Classifying the Safety of Drugs in Pregnancy

There was a time when drugs were believed to be unable to cross the placenta, as if it were some impenetrable fortress. If a drug was able to affect fetal development or lead to other birth defects, it was thought to be due to a "leaky" placenta. Fortunately, we now know that this is not the case.

Once the risk of harm was recognized, numerous control agencies developed classifications for the safety of certain drugs in pregnancy. In the United States, we are familiar with the following FDA classification:

Classification

Teratogenic Risk

Class A

Controlled studies have shown no risk.

Adequate well-controlled studies in pregnant women have failed to show risk to fetus.

Class B

No evidence exists of risk for humans.

Animal studies show risk or are negative, but no human studies have been done.

Class C

Use may engender risk for fetus.

Human studies are lacking, and animal studies may be positive or lacking

Potential for benefit may outweigh potential for harm.

Class D

Positive evidence of risk is based on studies or postmarketing data.

Potential for benefit may outweigh potential for harm.

Class X

Drugs are contraindicated in pregnancy based on human or animal studies or postmarketing reports that indicate benefit is clearly outweighed by risk.

There are, however, other classification systems that may help answer questions where the FDA classification falls short. In certain institutions, depending on the type of subscription purchased for the drug information databases, the Australian Drug Evaluation Committee (ADEC) and the Swedish Catalogue of Approved Drugs (FASS) are available through MICROMEDEX.¹ However, the commonly available resource that often sits on the shelf collecting dust (since it’s still an actual book) is Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk.²

The textbook's classification system offers several advantages over the FDA's simplistic one. In the new edition, the authors actually did away with their modification of the FDA classification. Rather, it focuses on the Pregnancy and Fetal Risk summaries and discusses the data supporting the Pregnancy Recommendation. The data is presented in such a style that allows the reader to determine the risks and benefits of the drug in pregnancy. The pregnancy recommendations are divided as follows:²

Pregnancy Recommendation

Description

Compatible

Human data demonstrates benefit >>>>> risk

Probably Compatible

No (limited) human data, but the characteristics of the drug suggest there may not be fetal risk.

Compatible — Maternal Benefit >> Embryo-Fetal Risk

Limited human data, but the potential maternal benefit the known (or unknown) embryo-fetal risk.

Human Data Suggests Low Risk

Limited human pregnancy experience that suggests the drug does not represent a significant risk of developmental toxicity at any time in pregnancy. The limited human pregnancy data outweighs any animal reproduction data.

Animal Data Suggest Low Risk

The drug does not cause developmental toxicity (at doses that did not cause maternal toxicity) in all animal species studied at doses ≤10 times the human dose based on body surface area (BSA) or area under the curve (AUC).

Animal Data Suggest Moderate Risk

The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in 1 animal species at doses ≤10 times the human dose based on BSA or AUC.

Animal Data Suggest Risk

The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in 2 animal species at doses ≤10 times the human dose based on BSA or AUC.

Animal Data Suggest High Risk

The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in 3 or more animal species at doses ≤10 times the human dose based on BSA or AUC.

Contraindicated — 1^st Trimester

Human exposures in the 1st trimester, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity.

Contraindicated — 2nd Trimester

Human exposures in the 2nd trimester, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity.

Contraindicated — 3rd Trimester

Human exposures in the 3rd trimester, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity.

Contraindicated

Human exposures at any time in pregnancy have been associated with developmental toxicity.

No (Limited) Human Data — No Relevant Animal Data

The risk in pregnancy cannot be assessed.

Human Data Suggest Risk in 1st and 3rd Trimesters

Evidence (for the drug or similar drugs) suggests that there may be an embryo-fetal risk for developmental toxicity in the 1st and 3rd trimesters, but not in the 2nd trimester. The human pregnancy data outweigh any animal reproduction data.

Human Data Suggest Risk in 2nd and 3rd Trimesters

Evidence (for the drug or similar drugs) suggests that there may be an embryo-fetal risk for developmental toxicity in the 2nd and 3rd trimesters, but not in the 1st trimester. The human pregnancy data outweigh any animal reproduction data.

Human Data Suggest Risk in 3rd Trimester

Evidence (for the drug or similar drugs) suggests that there may be an embryo-fetal risk for developmental toxicity in the 3rd trimester or close to delivery, but not in the 1st or 2nd trimesters. The human pregnancy data outweigh any animal reproduction data.

Human (and Animal) Data Suggest Risk

Usually, pregnancy exposure should be avoided, but the risk may be acceptable if the maternal condition requires the drug.

While this may seem overly complex, let’s look at an example drug we frequently use in the emergency department: ketamine. Based on the FDA system, ketamine has not been officially classified. But, in the textbook, the pregnancy recommendation is "Limited Human Data - Animal Data Suggest Low Risk."

Looking at more detail in the pregnancy and fetal risk summaries, it’s stated that, although ketamine anesthesia close to delivery may induce dose-related, transient toxicity in the newborn, these effects are usually avoided with the use of lower maternal doses. Also, while the clinical consequences are unclear, ketamine usually demonstrates a dose-related oxytocic effect with an increase in uterine tone and frequency and intensity of uterine contractions.^3-8

The reason behind the disagreement between the systems is that the FDA data is based on human experience when ketamine is used as an anesthetic at or close to delivery, where a limited amount of ketamine reaches the fetus. It may be unclear if changes in uterine contractions are a result of ketamine or not. Knowing this information, in addition to considering the FDA classification, may lead clinicians in a different direction than simply utilizing the FDA system alone.

References:

1. Addis A, Sharabi S, Bonati M. Risk classification systems for drug use during pregnancy: are they a reliable source of information? Drug Saf. 2000 Sep;23(3):245-53

2. Briggs, Gerald G.; Freeman, Roger K.; Yaffe, Sumner J., Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th Edition, Copyright (c) 2011 Lippincott Williams & Wilkins.

3. Chodoff P, Stella JG. Use of CI-581 a phencyclidine derivative for obstetric anesthesia. Anesth Analg. 1966;45:527—30.

4. Bovill JG, Coppel DL, Dundee JW, Moore J. Current status of ketamine anaesthesia. Lancet. 1971;1:1285—8.

5. Moore J, McNabb TG, Dundee JW. Preliminary report on ketamine in obstetrics. Br J Anaesth. 1971;43:779—82

6. Little B, Chang T, Chucot L, Dill WA, Enrile LL, Glazko AJ, Jassani M, Kretchmer H, Sweet AY. Study of ketamine as an obstetric anesthetic agent. Am J Obstet Gynecol. 1972;113:247—60.

7. Galloon S. Ketamine for obstetric delivery. Anesthesiology. 1976;44:522—4.

8. Marx GF, Hwang HS, Chandra P. Postpartum uterine pressures with different doses of ketamine. Anesthesiology. 1979;50:163—6.