Drug safety in pregnancy
 

Background

 

Teratogenicity

 

Stages of foetal development

 Pharmacological risks

Effects of pregnancy on drug disposition (pharmacokinetics)

General principles

 

Recommended information sources

 

Information on specific drugs
 
Background
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.

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The effect of drugs on the pregnancy, foetus or neonate
Teratogenicity
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 this time.

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Pregnancy can be divided into pre-embryonic, embryonic and foetal stages:
  1. Pre-embryonic (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.
  2. Embryonic (days 18 – 56 post-conception): This is the most important time in terms of risk of foetal malformations (Table 1) [2,5].
Table I: Drugs considered to be human teratogens (not exhaustive) [1,2,6]
ACE inhibitors 
androgens 
antineoplastics (some) 
carbamazepine 
carbimazole 
danazol 
diethylstilboestrol 
ethanol 
lithium 		 misoprostil 
penicillamine 
phenytoin 
tetracyclines 
thalidomide 
valproic acid 
vitamin A & derivatives e.g. isotretinoin 
warfarin
 
  1. 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 [2,5].

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Pharmacological risks
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]
Drugs Adverse effect
ACE inhibitors Renal dysfunction, oligohydramnios, intrauterine growth retardation
Antidepressants Withdrawal reactions
Antihypertensives Foetal hypoxia with excessive treatment due to decreased placental perfusion
Corticosteroids Adrenal suppression
NSAIDs Premature closure of the ductus arteriosis, renal impairment
Opioids Withdrawal reactions

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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 studied.

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 [2].

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 [2]. 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 [2] but can be expected to result in increased dosage requirements in the third trimester for agents such as phenytoin and methadone.

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General principles
  • Avoid all drugs in pregnancy where possible, especially in the first-trimester.
  • 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.
  • Consider tapering and discontinuing unnecessary pharmacotherapy prior to attempting conception. Remember that some drugs or their metabolites may have long half-life and persist for some time after stopping therapy.
  • Many conditions are self-limiting and do not require drug treatment. Reassurance or lifestyle measures (e.g. avoidance of migraine triggers) may be sufficient.
  • Where possible, delay treatment until after results of laboratory testing (e.g. swabs), or until after delivery (e.g. for treatment of hypercholesterolaemia).
  • 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 (e.g. migraines) may improve in pregnancy allowing a reduction in the dosage of some drugs, or cessation of treatment.
  • It is also important to realise that some mothers may be very anxious about the risks that their drug therapy poses to their baby. This may lead to noncompliance with drug therapy, or unnecessary pregnancy terminations.

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References

  1. Schardein JL.  Chemically induced birth defects.  Marcel Dekker:New York (2nd ed), 1993.

  2. 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.

  3. 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 ed), 1999.

  4. Koren G (ed).  Maternal-fetal toxicology, a clinician’s guide.  Marcel Dekker:New York (2nd ed), 1994.

  5. Rubin P (ed).  Prescribing in pregnancy.  BMJ Publishing Group:London (2nd ed), 1995.

  6. Koren G, Pastuszak A, Ito S.  Drugs in pregnancy.  N Engl J Med 1998; 338: 1128-37.
 
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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Websites:
See our links page here
 
Drug Information bulletins:
 
Journal articles:
  • 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; 61-3.

  • Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998; 338: 1128-37.

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Books:
  • Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation (8th edition), 2008 [ISBN-13:978-0-7817-7876-3].
  • Schaefer C, Peters P, Miller RK, editors. Drugs during pregnancy and lactation (2nd edition), 2007 [ISBN: 978-0-444-52072-2].
  • Speight TM, Holford NHG, editors. Avery's Drug Treatment (4th edition), Auckland:Adis International Ltd, 1997 [ISBN 0-86471-036-4].
  • Koren G (editor). Maternal-fetal toxicology, a clinician’s guide, New York: Marcel Dekker (2nd edition), 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: druginfo@cdhb.govt.nz (please ensure sufficient information is supplied - see required information for e-mailed/written requests).
     

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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.govt.nz