Dermatology

 

 

The General Use of Medications
in Pregnancy

Volume II, Number 8 | November/December 1999
Christina H. Stack R.Ph., Pharm.D. Candidate

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Introduction

The decision to place patients with pre-existing conditions on medications can be difficult and pregnant women are no exception. There are few studies regarding the safety of drugs in pregnancy. When medications are used in pregnancy, there is the potential for major (i.e., those not compatible with life) and minor (e.g., extra digits, ear tags) malformations. Therefore, there is much to debate before placing pregnant patients on medications. Drug treatment in pregnant women is aimed at decreasing risks and providing benefits to the mother without causing harm to the fetus. The safest choice is to avoid placing a pregnant woman on medication; however, if it is necessary, the benefits and risks must be considered.

Classification of Drugs

The Food and Drug Administration (FDA) currently divides medications into five different pregnancy-risk categories. Drugs are placed in different risk categories based on available studies in humans and animals (See Table 1). Locating a pregnancy-risk category is the first step in evaluating the safety of drugs in pregnancy. There are resources that assist health care professionals by listing drugs in their prospective risk categories (See Table 2). However, there are limitations to using pregnancy-risk categories. First, drugs on the market were not required to have an assigned risk category until after December 1983; therefore, many drugs are not rated by the manufacturer. Second, it cannot be assumed that outcomes from animal studies are similar to outcomes found in humans. Caution should be advised in the use of drugs that fall under those categories for which only animal data is available (Categories B and C).  If a drug does not have a pregnancy-risk classification, primary literature should be retrieved and assessed for safety in pregnancy information.

Table 1: Pregnancy-Risk Categories
Category Definition
A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester, and the possibility of fetal harm appears remote.
B Either animal studies do not indicate a risk to the fetus and there are no controlled studies in pregnant women, or animal studies have indicated fetal risk, but controlled studies in pregnant women failed to demonstrate a risk.
C Either animal studies indicate a fetal risk and there are no controlled studies in women, or there are no available studies in women or animals.
D There is positive evidence of fetal risk, but there may be certain situations where the benefit might outweigh the risk (life-threatening or serious diseases where other drugs are ineffective or carry a greater risk).
X There is definite fetal risk based on studies in animals or humans or based on human experience, and the risk clearly outweighs any benefit in pregnant women.

The Cleveland Clinic Foundation; Adapted from: Briggs GG, Freeman RK, Yaffe SJ.
Drugs in pregnancy and lactation. 5th ed. Baltimore: Williams & Wilkins;1998.

Table 2: General References for Pregnancy Information
Source Comment
Drugs in Pregnancy and Lactation Pregnancy-risk categories; Case reports; Trials; Breastfeeding information
MICROMEDEX®(ReproRisk®) Chemicals and drugs; Case reports and series
Package Insert Manufacturer’s Rating; Limited information
Drug Topics® Red Book Table of pregnancy-risk categories
CCF Drug Information Center All references listed above plus access to Medline and Iowa Drug Information Service (IDIS)

 

General Considerations

The pregnancy risk to benefit ratio is defined as the risk to the fetus compared to the benefits to the mother. Components of this ratio are the 1) genotype of mother and fetus, 2) embryonic stage at exposure, 3) dose, and 4) exposure to other drugs or environmental agents that may increase or decrease potential abnormalities. The timing of exposure is associated with the most potential for teratogenic effect(s).Timing of exposure is defined as the stage of fetal development when the drug is consumed. In general the risk of teratogenicity of the drug decreases as growth of the fetus progresses. If the fetus is exposed at the time of conception and implantation, the embryo may be aborted.  As the fetus progresses through the first 12 to 15 days, the cells are still totipotential (i.e., if one cell is  damaged another cell can assume its function) and the embryo may be capable of survival. During the first 3 months of growth, the chance of physical malformations is increased because this is the critical stage of physical development. Later in gestation, risk of functional and behavioral abnormalities increases because of the continuous growth and development of the central nervous system.

Product Selection

Drug selection is easier when drugs fall under the categories A, D, or X.  The dilemma is with medications that fall under the categories B and C where adequate studies are not available to make a definitive judgement. Risk versus benefit, as well as some of the drug characteristics, are the next best steps to take in selecting an appropriate drug. There are four characteristics to evaluate in drug selection. These characteristics are molecular weight, ionization, lipophilicity, and degree of protein binding. The less the molecule weighs, the more likely it will be able to pass through the placenta. Most of the medications on the market fall between 250 and 400 daltons and, therefore, the likelihood for crossing into the fetal circulation is high. Ionization and lipophilicity are also important determinants in drugs crossing the placenta. More ionized and less lipophilic drugs tend to cross the placenta more readily than unionized and highly lipophilic drugs. Finally, the amount of protein binding plays a role. The more protein bound a drug, the less likely it is to cross the placenta.

Drug Selection in Selected Disease States

Nausea and Vomiting

Nausea and vomiting affect between 60 and 70% of women who become pregnant. Most women do not require treatment, though there are women (0.5-10 in a thousand) who require treatment to avoid adverse consequences (e.g., malnutrition, weight loss, dehydration) during pregnancy. First, nonpharmacologic options should be attempted. Some of these include avoiding foods that may trigger episodes of nausea and vomiting (e.g., spicy , fatty, or fried foods), eating when nausea is less severe, and avoiding of the smell of food. Additionally, supplements containing iron can be a source of nausea and vomiting in certain women. Women who are unable to maintain adequate hydration should be admitted to the hospital for intravenous (IV) fluid and electrolyte replacement. Antiemetics, which are generally third-line therapy, are given to women who do not respond to IV replacement. Clinical data to support the safety and efficacy of these drugs are minimal and use of the following medications should still be exercised with caution (See Table 3). Currently, no medications are approved for the treatment of nausea and vomiting in pregnant women. One other suggested therapy involves giving antihistamines in the morning to prevent nausea and vomiting. If hyperemesis is resistant to conventional treatment, then the use of ondansetron or corticosteroids may be considered.

Table 3: Drugs Used in the Management of Nausea and Vomiting During Pregnancy
Drug Pregnancy Risk Category
Metoclopramide (Reglan®) B
Cyclizine (Marezine®) B
Ondansetron (Zofran®) B
Promethazine (Phenergan®) C
Prochlorperazine (Compazine®) C
Chlorpromazine (Thorazine®) C

Adapted from: Nelson-Piercy C. Treatment if Nausea and Vomiting in Pregnancy: When Should It Be Treated and What Can Be Safely Taken? Drug Saf 1998; 19(2): 155-64

Hypertension

Chronic hypertension in pregnancy is defined as high blood pressure that is present before pregnancy or diagnosed before the 20th week of gestation. Antihypertensive agents are used in women with a diastolic pressure of 100 mm Hg or higher (lower if end organ damage or renal disease is present) and in women with acute hypertension when pressures are greater than 105 mm Hg. According to the JNC VI guidelines, pregnant women can be continued on most antihypertensive medications with the exception of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (Category X). ACE inhibitors are associated with chronic abnormalities (e.g., renal insufficiency requiring dialysis, growth retardation, and cranial malformations) and even death of the fetus. The drug of choice for high blood pressure diagnosed during pregnancy is methyldopa. Methyldopa has been studied extensively and is well tolerated in this population. When parenteral therapy is required, hydralazine is an effective alternative. (See Table 4).

Table 4: Drugs Used for the Management of Hypertension During Pregnancy
Drug Class Example Pregnancy Risk Category Comment
Central ΰ-agonist (Aldomet®) C Drug of choice by the NHBPEP* Working Group
α-Blockers Atenolol (Tenormin®)

Metoprolol (Lopressor®)

Labetolol(ΰ)®)

C

C

C

 

Calcium antagonists

Diltiazem (Cardizem® CD, Dilacor® XR, Trizac®

Verapamil (Calan®, Covera-HS®, Verelan®)

C

 

C

Potential synergism with magnesium sulfate may lead to precipitous hypotension

ACE inhibitors

Captopril (Capoten®)

D

Fetal abnormalities including death, can be caused, and should not be used in pregnancy

Angiotensin IIReceptor blockers

Enalapril (Vasotec®)

Lisinopril (Prinivil, Zestril®)

Losarten (Cozaar®)

Valsarten (Diovan®)

D

D

D

D

 

Diuretics

Bumetanide (Bumex®)

Frosemide (Lasix®)

Hydrochlorothiazide (HydroDIURIL®)

Indapamide (Lozol®)

Spironolactone (Aldactone®)

Triamterine (Dyrenium®)

DCCBBDB

Recommended for chronic hypertension if prescribed before gestation or if patients are salt-sensitive. Not recommended in preclampsia

Directvasodilators

Hydralazine (Apresoline®)

Minoxidil (Loniten®)

C

C

Hydralazine is parenteral drug of choice vased on its long history of safety and efficacy

* NHBPEP: National High Blood Pressure Education Program

Adapted from: The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The sixth report of the joint national committee on prevention, detection, evaluation, and treatmenrt of high blood pressure. Arch Intern Med 1997; 157: 2413-46.

 

Migraine

The drug of choice for migraine headaches during pregnancy is acetaminophen. There appears to be no effect on the fetus as well as minimal effects on platelet function. It can be given in doses up to 1000 mg per dose. Other typical medications used in migraine treatment are not recommended during pregnancy (See Table 5), which include the selective serotonin agonists (e.g., sumatriptan, naratriptan, zolmitriptan, and rizatriptan). Although they have not been proven to be harmful to humans, there have been no well-controlled studies to validate their use. Nonsteroidal anti-inflammatory drugs (NSAIDs) should also be avoided in pregnancy because of their ability to prolong pregnancy and labour. Ergotamine and dihydroergotamine are contraindicated in pregnancy because of their uterotonic effects.

Table 5: Drugs Used in the Treatment of Migraines during Pregnancy
Drug Pregnancy Risk Category
Acetominophen (Tylenol®) B
Ibuprofen (Motrin®) B
Ergotamine tartrate (Ergotrate®) D
Dihydroergotamine (Migranal®) X
Prochlorperazine (Compazine®) C
Sumatriptan (Imitrex®) C
Naratriptan (Amerge®) C
Zolmitriptan (Zomig®) C

Adapted from: Pfaffenrath V, Rehm M. Migraine in Pregnancy: What are the Safest Treatment Options? Drug Saf 1998; 19 (5): 383-8.

Conclusion

Pregnancy is full of difficult decisions. Drug selection in pregnant women is no exception. Drugs are placed in pregnancy-risk categories to aid in making these decisions. It is when these categories offer no definitive choice that health care professionals must investigate the specific properties of the drug to help guide the decision(s).

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Copyright © 2000-2017 The Cleveland Clinic Foundation. All Rights Reserved.
Center for Continuing Education | 1950 Richmond Road, TR204, Lyndhurst, OH 44124