Therapeutics in Pregnancy and Lactation

Anne Lee, Sally Inch, David Finegan

• Publisher: Routledge
• Year: 2019
• Print ISBN: 9781857752694
• eBook ISBN: 9781315348636
• Topic: Medicine
• Subtopic: Gynecology, Obstetrics & Midwifery

This book will assist doctors, pharmacists, midwives and other health professionals in dealing with the issue of medicine use in pregnant and breastfeeding women. It gives practical guidance on the principles of safe and effective prescribing, summarises the known effects of widely used drugs, and provides up-to-date information in one accessible source. With an impressive list of contributors, Therapeutics in Pregnancy and Lactation offers clear guidelines and comprehensive advice on a diverse range of topics from drug abuse to hypertension and epilepsy.

CHAPTER ONE

Principles of drug use in pregnancy

Anne Lee

Introduction

Drug use in pregnancy is an extremely difficult issue for health professionals. Since the thalidomide tragedy in the 1960s there has been increased public awareness of the risks that drug treatment can present to the developing fetus, yet most women still take medicines during pregnancy.^1,2 Many women take medicines before they know they are pregnant, and then ask whether the drug could have harmed the developing fetus. Doctors need to make decisions about which drugs to prescribe for pregnant women and which to avoid. Other health professionals, including midwives, pharmacists and health visitors, also have an important role in advising women about the potential risks of drug treatment in pregnancy.

All drugs should be avoided in pregnancy unless they are essential. In practice it may not be easy to know when drug treatment really is necessary or whether a particular medicine is an appropriate choice for a pregnant woman. This area of therapeutics, perhaps more than any other, requires a balanced approach. Being over-cautious could lead to women being denied medication of benefit or to unwarranted pregnancy termination when an exposure has already occurred. On the other hand, lack of due caution might lead to babies born harmed as a consequence of drug exposure.

The benefits of treating a pregnant woman should always be weighed against the risks of giving no medication. For example, in a woman with epilepsy it could be more hazardous not to give drug treatment, because of the risks to mother and fetus of uncontrolled seizures, than to give a drug which has the potential to cause fetal abnormality. Conversely, in a woman with acne taking long-term antibiotics, the risks associated with stopping drug treatment are minimal.

Before becoming pregnant, women may need information and advice, for example about the need to take a folic acid supplement in early pregnancy and about the possible fetal risks associated with smoking, alcohol and drugs of abuse. Health professionals need access to reliable and up-to-date information about therapeutics in pregnancy so they can give these women good advice.

Teratogenicity and drugs

The strict definition of a teratogen is an agent or factor which can cause congenital malformations. The term is now used for any agent which, given to the pregnant mother, causes or contributes to malformation or abnormal physiological function or mental development of the fetus or in the child after birth. For example, a teratogen can prevent implantation of the conceptus, cause abortion, produce intrauterine growth retardation or cause fetal death. Exposure may also have adverse effects on the neonate, or lead to functional impairment such as behavioural abnormalities or mental retardation which may not be apparent until later life.

The incidence of major malformations in the general population is estimated at between 2 and 5%, and drugs are thought to cause less than 1% of these.³ Thus, in quantitative terms, therapeutic drugs appear not to be a significant cause of birth defects. However, most birth defects have no known cause and exposure to drugs or other teratogens may play a part in some of these. Specific birth defects are not the only consequence of exposure to a teratogen and it is possible that drugs are a factor in problems such as spontaneous miscarriage, which occurs in up to 20% of pregnancies.

Evaluation of drug safety in pregnancy

For many reasons it is extremely difficult to determine whether or not a particular agent is a teratogen.³ Because most birth defects are rare, an increased risk posed by a teratogen may not be easily identified. Thalidomide is a potent teratogen, first-trimester exposure causing an up to 50% incidence of major malformations.⁴ Most suspected teratogens, however, cause a relatively small increase in the baseline risk of malformations. For example, sodium valproate exposure increases the risk of neural tube defects by a factor of about 200, yet the overall risk of an exposed mother having a baby with spina bifida is about 1–2%.⁵

Women are generally advised to avoid medicines during pregnancy because their safety is uncertain and the study of drugs in pregnant women is usually unethical. As a result, the available data on specific drugs are often sparse and incomplete.

Epidemiological studies of drug exposure in pregnancy require large numbers of exposed infants to prove or disprove the teratogenic potential of a given drug. Most studies have inadequate statistical power because they do not include sufficient patient numbers. For example, to establish with a 95% confidence level that a drug changes the naturally occurring frequency of a congenital malformation by 1% would require a study involving about 35 000 women.⁶ For this reason, no drug is safe beyond all doubt in early pregnancy.

Animal studies of reproductive toxicity are required before new drugs are licensed, but it is difficult to extrapolate the findings to human pregnancy. Drugs which produce defects in animals can be relatively safe in humans; for example, corticosteroids.⁷ Of over 2000 drugs, chemicals and environmental agents shown to be teratogenic in animals, only a small number has been proven to damage the human fetus.⁴

There may be problems in distinguishing between the effect of a drug on the fetus and that of the condition for which the drug is administered. For example, debate continues about whether defects attributed to anti-epileptic drugs might be due to epilepsy itself.⁸ Alternatively, a fetal disorder might produce symptoms in the mother which are treated with a drug and subsequently the drug is wrongly implicated as the cause of the disorder.

Only a few drugs (less than 50) are proven human teratogens (Table 1.1). However, no drug has proven safety based on reliable epidemiological data involving sufficient numbers of women.

Table 1.1: Some teratogenic drugs

ACE inhibitors	Renal dysfunction and hypotension in the newborn, decreased skull ossification, hypocalvaria and renal tubular dysgenesis^9
Alcohol	Fetal alcohol syndrome^10
Aminoglycosides	Deafness, vestibular damage^11
Androgens (e.g. danazol)	Masculinisation of female fetus^12
Anti-cancer drugs	Multiple defects, abortion^13
Anti-thyroid drugs	Fetal goitre^15
Carbamazepine	Neural tube defects^14
Cocaine	Cardiovascular, central nervous system defects^16
Diethylstilboestrol	Vaginal carcinoma after in utero exposure^17
Lithium	Cardiovascular defects (Ebstein’s anomaly)^18
Phenytoin	Fetal hydantoin syndrome^19
Retinoids	Craniofacial, cardiac, central nervous system defects^20
Sodium valproate	Neural tube defects^5
Thalidomide	Limb-shortening defects, renal malformations, congenital heart disease^21
Warfarin	Fetal warfarin syndrome^22

Drugs and the fetus

The placenta is not a barrier to drugs. Nearly all drugs, except those with a very high molecular weight, such as insulin and heparin, cross the placenta to the fetus.⁵ Lipid-soluble, un-ionised drugs cross more rapidly than polar drugs. In practice, virtually all drugs have the potential to affect the unborn child.

Timing of drug exposure

The effect of a drug on the developing fetus depends on several factors, including the timing of exposure, dosage, concomitant maternal disease and, in some cases, genetic susceptibility. In general, teratogens do not cause defects in all fetuses exposed at the critical period of gestation. A drug that harms a baby in one pregnancy may have no effect in a subsequent pregnancy in the same woman.

The timing of drug exposure is important in determining whether it is likely to harm the fetus. During the pre-embryonic period, which lasts until 14 days post-conception, exposure to a teratogen is believed to have an ‘all or nothing’ effect. Damage to all or most cells results in death of the conceptus. If only a few cells are injured, normal develop...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Preface
• List of contributors
• 1 Principles of drug use in pregnancy
• 2 Principles of prescribing in lactation
• 3 Common problems in pregnancy
• 4 Common problems in the lactating woman
• 5 Gastrointestinal disorders
• 6 Hypertension
• 7 Other cardiovascular disorders
• 8 Respiratory disorders
• 9 Epilepsy
• 10 Psychiatric disorders
• 11 Infections
• 12 Endocrine disorders
• 13 Nutrition in pregnancy
• 14 Rheumatic disorders
• 15 Skin disorders
• 16 Complementary/alternative medicine during pregnancy
• 17 Social drugs
• 18 Street drugs
• Index