPiro JT, Talbert RL, Yee GC et al (eds). Pharmacotherapy. A
pathophysiologic approach p1298-312. Appleton & Lange:Stamford (4th
Koren G (ed). Maternal-fetal toxicology, a clinician’s guide. Marcel
Dekker:New York (2nd ed), 1994.
Rubin P (ed). Prescribing in pregnancy. BMJ Publishing Group:London (2nd
Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998;
Recommended information sources
Most health professionals have insufficient information at
their workplace to readily and safely advise on drug use in pregnant women.
Statements such as the drug "should not be used in pregnancy unless
the benefits outweigh the risks" or "this medicine should
only be used when clearly needed" are inadequate to assess risk. Some
references offer grading systems (eg. FDA) that classify drugs according to
available data and magnitude of risk (FDA categories A – D, X). However,
these systems should not be used as the sole means of determining drug safety
in pregnancy as they are oversimplified and may be difficult to interpret. If
there is any doubt as to whether it is safe to administer a drug to a pregnant
woman, a speciality service should be consulted.
See our links page here
of vulvovaginitis in pregnancy and breastfeeding
of allergic rhinitis in pregnancy and breastfeeding
Hughes RC, Gardiner SJ, Begg EJ, Zhang M. Effect
of pregnancy on the pharmacokinetics of metformin. Diabet Med. 2006;
23(3): 323-6. [abstract]
Gardiner SJ. Drugs in Pregnancy. New Ethicals Journal June 2002;
Koren G, Pastuszak A, Ito S. Drugs in pregnancy.
N Engl J Med 1998;
Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation (6th
ed), 2002 [ISBN 0-7817-3203-4].
Speight TM, Holford NHG, editors. Avery's Drug Treatment (4th ed),
Auckland:Adis International Ltd, 1997 [ISBN 0-86471-036-4].
Koren G (ed). Maternal-fetal toxicology, a clinician’s
guide, New York: Marcel Dekker (2nd ed), 1994.
Information on specific drugs
These are written, referenced reports prepared as part of our
routine Drug Information Service practice. In general, we have included only
those reports that were prepared from 2000 onwards. If you are a health
professional in New Zealand and would like information about a specific drug(s)
in pregnancy, please phone 0800 DRUGINFO (3784 4636) or (03) 364 0900, or e-mail:
email@example.com (please ensure sufficient
information is supplied - see required information for e-mailed/written
Last Updated: November 1 2006
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