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Pregnancy and Lactation

Testing pregnant animals is done as part of the usual preclinical development of new drugs, but a drug that is not teratogenic (leading to congenital malformations) in some or all animal species tested may sometimes, unfortunately, still be noxious in women. For obvious reasons, clinical testing is almost never done in pregnant women during the development of new drugs unless the drug is developed expressly for use in pregnancy. Thus, the safety and efficacy of drugs in pregnant women is largely unknown at the time of marketing, and only a little additional information is gained from spontaneous reporting of adverse events (AEs).

Some drugs are used and, to some degree, tested in pregnancy, usually in situations in which treatment is obligatory for either the mother or unborn child (e.g., hypertension, asthma, rheumatoid arthritis, epilepsy). These studies are usually not blinded and are prospective or retrospective observational or surveillance studies. Pregnancy registries are now required for manufacturers and Marketing Authorization/New Drug Application holders for most marketed drugs. That is, every use of the drug that the company becomes aware of in a pregnant woman or by a pregnant woman’s partner is recorded and followed to outcome (birth, miscarriage, etc.).

The U.S. Food and Drug Administration’s current pregnancy categories are as follows:

A: Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities to the fetus in any trimester of pregnancy.

B: Animal studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women.

Or

Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

C: Animal studies have shown an adverse effect, and there are no adequate and well-controlled studies in pregnant women.

Or

No animal studies have been conducted, and there are no adequate and well-controlled studies in pregnant women.

D: Adequate, well-controlled, or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.

X: Adequate, well-controlled, or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks. The use of the product is contraindicated in women who are or may become pregnant.

In 2008, the FDA issued proposed changes in the rules for pregnancy and lactation labeling. The proposed rule would remove the letter categories noted above and would replace them with three new sections:

1. The “Fetal Risk Summary” section would describe what is known about the effects of the drug on the fetus, and if there is a risk, whether this risk is based on information from animals or humans. A risk conclusion would be made, such as “Human data indicate that (name of drug) increases the risk of cardiac abnormalities,” followed by a summary of the data.
   
2. The “Clinical Considerations” section would include information about the effects of the use of the drug on the mother and fetus if it is taken before a woman knows she is pregnant.
   
   
   
   • Inadvertent exposure
     
   • Risk from the disease
     
   • Dosing adjustments during pregnancy
     
   • ARs unique to pregnancy with this drug
     
   • Interventions needed (e.g., monitoring)
     
   • Complications associated with the drug
     
   • Effects during labor and delivery
   
   
3. The “Data” section would describe in more detail the available data.

Information on the pregnancy registry would also be included. See FDA’s pregnancy/lactation section for further information (Web Resource 35-1).

The lactation section of the labeling would use the same format as the pregnancy section noted above.

This change in label presentation does not change or alter the data collected; it is simply a better way to present the known data.

In August 2002, the FDA issued a guidance for industry on establishing pregnancy registries. In this guidance, the FDA gives a specific definition of a birth registry to differentiate it from a teratology registry:

This type of registry is not a pregnancy prevention program. The FDA does not recommend a registry for all drugs:

• Inadvertent exposures to the medical product in pregnancy are or are expected to be common such as when products have a high likelihood of use by women of childbearing age.
  
• The medical product presents special circumstances, such as the potential for infection of mother and fetus by administration of live, attenuated vaccines.

A registry can be established at any time during the life of a drug. The sponsor or the FDA may initiate the request. The design of the registry is a function of the objective. It may be an open-ended surveillance to the specific testing of a hypothesis-using standard.

The guidance then details critical elements of a registry, including objectives, exposure, sample size, eligibility requirements, data source and content, fetal anomalies sought, use of an independent data monitoring committee, an investigational review board, and informed consent. The reader is referred to the guidance for these epidemiologic details.

A few points of note:

Birth defects occur “spontaneously” in a high number of women. The March of Dimes Birth Defect Foundation, Fact Sheet 2001, available on its website (Web Resource 35-2), reports the following rates for various pregnancy outcomes and fetal abnormalities:

• Spontaneous abortions/miscarriage (loss before 20 weeks): 1 in 7 known pregnancies
  
• Low birth weight (<2,500 grams): 1 in 12 live births
  
• Fetal death/stillbirth (loss after 20 weeks): 1 in 200 known pregnancies
  
• Any major birth defect: 1 in 25 live births
  
• Heart and circulation defects: 1 in 115 live births
  
• Genital and urinary tract defects: 1 in 135 live births
  
• Nervous system and eye defects: 1 in 235 live births
  
• Club foot: 1 in 735 live births
  
• Cleft lip with or without cleft palate: 1 in 930 live births

The guidance also notes that other types of studies, such as case-control studies, may be useful to evaluate rare adverse birth outcomes and to identify whether the drug in question is an associated risk factor. They are useful when long-term follow-up is needed. They can be nested within other existing pregnancy registries. Automated database studies (e.g., health maintenance organizations, Medicaid) may be useful also.

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