Clinical Review

What you need to know about medication safety in pregnancy

OBG Manag. 2007 November;19(11):66-82
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References

In addition, it is necessary to distinguish between a defect’s natural prevalence—i.e., the rate at which it occurs in a population—and the additional risk posed by exposure to a particular drug. Studies in large populations are needed—but usually unattainable—to determine the relative risk from specific potential teratogens.

Finally, it is very difficult to assess neurobehavioral effects of in utero exposure to centrally acting drugs beyond the immediate neonatal period. The dose, offspring’s age and gender, and behavioral test system must all be considered.

Few drugs are implicated in restricting fetal growth or reducing organ size. We also lack consistent information about long-term effects such as learning or behavioral problems (i.e., functional teratogenesis) that may result from chronic prenatal exposure to a certain medication.

Why FDA pregnancy categories have to go

In 1979, the Food and Drug Administration created five pregnancy risk categories to be used by manufacturers to rate their products in the drug formulary for use during pregnancy: categories A, B, C, D, and X, which range from no evidence of damage to the fetus (category A) to clear teratogenicity (D and X).

The D rating is generally reserved for drugs with no safer alternatives, such as secobarbital, doxycycline, and lorazepam. The X rating means there is absolutely no reason to risk using the drug in pregnancy, as in the case of oral contraceptives, benzodiazepines, and misoprostol.

Approximately 2% of drugs fall into category A, 50% in category B, 38% in category C, 3–5% in category D, and 1–5% in category X.3 These categories do not often accurately reflect the available information on risk to the fetus. A major initiative is under way to declare these categories obsolete and provide more informative drug labeling. Pregnancy labels of the future will likely address three important areas:

  • clinical considerations–issues relevant to prescription of a particular drug in pregnancy, including the risk of disease versus no treatment. Also included will be information of use when counseling a patient whose fetus was inadvertently exposed to a medication in early gestation
  • summary risk assessment–a narrative text that describes, as comprehensively as possible, the risk of exposure based on animal and human data
  • data to support the assessment.

All drugs cross the placenta

Most medications are easily absorbed during pregnancy, and serum concentrations of albumin for drug binding are lower than in the nonpregnant state. Pharmacokinetic changes during pregnancy include:

  • higher volume of distribution
  • lower maximum plasma concentration
  • lower steady-state serum concentration
  • shorter plasma half-life
  • higher clearance rate.1

The small spatial configuration and high lipid solubility of most medications permit easy transfer of an unbound drug or its metabolite across the placenta or into breast milk. Virtually all drugs and their end products cross the placenta, with unbound concentrations of the drug in the fetal serum similar to the level in maternal serum—sometimes even higher (FIGURE).

A few drugs with high molecular weight do not cross the placenta in significant amounts (e.g., glyburide, interferon, thyroid supplements, insulin).

FIGURE An elaborate nutrient (and drug) delivery system

The placenta and umbilical cord deliver the nutrients and oxygen the fetus needs for normal growth—as well as most medications used by the mother.

Medication use tends to increase as pregnancy progresses

The drugs most commonly taken during pregnancy include vitamins, iron preparations, calcium, analgesics, antibiotics, and antacids. Excluding vitamins and mineral supplements, an average of one to two medications are taken during gestation. Over-the-counter formulations account for about half of these drugs, with acetaminophen being the single most commonly used medication during pregnancy. Antibiotics are the most widely prescribed drugs.

Although caffeine, tobacco, alcohol, and illicit substance use tends to diminish as pregnancy progresses, medications are usually taken at the same frequency or more often during gestation.

My colleagues and I found a significantly higher mean number of medications (3.3 and 4.1, respectively) used during the second and third trimesters of gestation than were taken before pregnancy (2.6).2

How to counsel the patient

Counseling a woman before or during pregnancy about the continuation or initiation of a medication should take place in an open, supportive, and informative manner. Most inquiries relate to exposures involving very low levels of relative and absolute risk.

A detailed fetal ultrasonographic examination is often used to accurately date the pregnancy and, if possible, screen for any structural defects. The patient should be advised that first-trimester screening, chorionic villus sampling, maternal serum quadruple screening, amniocentesis, and fetal blood sampling are not very predictive of a drug’s fetal effects. Exceptions may be the observation of open neural tube defects (approximate 1% risk associated with valproic acid and carbamazepine) by maternal serum quadruple screening and facial clefting by targeted ultrasonography.

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