Drugs in Pregnancy

A Handbook for Pharmacists and Physicians

Radhwan Nidal Al-Zidan

• Publisher: Apple Academic Press
• Year: 2020
• ISBN:
  9781000030051
• Edition: 1
• Topic: Medicine
• Subtopic: Gynecology, Obstetrics & Midwifery

This first-of-its-kind handbook offers crucial information on the safety of drugs taken during pregnancy. It covers an exhaustive list of common and less common drugs and provides for each drug the FDA letter categorization and newly approved "Pregnancy and Lactation Labeling Rule (PLLR)" systems for rating drug risks in pregnancy, imposed by the U.S. Food and Drug Administration (FDA).

Drugs in Pregnancy: A Handbook for Pharmacists and Physicians covers the pregnancy ramifications of using anti-infective, cardiovascular, hematologic, dermatologic drugs and drugs affecting the endocrine, central, autonomic, gastrointestinal, musculoskeletal systems in addition to herbs, vitamins and dietary supplements. To enable the reader to develop well-informed knowledge about a drug safety profile during pregnancy, three sections of data have been provided for each drug: FDA Category, Risk Summary, and Further Reading.

CHAPTER 1

Introduction

1.1 HISTORICAL BACKGROUND

Humans have a long history of using different chemicals and herbs in treating a variety of medical conditions in both genders. The use of such compounds for pregnant women was not an exception. There is a translated Assyrian Script, dating back 3500 years, which describes three different prescriptions to relieve abdominal cramps in pregnant women [1]. However, the concern about the safety of chemical agents (drugs and herbs) given to females during pregnancy was not raised until the tragedy of the thalidomide. In 1957, thalidomide gained marketing approval as a safe over-the-counter (OTC) drug for treating insomnia in pregnant women. Unfortunately, a few years later case reports of phocomelia (malformation of the limbs) began to accumulate. With thousands of children born with tragic limb deformities, the health care providers and the public around the world were shocked by the unforeseen relationship of thalidomide use in pregnant women and the development of serious birth defects in the newborns.

The moral impact of the thalidomide tragedy and subsequent demands of the public in the mid-1960s were the driving force for the researchers and health care professionals to better scrutinize the potential effects of a drug on both the conceptus and the mother. Furthermore, the governmental regulations of drugs approval around the globe became more restricted as to thoroughly examine the safety profile of the drug use in pregnancy before granting marketing approval. In addition, the pharmaceutical companies became obliged to provide enough data, within the patient information leaflet, about the use of their drug in pregnant women.

Aiming to make it easier for the health care providers to deal with the safety of drug use in pregnancy, a number of classification systems were adopted in different countries around the globe. The United States Food and Drug Administration (FDA) letter categorization system (A, B, C, D, and X) was the most commonly used one since 1979. However, in December 2014, the FDA replaced the old categorization system with a completely different pregnancy and lactation labeling rule (PLLR), which became effective in mid-2015. By the year 2020, all the manufacturers of the FDA approved prescription drugs and biologic products are required to comply with the PLLR rule obligations [2]. Therefore, the need for books like this one became inevitable to bridge the gap between the outdated FDA categorization system, which has been used for more than three decades, and the considerably different style of information provided in accordance with the PLLR rule. The FDA is changing the regulations and by 2020 the letter categorization, which has been used for more than three decades, will be removed from all of the FDA approved prescription drugs and biologic products. Therefore, physicians and pharmacists urgently need a book that merges the old categorization system with a considerably different style of information provided in accordance with the PLLR rule.

1.2 SCOPE OF THE PROBLEM

Women can be prescribed a variety of drugs for treating a medical condition or a disease without considering the possibility of pregnancy. For example, a sexually-active young female suffering from recurrent convulsions are usually prescribed an antiepileptic drug—to be taken continuously. It is quite possible for such a woman to become pregnant while taking the anti-epileptic drug. Since most of the antiepileptic drugs are teratogenic, serious damage to the conceptus as well as a significant psychological burden on the mother may occur.

The previous case-scenario is not uncommon. For instance, a multinational, cross-sectional study performed by Lupattelli [3] found that 81.2% of women have taken at least one drug (prescribed or OTC) during pregnancy. Sedgh [4] estimated that only in 2012 there were nearly 213 million pregnancies world-widely. Therefore, it is reasonable to anticipate that every year there are, at least, tens of millions of pregnant women around the globe who are being exposed to medications. Some of these medications could be extremely harmful to the development of the fetus and could lead to loss of the conceptus. For example, a cohort study conducted in Finland on 43,470 pregnant women found that 20.4% of the sample bought at the minimum one drug classified as possibly harmful during conception, and 3.4% bought at the minimum one drug categorized as clearly harmful [5].

Accurate numbers of birth defects due to the intake of drugs by pregnant women has not been determined, yet, for many reasons. First of all, there is a global lack of well-designed cohort studies, which are the most reliable source of information regarding drug safety in pregnancy, to exactly determine the negative effect(s) of each drug given during pregnancy. Secondly, it is not uncommon for addicted mothers to avoid mentioning the intake of alcohol or illicit drugs to their general practitioners, which makes it even harder to determine the true cause of birth defects in the newborns. However, not all birth defects are caused by drugs. A study found that 4% of newborns in the U.S. suffer from birth defects, and that approximately only 1% of those neonates were born to mothers who have ingested harmful drug(s) during pregnancy [6].

1.3 CRITICAL TIME PERIODS DURING PREGNANCY

In general, the anticipated effect(s) of a given drug during pregnancy can be divided according to the fetal age, as follows:

• From the 1^st day until the 20^th day after fertilization: Interestingly, teratogenesis is unlikely to occur during this period. However, the effect(s) of any harmful drug given during this period could lead either to the death of the conceptus or to no adverse effects at all, which is commonly known as the all-or-nothing effect.
• From the 21^st day until the 56^th day after fertilization: The hallmark of this fetal period is characterized by organogenesis. Therefore, teratogenesis is most likely to occur at this stage of conception. The spectrum of harmful effects of a drug given during this period could range from spontaneous abortion, through teratogenicity (revealed as a gross anatomical defect), to a hidden embryopathy (like a permanent subtle functional or metabolic defect that may become noticeable later in life). Furthermore, the harmful effect(s) of the given drug may result in increased rates of childhood malignancies (for example, a child of a mother treated, during pregnancy, with radioactive iodine for thyroid malignancy).
• From the start of the 2^nd trimester till delivery: The exposure of the conceptus to a drug during this period is unlikely to cause teratogenic effects because the stage of fetal organogenesis has completed. However, the exposure of the fetus to certain drugs during this period may lead to a change in the growth and/or function of the normally formed fetal tissues and organs. It is worth mentioning that at this stage, the contribution of the placenta in the metabolism of drugs rises. Therefore, for fetal toxicity to occur, higher doses are required to be used by the mother.

In general, the developmental and reproductive toxicological effects of a drug on the conceptus vary depending on multiple factors. The fetal age at the time of exposure, which is described above, represents only one of the factors that determine the effect of the given drug on the fetus. Another important factor is related to the given drug itself, in terms of the dose, the duration, and the route of administration. In addition, the factors related to the mother also play crucial roles in governing the occurrence and/or the severity of adverse events in the conceptus. For example, nausea, and vomiting associated with pregnancy may decrease the absorption and bioavailability of drugs taken orally. Therefore, the same dose of a certain drug that is ingested by two different women, at the same gestational age, could lead to the development of adverse event(s) in one fetus but not the other.

1.4 CLINICAL TOOLS FOR EVALUATING DRUGS’ SAFETY IN PREGNANCY

In general, the available sources of drug information regarding their safety during pregnancy are mainly obtained from animal and human studies. Although animal tests are extensively used in the study of drugs’ safety during pregnancy, they are considered weak predictors of whether a drug is harmful or has a teratogenic effect in humans. The specificity and sensitivity of animal models as predictors of human teratogenicity is determined by the relative proximity of the used animal species to Homo sapiens. For example, it is known that the sensitivity and specificity of rodent studies are less than 60% [7]. There are a number of explanations to describe the differences in the response to the same drug by different species, such as the dissimilarities in the pharmacodynamics and pharmacokinetics of the same drug in different species. Additionally, there are variations in the placentation and embryonic development timing of the conceptus.

On the other hand, more accurate and realistic data, regarding the safety of drugs during pregnancy, are obtained from case reports, case-control studies, and cohort studies that have been conducted in humans [8]. The case reports are crucial in raising the causal hypothesis, which appeals to the health care providers and clinical researchers to carry out more sophisticated epidemiological studies. The case-control and cohort studies are more informative, than case reports, and have a higher degree of accuracy. Case-control studies examine the frequencies of exposure to the drug before the delivery between children having or lacking certain birth defect, whereas cohort studies examine the frequencies of anomalies in the females’ youngsters who were exposed to a drug in comparison to youngsters of women who were not exposed to the drug of interest.

The discovery of the teratological effects of carbamazepine, the anti-epileptic drug, gave a hint about the significance of the epidemiological studies in discovering the toxic effects of drugs given during pregnancy. For years, carbamazepine was considered safer than phenytoin in the treatment of epilepsy during pregnancy. However, in 1989 Jones [9] published a retrospective case-control study that linked the use of carbamazepine during pregnancy with increased frequency of birth defects. This case-control study paved the way for conducting further epidemiological studies ...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Contents
• About the Author
• Abbreviations
• Disclaimer
• Acknowledgments
• Preface
• 1. Introduction
• 2. Anti-Infective Agents
• 3. Cardiovascular Drugs
• 4. Hematologic Drugs
• 5. Drugs Affecting the Endocrine System
• 6. Drugs Affecting the Respiratory System
• 7. Drugs Affecting the Central Nervous System
• 8. Drugs Affecting the Autonomic Nervous System
• 9. Drugs Affecting the Gastrointestinal System
• 10. Drugs Affecting the Musculoskeletal System
• 11. Drugs Affecting the Urinary Tract
• 12. Dermatologic Drugs
• 13. Diagnostic Agents
• 14. Vitamins and Dietary Supplements
• 15. Medicinal Herbs
• Index>