DRUG UTILIZATION PATTERN DURING PREGNANCY-A REVIEW

413 | P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 2(6): November-December 2013

INTERNATIONAL JOURNAL OF UNIVERSAL

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Pharmaceutical Sciences REVIEW ARTICLE……!!!

DRUG UTILIZATION PATTERN DURING PREGNANCY-A REVIEW

Aparna Sharma*1, Prashant Mathur

1, Preeti Kothiyal

2

Department of 1Clinical Pharmacy &

2Pharmacology, Division of Pharmaceutical Sciences, Sri

Guru Ram Rai Institute of Technology & Science, Patel Nagar, Dehradun-248001.

KEYWORDS:

Pregnancy, Drug

Utilization Review, Over-

the-counter drugs, Herbal

Drugs, Prescription

Drugs.

For Correspondence:

Aparna Sharma*

Address:

590/14, Chauhan House,

Sector 14, Gurgaon,

Haryana-122018

(INDIA).

ABSTRACT

Pregnancy is a special physiological condition where drug treatment

presents a special concern. Careful consideration of the benefit to the

mother and the risk to the foetus is required while prescribing drugs

during pregnancy. The drugs given to pregnant mothers for therapeutic

purposes may cause serious structural and functional adverse effects in

the developing child. Since it is very difficult to determine the effects

on the foetus before marketing new drugs due to obvious ethical

reasons, most drugs are not recommended to be used during pregnancy.

Drugs play an important role in improving human health and promoting

well-being. However, to produce the desired effect, they have to be

safe, efficacious and have to be used rationally. The safety of herbal

drugs becomes particularly important in some subpopulations of

patients such as pregnant women and children, who are more vulnerable

to the effects of drugs as well as of natural products for their

physiological characteristics. Pharmaco-epidemiological studies can

help in minimizing the inherent risk of drug use in pregnancy, by

establishing a profile of drug consumption, by evaluating the existing

health services and by investigating the interventional measures. It

therefore becomes important to examine the pattern of drug use in

pregnancy to see to what extent there may be room for improvement in

the light of current knowledge.

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INTRODUCTION:

Drug Utilization Review (DUR) is an ongoing, systematic process designed to maintain the

appropriate and effective use of medications (Navarro, 2008). DUR is an authorized and structured

ongoing review of practitioner prescribing, pharmacist dispensing and patient use of medications.

The purpose of DUR is to ensure drugs are used appropriately, safely and effectively to improve

patient health status. Predetermined criteria for appropriate drug therapy are compared against a

patient’s or a population’s records. Non-adherence to criteria results in drug therapy changes. In

addition, continual improvement in the appropriate, safe and effective use of drugs has the potential

to lower the overall cost of care (World Health Organization, 2009; Academy of Managed Care

Pharmacy, 2009). DUR allows the pharmacist to document and evaluate the benefit of pharmacy

intervention in improving therapeutic and economic outcomes while demonstrating the overall value

of the pharmacist. DUR is typically classified in three different categories: prospective, concurrent

and retrospective.

DUR is classified in three categories:

• Prospective - evaluation of a patient's drug therapy before medication is dispensed

• Concurrent - ongoing monitoring of drug therapy during the course of treatment

• Retrospective - review of drug therapy after the patient has received the medication.

How Drugs affect the Fetus

During the first 2 to 8 weeks of pregnancy, the developing human is referred to as an embryo, after

which it is called a fetus. The placenta begins to form at approximately 4 weeks, and the heartbeat

appears at approximately 5 weeks. Because major organs begin to develop in the embryonic stage,

the use of certain drugs from the first weeks and months of pregnancy may result in fetal defects.

Pharmacologic agents can be transferred to the developing fetus in much the same way as the

nutrients necessary for its development. Drugs can exert their effect on a fetus by:

Acting directly on the fetus and causing birth defects.

Altering the placenta by narrowing blood vessels, thereby limiting the supply of nutrients

and oxygen to the fetus, often resulting in an underdeveloped baby.

Causing contraction of the uterine muscles so that the blood supply to the fetus is

compromised, resulting in premature labor.

The effect of a drug on the fetus can also be influenced by the stage of the pregnancy. In other

words, in the early stages, a drug may or may not have an adverse effect on the fetus, yet between

weeks 3 and 8 of the pregnancy, some drugs may put the fetus at risk due to the fact that organs are

gradually developing.



The potential harm that can come to a fetus from exposure to pharmacologic drugs validates the

need for an effective study that will provide indispensable information to health care professionals

on the effects of specific drug therapies on the developing fetus.

One large US study estimated that 64% of women are being prescribed one or more drugs, not

including vitamins and minerals, during pregnancy (Andrade et al, 2004). In part, this is due to

inadvertent exposures to medications that occur before a woman knows that she is pregnant, as

approximately half of all pregnancies are unplanned (Henshaw, 1998) and <50% of pregnancies are

recognized before the 4th week after conception (Floyd, 1999). Intentional exposures throughout

gestation are also common, and treatment of acute or chronic conditions such as hypertension,

depression, or asthma may be necessary to protect the health of both the woman and her fetus or

infant. Thus, the clinician and the pregnant patient are frequently faced with the dilemma of

assessing the potential risk of exposure to a medication that occurred early in a pregnancy or of

making the decision to initiate, continue, or modify a medication regimen during pregnancy or

breastfeeding. The preclinical reproductive toxicity studies in animal models that are required for

regulatory approval of most drugs are not completely predictive of human risk, and randomized

clinical trials of medications usually cannot be ethically justified. Formal controlled observational

studies of outcomes of exposed pregnancies are conducted in a piecemeal fashion for only a small

fraction of available medications through the uncoordinated efforts of various individual

investigators or state or federal agencies. As a result, there are insufficient human pregnancy safety

data available for >80% of 468 new drugs marketed over a recent 20-year period in the United States

(Lo et al, 2002). In the last few years, these issues have played out in a particularly high profile

manner, with a number of studies addressing the risks of selective serotonin reuptake inhibitors

during pregnancy.

Although several small human studies published in the 1990s suggested that first-trimester exposure

to medications of this type does not greatly increase the risk for birth defects overall (Chambers et

al, 1996; Kulin et al, 1998). More recently, some studies with larger sample sizes and more efficient

study designs have suggested small but significantly increased risks for a few major structural

defects and other rare outcomes (Kallen et al, 2007; Chambers et al, 2006; Louik et al, 2007; Alwan

et al, 2007).

It is estimated that up to 60 percent of patients consult a health care professional when selecting an

OTC product (Jacobs , 1998). At least 10 percent of birth defects are thought to result from maternal

drug exposures (Wilson, 1977). The issue is complicated by the fact that the safety and efficacy

profile of a given medicine often changes during the course of a normal pregnancy (Wilson et al,

1995). Since 1975, the U.S. Food and Drug Administration (FDA) has assigned pregnancy risk



factors to all drugs used in the United States (Briggs et al, 1998) [see table]. Unfortunately, many

drugs have not been adequately researched during pregnancy and, because of ethical considerations,

probably will not be in the future.

Although appealing in their simplicity, these pregnancy categories are almost exclusively derived

from animal data and have been sharply criticized for failure to differentiate between severity of

adverse outcomes, the range of adverse pregnancy outcomes, or the importance of dose, route,

gestational timing, or indication (FDA classification of drugs for teratogenic risk, 1994). For

example, both doxycycline and valproic acid are classified as pregnancy category D (indicating that

―there is positive evidence of human fetal risk based on adverse reaction data from investigational or

marketing experience or studies in humans, but potential benefits may warrant use of the drug in

pregnant women despite potential risks‖). However, doxycycline treatment is associated with a risk

of staining the baby’s teeth, and valproic acid treatment is associated with a high incidence of

several specific major birth defects such as spina bifida.

In the last decade, the Food and Drug Administration has developed and proposed rules for

restructuring the ―pregnancy label‖ (Public Affairs Committee of the Teratology Society, 2007). No

less challenging for the clinician is communication of a risk assessment to a woman who is or who

may become pregnant in a comprehensible manner that allows her to consider the issues

appropriately (Bonari et al, 2005). Although perceived small risks for uncertain outcomes may not

alter behavior under usual circumstances, any perceived risk to the baby, no matter how small, may

be unacceptable to women and their partners or physicians (Lyerly, 2007). A woman may view the

benefit for herself as insufficient relative to the perceived risk or even the undefined possibility of

risk to her infant. In some cases, wanted pregnancies may be terminated because of misperceptions

regarding the presence or magnitude of risk to the developing baby (Koren, 1990). However, by far,

the overriding challenge in this area of women’s health is obtaining adequate information on drug

safety during pregnancy as quickly as possible after a new drug is marketed.

Pregnancy registries are one method of collecting information on newly marketed medications.

These registries are increasing in number, and more rigorous standards are being employed for their

design (US Department of Health and Human Services, 2002; Chambers et al, 2006). However,

registries are not required for all new drugs. Furthermore, this approach alone cannot provide

sufficient information to assess the risks for all major adverse pregnancy outcomes with an

appropriate level of confidence. A national mandatory and systematic surveillance system for all

newly marketed drugs used by women of childbearing age is imperative to deal with this issue.

People of all ages are entitled to drug safety information for products marketed for their use. Women

of childbearing age and their babies are no exception.



Rules for restructuring the pregnancy label

Proposed rule changes to the pregnancy and lactation portions of the product label

1. Information on pregnancy registries, if any, for the product and how the registries can be

contacted.

2. A general statement about background risk of adverse pregnancy outcome.

3. A ―Fetal Risk Summary‖ containing a narrative description of the risks of use of the

medication, including a characterization of the likelihood that the drug increases the risk of

abnormal development including structural malformations, miscarriage, stillbirth, neonatal

death, functional abnormalities, and alterations in growth. Conclusions about risk will use

standardized statements and will differentiate between animal and human data. If a drug is

contraindicated, the specific circumstances, such as timing, under which its use is

contraindicated will be described.

4. A section on clinical considerations to address inadvertent vs. intentional exposures, risks of

untreated disease, gestational timing, and dose considerations in pregnancy.

5. A summary of the data underlying the fetal risk and clinical consideration statements.

Pain Medications

The most commonly used OTC pain medications are aspirin, acetaminophen (Tylenol), and

nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen (Advil, Motrin), ketoprofen

(Orudis), and naproxen (Aleve). The safety of these medications during pregnancy is outlined in

Table (Macones et al, 2001). Acetaminophen is widely used during pregnancy. Although there is

no known association with teratogenicity, few clinical data are available to support the lack of

association (Collins, 1981). The extensive use of acetaminophen in pregnancy combined with the

paucity of documented adverse effects have served to validate the selection of this medication as the

pain reliever of choice during pregnancy. Salicylates have been associated with increased perinatal

mortality, neonatal hemorrhage, decreased birth weight, prolonged gestation and labor, and possible

birth defects (Collins, 1981). However, one study (Hauth et al, 1995) found that low-dose aspirin is

not associated with an increased risk of abruptio placentae or increased rates of perinatal mortality.

Pregnant women should use salicylates only under the guidance of a medical professional.

Indomethacin (Indocin) is the most studied NSAID that is commonly used during pregnancy.

Physicians may employ indomethacin during pregnancy to treat pain Unfortunately, indomethacin

use during pregnancy may result in oligohydramnios, premature closure of the fetal ductus arteriosus

with subsequent persistent pulmonary hypertension of the newborn, fetal nephrotoxicity, and

periventricular hemorrhage (Macones et al, 2001). Other NSAIDs, such as ibuprofen, have been



studied less often during pregnancy. However, an analysis (Barry et al, 1984) of 50 pregnant patients

who overdosed on ibuprofen revealed no evidence of fetal abnormalities. Because of the possibility

of adverse effects of NSAIDs on the fetus, it is our opinion that these medications should be used

sparingly during pregnancy.

Decongestants, Expectorants, and Antihistamines

Women commonly use cold medications during pregnancy. These medications, like most of the

other OTC drugs, have not been studied well in pregnancy (Werler et al, 1992; ACOG and ACAAI,

2000). The most commonly used cold medications include decongestants and expectorants such as

pseudoephedrine (Novafed), guaifenesin (Humibid L.A.), and dextromethorphan (Benylin DM), and

the antihistamines diphenhydramine (Benadryl), chlorpheniramine (Chlor-Trimeton), and clemastine

fumarate (Tavist). Diphenhydramine is widely used in pregnancy as a sedative, an antihistamine,

and an anti-nausea drug, although few data confirm its safety during pregnancy. The drug has been

shown to have oxytocin-like effects, especially in high dosages (Brost et al, 1996). In addition,

adverse drug interactions that do not occur in nonpregnant patients may occur in pregnant patients.

For example, one study (Kargas et al, 1985) showed a significant increase in fetal morbidity when

diphenhydramine was taken in combination with temazepam (Restoril). Another study (Aselton et

al, 1985) of 59 women who had used dextromethorphan in the first trimester documented one

malformation.

Thus, sufficient evidence indicates a lack of adverse effects of dextromethorphan use during

pregnancy. When used during the first trimester in the presence of a febrile illness, guaifenesin has

been associated with an increased risk of neural tube defects (Shaw et al, 1998).

Antidiarrheal Agents

The most commonly used antidiarrheal medications include kaolin and pectin preparations (such as

Kaopectate), bismuth subsalicylate (Pepto Bismol), loperamide (Imodium), and

atropine/diphenoxylate (Lomotil A possible association has been identified between the ingestion of

clays containing kaolin and the development of iron deficiency anemia (Patterson et al, 1977). Use

of bismuth subsalicylate can result in absorption of salicylate and should be avoided in pregnancy.

Loperamide has not been found to be teratogenic in animals. However, at least one study (Briggs et

al, 1998) involving first-trimester exposure in humans showed a possible increase in fetal cardiac

malformation. Atropine/diphenoxylate has been found to be teratogenic in animals; however, there

is insufficient evidence of teratogenicity in human pregnancy (Bonapace, 1998).

Antacid Preparations

Several antacids are available in OTC forms, including preparations that contain alginic acid,

aluminum, magnesium, and calcium. All of these preparations generally are regarded as safe in



pregnancy . There have been sporadic reports of fetal maldevelopment and injury associated with

prolonged use of high dosages of aluminum-containing antacids during pregnancy (Gilbert-Barness

et al, 1998). The histamine H2-receptor blockers are effective in treating symptoms of heartburn

and gastroesophageal reflux disease in pregnancy, (Larson et al, 1997) but these drugs readily cross

the placenta (Dicke et al, 1988). Their use is recommended in pregnant women whose symptoms

cannot be adequately controlled with lifestyle modification and antacids (Katz et al, 1998).

The most studied H2 blockers are cimetidine (Tagamet) and ranitidine (Zantac). Studies of these

agents generally have shown significant improvement of symptoms with no significant adverse

effects. Animal studies also fail to show an increased fetal risk with the use of these medications in

pregnancy, the notable exception being nizatidine (Axid) (Katz et al, 1998). Nizatidine has been

associated with an increased risk of fetal death, spontaneous abortion, and decreased fetal weight in

rabbits (Katz et al, 1998). These studies used the common prescription- strength doses. The OTC

doses are one half of the prescription strength. Although studies have indicated that there is probably

no increased risk of fetal morbidity or mortality, few studies have evaluated first trimester use of H2

blockers. Therefore, most investigators recommend avoiding these drugs in the first trimester

(Lagace, 1996).

Antifungals

The most common antifungal medications available as OTC drugs include the imidazole agents

clotrimazole (Mycelex), butoconazole (Femstat), miconazole (Monistat), and tioconazole (Vagistat-

1) One of the largest studies (Czeizel et al, 1999) to date investigated the teratogenicity of

clotrimazole. The population-based, case-control study of 18,515 case pregnancies and 32,804

control pregnancies did not show an association between fetal malformations and the use of

clotrimazole.

Several small trials have indicated that butoconazole and miconazole are likely to be safe during the

second and third trimesters. Insufficient data are available regarding the safety of tioconazole in

pregnancy (Mastroiacovo et al, 1996). Many clinicians use oral fluconazole (Diflucan) to treat

vulvovaginal candidiasis. A study (King et al, 1998) of 226 women exposed to fluconazole during

the first trimester of pregnancy revealed that patients taking fluconazole were no more likely than

unexposed control patients to experience miscarriage, stillbirth, or congenital anomalies.

Ketoconazole (Nizoral), flucytosine (Ancobon), and griseofulvin (Grisactin) may be teratogenic or

embryotoxic in animals (Mastroiacovo et al, 1996). The Centers for Disease Control and Prevention

recommends using only topical vaginal antifungal agents (including butoconazole, clotrimazole,

miconazole, and the prescription medications terconazole [Terazol] and nystatin [Mycostatin]) in

pregnancy (Centers for Disease Control and Prevention, 1998) Because imidazole agents are likely



to be safe when used during pregnancy and may be more effective than nystatin, (Young et al, 2001)

they should be considered as firstline therapy in pregnant patients.

Smoking Deterrents

Researchers believe that nicotine and its metabolic byproduct, cotinine, are harmful to the

developing fetus because smoking is known to cause harmful fetal effects, including intrauterine

growth retardation, premature birth, hyperviscosity

in the newborn, spontaneous abortion, fetal neurotoxicity, and pulmonary defects, and an increased

risk of sudden infant death syndrome (DiFranza et al, 1995). For these reasons, the FDA classifies

nicotine as a Pregnancy Category D drug.

Physicians should educate pregnant patients about the harmful effects of smoking to themselves and

the developing fetus, and help these patients develop a plan for smoking cessation. The safety of

nicotine replacement products in pregnancy has not been adequately studied. However, smoking is

likely to be more harmful than nicotine replacement therapy, Until further research is available,

physicians should consider recommending the intermediate-release nicotine preparations (nicotine

gum, nicotine spray, and nicotine inhaler) rather than the continuous-release method (nicotine

patches) (Dempsey et al, 2001).

Role of DUR in safe drug use

Using DUR information, managed care pharmacists can identify prescribing trends in patient

populations and initiate corrective action to improve drug therapy for groups of patients as well as

individuals. As the variety of health care professionals

(e.g., pharmacists, prescribers, nurses, optometrists, naturopaths, chiropractors) involved in the

medication use process expands, DUR will require a more multidisciplinary approach to improving

patient care. In addition, rapidly improving data systems will soon provide the methodology for

marrying medical and pharmacy data with patient outcome data. This will lead to the next logical

step, the evolution of DUR into a more comprehensive health care utilization evaluation.

The studies conducted in developed countries where drug-prescribing practices are considered to be

superior, have identified need for interventional measures aimed at rational prescription during the

prenatal period (Beyens et al, 2003; Collaborative Group on Drug Use in Pregnancy, 1992). It has

been reported that about 8% of pregnant women need drug treatment due to various chronic diseases

and pregnancy related complications (Sharma et al, 2006).

All drugs used during the first (first 12 weeks), second (13th to 24th week) and third (24th week

onwards) trimester of pregnancy are classified into category-A, category-B, category-C, category-D

and category-X, according to the classification for drug use during pregnancy, introduced by the US

Food and Drug Administration (FDA) in 1979 (Baltimore, 1998). Folic acid supplementation in



pregnancy is associated with the decreased incidence of habitual spontaneous abortion and

pregnancy complications (Malm et al, 2004).

In a prospective survey in Southwestern Finland (Heikkila et al, 1994), iron and vitamin

supplementation were the most frequently used drugs, followed by analgesics, tocolytic agents and

drugs for chronic conditions and common pregnancy symptoms. In another study from Australia

(Maats et al, 2002), folate (69%), iron (39%) and multivitamins (27%) were the most frequently

taken drugs by pregnant women; along with herbal drugs like, ginger (20%) and raspberry leaf (9%)

In a study from Bratislava and Nitra (Tisonova et al, 2006), it was reported that a vast majority of

prescribed drugs during pregnancy, belonged to category-C. In a study from USA, OTC

medications (e.g., ibuprofen) that are contraindicated in pregnancy, were used at unexpectedly high

rates during pregnancy (Glover et al, 2003). In a similar study on general public, according to 36, 19

and 5% of the respondents, the use of common OTC drugs during pregnancy represents a small risk,

a great risk and completely risk-less picture, respectively (Drhova, 2005).

A survey of women giving birth in Oklahoma (Splinter et al, 1997) reports that the average number

of medications taken during pregnancy ranged from 1.6-2.9 (excluding vitamin and mineral

supplements), depending on the trimester. The same survey reported that 54% of all products

consumed in pregnancy were over-the-counter (OTC) medications. Another source estimates that

more than 80% of pregnant women take OTC or prescription drugs during pregnancy (Matt et al,

1995). National surveys among women of reproductive age document that chronic conditions often

requiring the ongoing administration of medications for maintenance are not uncommon among

women of reproductive age (United States Department of Health and Human Services, 2004).

Presently, congenital anomalies are among the leading causes of infant mortality in the United States

(Kochanek, 2004).

It is estimated that approximately 10-15% of congenital anomalies are due to teratogenic maternal

exposures. Congenital anomalies caused by teratogenic exposures, such as certain medications, are

considered preventable, as they are linked with modifiable maternal exposures during the period of

organogenesis (Czeizel et al, 1996). It follows that maternal avoidance of teratogenic exposures

would minimize congenital anomalies.

However, as women of reproductive age and those who are pregnant experience acute and chronic

health conditions that must be medically managed. In many instances avoidance of medications is

neither possible nor advisable. The benefits of medication use during pregnancy are not restricted to

the recovery of maternal health, but extend to the protection of the fetus in many instances. Poorly

controlled diabetes mellitus is teratogenic, whereas the appropriate management of diabetic pregnant

women can prevent diabetic embryopathy (Nielsen et al, 2005) Uncontrolled asthma can decrease



oxygen in the fetal blood, possibly impairing fetal growth and survival (Alexander et al, 1998).

Uncontrolled high blood pressure increases the risks of placental problems and fetal growth

retardation (Sibai, 2002). The treatment of infectious diseases of the reproductive tract can

significantly reduce the prevalence of preterm birth and its effects (Centers for Disease Control and

Prevention, 2006). For all pregnant women infected with HIV, the Center for Disease Control

(CDC) recommends the drug zidovudine (AZT) to minimize perinatal transmission (Centers for

Disease Control and Prevention, 2002). The periconceptional use of folic acid can prevent most

neural tube defects (Czeizel et al, 1992) and a considerable number of congenital anomalies of the

cardiovascular system, urinary tract, and limb deficiencies (Czeizel,1996; Czeizel,1993).

Teratogenicity is a complex process and is dependent on the timing of the exposure in relation to the

gestational age, the dose, and route of administration. The period of greatest sensitivity to most

teratogenic exposures is the period of organogenesis, from 18-60 days postconception

(approximately 4.5-11 weeks after the last menstrual period) (Rutledge, 1997). Exposures after the

period of organogenesis usually do not result in structural anomalies, although there are exceptions.

Rather, teratogenic exposures during the fetal period (after 60 days postconception) typically result

in growth restriction or functional disorders of the central nervous system, kidneys, or other organs.

The dose and route of administration of the agent are other important features of potential

teratogenicity. Teratogenic effects occur only when the dose of an agent exceeds a threshold (Brent,

2004). In addition, physiologic changes that occur during pregnancy and affect the pharmacokinetics

and/or pharmacodynamics include: changes in body weight and body composition; delayed gastric

emptying and gastrointestinal transit time; expanded plasma volume; increased cardiac output and

blood flow to the uterus, kidneys, skin, and mammary glands; decreased plasma albumin; increased

glomerular filtration rate; and changes in the activity of hepatic enzymes (Uhl, 2004). It may be

necessary to adjust the dosage and/or frequency of medication used during pregnancy. For most

medications, little information about teratogenic risk or safety is available at the time of marketing,

as pregnant women are traditionally excluded from clinical trials. Premarketing animal studies do

not necessarily predict the effects of treatment in human pregnancy.

A review conducted in 2001 concluded that there was not enough information to assess the

teratogenic risk or safety during pregnancy of more than 90% of prescription medications approved

by the US Food and Drug Administration (FDA) in the previous 20 years (Lagoy et al, 2005). Gaps

in information are even more substantial for OTC and dietary supplements. The US FDA uses a risk

classification system for medications based on data from human and animal studies to help interpret

the risks associated with use of medications during pregnancy (FDA, 1994). The current FDA

classification system uses the letters A, B, C, D, and X for the 5 categories (see Table 1). Critics of



the FDA classification system argue that the risk categories are limited in that they do not indicate

the risk based on time during gestation in which the medication is used. In response to criticism of

the current system of classification, the FDA has proposed to amend its regulations concerning the

format and content of the ―Pregnancy,‖ ―Labor and delivery,‖ and ―Nursing mothers‖ subsections of

the ―Use in Specific Populations‖ section of the labeling for human prescription drug and biological

products.

Prescription medications

A table of medications generally accepted to be contraindicated in the preconception period and

pregnancy is found in Table 2. A more complete listing of potential teratogens (class D or X) is

found as an appendix in another article (Schwarz et al, 2005).

Several professional organizations have issued recommendations regarding the use of drugs related

to their specialty in pregnancy. Specifically, there are established practice guidelines for use of

medications to manage diabetes (American Diabetes Association, 2004), hypertension (Chobanian et

al, 2003), seizure disorders (American Academy of Neurology, 1998), thyroid disorders (American

Association of Clinical Endocrinologists, 2002), disorders requiring anticoagulation (Hirsh et al,

2003), asthma 9 National Asthma Education and Prevention Program, 2005), gastrointestinal

disorders (Mahadevan et al, 2006), tuberculosis (MMWR, 2003), sexually transmitted infections

including HIV (Centers for Disease Control and Prevention, 2006), migraine headaches (Diamond,

2004), the management of acne using isotretinoin, and psychiatric and psychologic disorders

including depression and bipolar disorders (Practice guideline for the treatment of patients with

bipolar disorder, 2002; Committee on Drugs 2000).



TABLE 1

FDA classification of medication safety during pregnancy

Category Description

A- Adequate, well-controlled studies in pregnant women have not shown an

increased risk of fetal abnormalities.

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.

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- Studies, adequate well-controlled or observational, in pregnant women

have demonstrated a risk to the fetus. However, the benefits of therapy may

outweigh the potential risk.

X- Studies, adequate well-controlled or observational, in animals or pregnant

women have demonstrated positive evidence of fetal abnormalities. The use of

the product is contraindicated in women who are or may become pregnant.

Dunlop. The clinical content of preconception care: the use of medications and

supplements among women of reproductive age. Am J Obstet Gynecol 2008.

TABLE 2

Medications contraindicated (class X) in pregnancy

Agent Comments

Angiotensin-converting enzyme inhibitors

(antihypertensive),

and angiotension II receptor blockers

May cause kidney abnormalities in fetus when used

in 2nd or 3rd trimesters.

HMG-CoA reductase inhibitors (statins) A range of abnormalities has been reported for

exposures during the 4th -9

th week of gestation.

Androgens and testosterone derivatives Cause masculinization of female fetus.



Carbamazapine (anticonvulsant) Risk of fetal death, mental retardation, and

malformed hearts, genitals, cleft palates, and

arteries. Should be switched to another, less

teratogenic agent before conception whenever

possible. Use should be reserved only for cases

where benefit outweighs risk.

Coumadin derivatives Risk of bone and cartilage deformities, mental

retardation, and vision problems.

Should be switched to heparin before conception

whenever possible.

Folic acid antagonists Risk of spontaneous abortion and malformations.

Leflunomide, thalidomide Risk of limb deformities. Use only with strict

pregnancy prevention protocols.

Lithium (antidepressant) Associated with increased risk of cardiovascular

anomalies.

Phenytoin (anticonvulsant) Risk of fetal hydantoin syndrome, including

intrauterine growth restriction with small head

circumference, dysmorphic facies, orofacial clefts,

cardiac defects, and distal digital hypoplasia. Use

should be reserved only for when benefit outweighs

risk.

Streptomycin and kanamycin

(antiinfective)

Risk of ototoxicity.

Tetracycline (antiinfective) Risk to developing bones and teeth causing

discoloration of teeth and skeletal

abnormalities.

Valproic acid (anticonvulsive) Risk of central nervous system dysfunction, spina

bifida, development delay, intrauterine growth

retardation, and cardiac anomalies. Should be

switched to another, less teratogenic agent before

conception whenever possible. If benefit

of use outweighs risk, should be administered in 3-4

divided doses and should not be combined with

carbamazapine and phenobarbitol.

Isotretinoin, known as Accutane (antiacne) Elevated risk of spontaneous abortion and many

anomalies.

OTC medications

Commonly used OTC medications among women of reproductive age include analgesics; cough,

cold, and allergy remedies; and remedies for gastrointestinal upset (Buitendijk et al, 1991; Weler et

al, 1992).



Dietary Supplements

The 1994 Dietary Supplement Health and Education Act (DSHEA) defined dietary supplements

(DSs) as vitamin, mineral, herb/botanical, amino acid, enzyme, protein, probiotic, glandular, or

hormone-like substances. Various national surveys have estimated that 18-52% of the US population

uses dietary supplements and many women use dietary supplements before and during pregnancy

(Radimer et al, 2004; Ervin et al, 2004; Kelly et al, 2005). In the United States, dietary supplements

are not regulated in the same way as prescription medications and do not necessarily undergo

clinical trials for safety and efficacy, especially in pregnancy. However, concerns about safety,

effectiveness, quality control, contamination, adverse events, and interactions with medications have

been raised in the literature about dietary supplements (Gardiner et al, 2006). Although many health

care professionals will recommend certain dietary supplements before and during pregnancy (eg,

folate, iron, and calcium), the safety and efficacy of many dietary supplements (eg, botanicals and

weight loss products) has not been well established before or during pregnancy (Barnes et al, 2004).

Health Canada has reported that at this time there is not enough scientific information about the

safety of various herbs and herbal products to recommend their general use during pregnancy and

lactation. Women should use these products cautiously, and critically examine any information

about their proposed benefits (Pinn et al, 2002) Given the widespread use of prescription and OTC

medications and dietary supplements— including herbs, weight loss products, and sport

supplements— among women of reproductive age, the growing prevalence of women with chronic

conditions during their reproductive years, and the unknown safety profile or known risk of

teratogenicity of many medications and supplements, health care providers should educate women

of reproductive age about the need to discuss the use of all medications and supplements with their

health care provider, particularly if they are planning a pregnancy or could become pregnant.

Numerous resources exist to aid health care providers in selecting appropriate medications that

balance the risk and benefit (for both the woman and any offspring she may conceive) of using

particular medications while planning a pregnancy or during pregnancy.

In general, the goals of preconception medical management include the following (Cragan et al,

2006):

Identify the pattern of medication and supplement use before conception.

Counsel women with chronic conditions about the potential impact of the condition and its

various treatments on the health of the woman and the fetus. Provide preconception

counseling of women for whom drugs are essential to allow them to make informed

decisions regarding the avoidance or timing of pregnancy.

Establish effective treatment for chronic conditions before conception.



Manage all chronic conditions and acute illnesses throughout pregnancy.

Counsel women to avoid the use of nonessential medications, including prescription (eg,

isotretinoin for acne) and OTC medications and dietary or herbal supplements.

Avoid the use of medications with high teratogenic risk when equally effective

treatments with lower risks are available, for example, warfarin (an anticoagulant), and

valproic acid (an anticonvulsant).

Limit the use of essential medications to the smallest number of drugs possible

that will effectively treat maternal disease without compromising the health of the woman or

her fetus.

Limit each essential medication to the smallest dose that can be used to effectively treat

maternal disease without compromising the health of the woman or her fetus.

Absent a gold standard for documenting exposure, we believe that carefully constructed, systematic

questionnaires administered by trained interviewers elicit relatively accurate information on actual

exposure and duration and that the direct to- consumer approach used by both studies provides the

most valid estimates of medication exposure during pregnancy.

Clinical Implications

Medication use in pregnancy is widespread, varies by demographic factors, and has been

increasing over time.

Most medications used in pregnancy have not been sufficiently evaluated for their potential

risks to the fetus.

Research efforts should focus on medications that are now used most commonly.

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