|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 (e.g. 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
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 this time.
|Pregnancy can be divided into pre-embryonic, embryonic and foetal stages:|
|Table I: Drugs considered to be human teratogens (not exhaustive) [1,2,6]|
vitamin A & derivatives e.g. isotretinoin
|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 (e.g. 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 risks [1,2,6]|
|ACE inhibitors||Renal dysfunction, oligohydramnios, intrauterine growth retardation|
|Antihypertensives||Foetal hypoxia with excessive treatment due to decreased placental perfusion|
|NSAIDs||Premature closure of the ductus arteriosis, renal impairment|
|The 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
Oral availability: 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 .
Distribution: 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 required.
Metabolism/elimination: 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 methadone.
|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 (e.g. 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.|
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|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 requests).|
Page Last Updated: 26/09/08
Clinical Pharmacology Department : Christchurch Hospital : Private Bag 4710 : Christchurch : 8140 : NZ
Phone 0800 DRUGINFO (378 446) : email druginfo[AT]cdhb.health.nz