DRUG UTILIZATION PATTERN DURING PREGNANCY-A REVIEW
Transcript of DRUG UTILIZATION PATTERN DURING PREGNANCY-A REVIEW
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International Journal of Universal Pharmacy and Bio Sciences 2(6): November-December 2013
INTERNATIONAL JOURNAL OF UNIVERSAL
PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***
ICV 5.13***
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.
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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
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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.
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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
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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
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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
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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
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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
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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
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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).
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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.
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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).
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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.
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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.
BIBLIOGRAPHY
1. Academy of Managed Care Pharmacy. Concept in Managed Care Pharmacy Series:
Pharmaceutical Care, 2003. www.amcp.org/amcp.ark?p=AAAC630C (accessed September
7, 2009)
2. Alexander S, Doods L, Armson BA. Perinatal outcomes in women with asthma during
pregnancy. Obstet Gynecol 1998;92:435-40.
3. Alwan, S., Reefhuis, J., Rasmussen, S.A., Olney, R.S. & Friedman, J.M. Use of selective
serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N. Engl. J. Med. 356,
2684–2692 (2007).
4. American Academy of Neurology. Practice parameter: management issues for women with
epilepsy (summary statement): report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 1998; 51:944-8.
- 428 - | P a g e International Standard Serial Number (ISSN): 2319-8141
Full Text Available On www.ijupbs.com
5. American Association of Clinical Endocrinologists. Medical guidelines for clinical practice
for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract
2002;8:457-69.
6. American Diabetes Association. Preconceptional care of women with diabetes. Diabetes
Care 2004;27(Suppl 1):S76-8.
7. Andrade, S.E. et al. Prescription drug use in pregnancy. Am. J. Obstet. Gynecol. 191, 398–
407 (2004).
8. Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First-trimester drug use and
congenital disorders. Obstet Gynecol 1985;65:451-5.
9. Banhidy F., Lowry R.B., Czeizel A.E. — Risk and Benefit of Drug Use During Pregnancy.
Int J Med Sci. 2: 100-106, 2005.
10. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative
medicine use among adults: United States, 2002. Adv Data 2004;343:1-19.
11. Barry WS, Meinzinger MM, Howse CR. Ibuprofen overdose and exposure in utero: results
from a postmarketing voluntary reporting system. Am J Med 1984;77:35-9.
12. Benjamin D.M. — Reducing medication errors and increasing patient safety: case studies in
clinical pharmacology. J Clin Pharmacol. 43: 768–783, 2003.
13. Beyens M.N., Guy C., Ratrema M., Ollagnier M. — Prescription of drugs to pregnant
women in France: the HIMAGE study. Therapie. 58: 505–511, 2003.
14. Bonapace ES Jr, Fisher RS. Constipation and diarrhea in pregnancy. Gastroenterol Clin
North Am 1998;27:197-211.
15. Bonari, L. et al. Perinatal risks of untreated depression during pregnancy. Can. J. Psychiatry
49, 726–735 (2004).
16. Bonari, L., Koren, G., Einarson, T.R., Jasper, J.D., Taddio, A. & Einarson A. Use of
antidepressants by pregnant women: evaluation of perception of risk, efficacy of evidence
based counseling and determinants of decision making.
17. Arch. Womens Ment. Health 8, 214–220 (2005).
18. Brent RL. Environmental causes of human congenital malformations: the pediatrician’s role
in dealing with these complex clinical problems caused by a multiplicity of environmental
and genetic factors. Pediatrics 2004;1134 (Suppl 4):957-68.
19. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation: a reference guide
to fetal and neonatal risk. 5th ed. Baltimore: Williams & Wilkins, 1998:577-8,627-8.
20. Brost BC, Scardo JA, Newman RB. Diphenhydramine overdose during pregnancy: lessons
from the past. Am J Obstet Gynecol 1996;175:1376-7.
- 429 - | P a g e International Standard Serial Number (ISSN): 2319-8141
Full Text Available On www.ijupbs.com
21. Buitendijk S, Bracken MB. Medication in early pregnancy: prevalence of use and
relationship to maternal characteristics. Am J Obstet Gynecol 1991;165:33-40.
22. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually
transmitted diseases. MMWR Recomm Rep 1998;47(RR-1):1-111.
23. Centers for Disease Control and Prevention. US Public Health Service Task Force
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for
Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United
States. MMWR Morb Mortal Wkly Rep 2002;51(RR18): 1-38.
24. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment
guidelines, 2006. MMWR Morb Mortal Wkly Rep 2006;55(No. RR-11):1-100.
25. Chambers, C.D. et al. Selective serotonin-reuptake inhibitors and risk of persistent
pulmonary hypertension of the newborn. N. Engl. J. Med. 354, 579–587 (2006).
26. Chambers, C.D., Johnson, K.A., Dick, L.M., Felix, R.J. & Jones, K.L. Birth outcomes in
pregnant women taking fluoxetine. N. Engl. J. Med. 335, 1010–1015 (1996).
27. Chambers, C.D., Tutuncu, Z.N., Johnson, D. & Jones, K.L. Human pregnancy safety for
agents used to treat rheumatoid arthritis: adequacy of available information and strategies for
developing post-marketing data. Arthritis Res. Ther. 8, 215 (2006).
28. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension
2003;42:1206-52.
29. Cohen, L.S. et al. Relapse of major depression during pregnancy in women who maintain or
discontinue antidepressant treatment. JAMA 295, 499–507 (2006).
30. Collins E. Maternal and fetal effects of acetaminophen and salicylates in pregnancy. Obstet
Gynecol 1981;58(5 Suppl):57S-62S.
31. Committee on Drugs. Use of psychoactive medication during pregnancy and possible effects
on the fetus and newborn. Pediatrics 2000;105:880-7.
32. Cragan JD, Friedman JM, Holmes LB, Uhl K, Green NS, Riley L. Ensure the safe and
effective use of medications during pregnancy: planning and prevention through
preconception care. Matern Child Health J 2006;10:S129-35.
33. Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by
periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-5.
34. Czeizel AE. Prevention of congenital abnormalities by periconceptional multivitamin
supplementation. Br J Med 1993;306:1645-8.
- 430 - | P a g e International Standard Serial Number (ISSN): 2319-8141
Full Text Available On www.ijupbs.com
35. Czeizel AE. Reduction of urinary tract and cardiovascular defects by periconceptional
multivitamin supplementation. Am J Med Gent 1996;72:179-83.
36. Czeizel AE, Intödy Z, Modell B. What proportion of congenital abnormalities can be
prevented? Br Med J 1996;306:499-503.
37. Czeizel AE, Toth M, Rockenbauer M. No teratogenic effect after clotrimazole therapy during
pregnancy. Epidemiology 1999;10:437-40.
38. Damase-Michel C, Lapeyre-Mestre M, Moly C, Fournié A, Montastruc JL. drug use during
pregnancy: survey in 250 women consulting at a university hospital center. J Gynecol Obstet
Biol Reprod (Paris) 2000; 29: 77–85.
39. De Jong-van den Berg L.T., Berg P.B. Van den, Haaijer- Ruskamp F.M., Dukes M.N.,
Wesseling H. — Investigating drug use in pregnancy. Methodological problems and
perspectives. Pharm Weekbl Sci. 13:32–38, 1991.
40. Dempsey DA, Benowitz NL. Risks and benefits of nicotine to aid smoking cessation in
pregnancy. Drug Saf 2001;24:277-322.
41. Diamond M. Special treatment situations: menstrual migraine and menstrually-related
migraine. In: Standards of care for headache diagnosis and treatment. Chicago (IL): National
Headache Foundation; 2004.
42. Dicke JM, Johnson RF, Henderson GI, Kuehl TJ, Schenker S. A comparative evaluation of
the transport of H2-receptor antagonists by the human and baboon placenta. Am J Med Sci
1988;295:198-206.
43. DiFranza JR, Lew RA. Effect of maternal cigarette smoking on pregnancy complications and
sudden infant death syndrome. J Fam Pract 1995;40:385-94.
44. Drhova L. — Knowledge, attitudes and behaviour of the population of the Czech Republic to
selfmedication- II. Knowledge of and information about drugs. Ceska Slov Farm. 54:168,
2005.
45. Drugs in Pregnancy and Lactation, 5th edi. Wilkins and Wilkin: Baltimore; 1998.
46. Ervin RB, Wright JD, Reed-Gillette D. Prevalence of leading types of dietary supplements
used in the Third National Health and Nutrition Examination Survey, 1988-94. Adv Data
2004:1-7.
47. FDA classification of drugs for teratogenic risk. Teratology Society Public Affairs
Committee. Teratology 1994;49:446-7.
48. Floyd, R.L. Dencoufle, P. & Hungerford, D.W. Alcohol use prior to pregnancy recognition.
Am. J. Prev. Med. 17, 101–107 (1999).
- 431 - | P a g e International Standard Serial Number (ISSN): 2319-8141
Full Text Available On www.ijupbs.com
49. Gardiner P, Graham RE, Legedza A, Eisenberg DM, Phillips RS. Factors associated with
dietary supplement use among prescription medication users. Arch Intern Med 2006;166:
1968-74.
50. Gilbert-Barness E, Barness LA, Wolff J, Harding C. Aluminum toxicity. Arch Pediatr
Adolesc Med 1998;152:511-2.
51. Glover D.D., Amonkar M., Rybeck B.F., Tracy T.S. — Prescription, over-the-counter and
herbal medicine use in a rural, obstetric population. Am J Obstet Gynecol. 188:1039-1045,
2003.
52. Hauth JC, Goldenberg RL, Parker CR Jr, Cutter GR, Cliver SP. Low-dose aspirin: lack of
association with an increase in abruptio placentae or perinatal mortality. Obstet Gynecol
1995;85:1055-8.
53. Heikkila A.M., Erkkola R.U., Nummi S.E. — Use of medication during pregnancy- A
prospective cohort study on use and policy of prescribing. Ann Chir Gynaecol Suppl.
208:80-83, 1994.
54. Henshaw, S.K. Unintended pregnancy in the United States. Fam. Plann. Perspect. 30, 24–29
(1998).
55. Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of
Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol 2003;41:1633-52.
56. Irl C, Haasford J, Pegasus study group. The PEGASUS project: a prospective cohort study
for the investigation of drug use in pregnancy. Int J Clin Pharmacol Ther 1997; 35: 572–76.
57. Jacobs LR. Prescription to over-the-counter drug reclassification. Am Fam Physician
1998;57:2209- 14.
58. Kacew S. — Foetal consequences and risks attributed to the use of prescribed and over-the-
counter (OTC) preparations during pregnancy. Int J Clin Pharmacol Ther. 32: 335, 1994.
59. Kallen, B.A. & Olausson, P.O. Maternal use of selective serotonin re-uptake inhibitors in
early pregnancy and infant congenital malformations. Birth Defects Res. A Clin. Mol.
Teratol. 79, 301–308 (2007).
60. Kargas GA, Kargas SA, Bruyere HJ Jr, Gilbert EF, Opitz JM. Perinatal mortality due to
interaction of diphenhydramine and temazepam. N Engl J Med 1985;313:1417-8.
61. Katz PO, Castell DO. Gastroesophageal reflux disease during pregnancy. Gastroenterol Clin
North Am 1998;27:153-67.
62. Kelly JP, Kaufman DW, Kelley K, Rosenberg L, Anderson TE, Mitchell AA. Recent trends
in use of herbal and other natural products. Arch Intern Med 2005;165:281-6.
- 432 - | P a g e International Standard Serial Number (ISSN): 2319-8141
Full Text Available On www.ijupbs.com
63. King CT, Rogers PD, Cleary JD, Chapman SW. Antifungal therapy during pregnancy. Clin
Infect Dis 1998;27:1151-60.
64. Kochanek KD, Smith BL. Deaths: preliminary data for 2002. National vital statistics reports;
vol 52 no 13. Hyattsville, Maryland: National Center for Health Statistics. 2004.
65. Koren, G. & Pastuszak, A. Prevention of unnecessary pregnancy terminations by counselling
women on drug, chemical, and radiation exposure during the first trimester. Teratology 41,
657–661 (1990).
66. Koren G., Pastuszak A., Ito S. — Drugs in pregnancy. N Eng J Med. 338: 1135–1137, 1998.
67. Kraemer K — Placental transfer of drugs. Neonatal Network. 16: 65-67, 1997. Kulin, N.A. et
al. Pregnancy outcome following maternal use of the new selective serotonin reuptake
inhibitors: a prospective controlled multicenter study. JAMA 279, 609–610 (1998).
68. Lagace E. Safety of first trimester exposure to H2 blockers. J Fam Pract 1996;43:342-3.
69. Lagoy CT, Joshi N, Cragan JD, Rasmussen SA. Medication use during pregnancy and
lactation: an urgent call for public health action. J Womens Health 2005;14:104-9.
70. Larson JD, Patatanian E, Miner PB Jr, Rayburn WF, Robinson MG. Double-blind, placebo-
controlled study of ranitidine for gastroesophageal reflux symptoms during pregnancy.
Obstet Gynecol 1997;90:83-7.
71. Louik, C., Lin, A.E., Werler, M.M., Hernandez-Diaz, S. & Mitchell, A.A. First trimester use
of selective serotonin-reuptake inhibitors and the risk of birth defects. N. Engl. J. Med. 356,
2675–2683 (2007).
72. Lo, W.Y. & Friedman, J.M. Teratogenicity of recently introduced medications in human
pregnancy. Obstet. Gynecol.100, 465–473 (2002).
73. Lyerly, A.D. Risks, values, and decision making surrounding pregnancy. Obstet. Gynecol.
109, 979–984 (2007).
74. Maats F.H., Crowther C.A. — Patterns of vitamin, mineral and herbal supplement use prior
to and during pregnancy. Aust N Z J Obstet Gynaecol. 42:494-496, 2002.
75. Mahadevan U, Kane S. American Gastroenterological Association Institute medical position
statement on the use of gastrointestinal medications in pregnancy. Gastroenterology
2006;131:278-82.
76. Malm H., Martikainen J., Klaukka T., Neuvonen P.J. — Prescription of hazardous drugs
during pregnancy. Drug Saf. 27:899-908, 2004
77. Mastroiacovo P, Mazzone T, Botto LD, Serafini MA, Finardi A, Caramelli L, et al.
Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole.
Am J Obstet Gynecol 1996; 175:1645-50.
- 433 - | P a g e International Standard Serial Number (ISSN): 2319-8141
Full Text Available On www.ijupbs.com
78. Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy,
parturition, and lactation. In: Witorsch RJ, ed. Reproductive toxicology. 2d ed. New York:
Raven, 1995:175-93.
79. Medication during pregnancy: an intercontinental cooperative study. Collaborative Group on
Drug Use in Pregnancy (C.G.D.U.P.). Int J Gynaecol Obstet. 39:185–196, 1992.
80. National Asthma Education and Prevention Program. Managing asthma during pregnancy:
recommendations for pharmacologic treatment. Bethesda (MD): National Heart, Lung, and
Blood Institute; 2005.
81. Navarro, Robert. Chapter 8: Drug Utilization Review Strategies. In Managed Care Pharmacy
Practice, published 2008, pp. 215 – 229.
82. Nielsen GL, Norgaard B, Puho E, Rothman KJ, Sørensen HT, Czeizel AE. Risk of specific
congenital abnormalities in offspring of women with diabetes. Diabet Med 2005;22:693-6.
83. Olesen C, Hald Steffensen F, Lauge Nielsen G, de Jong-van den Berg L, Olsen J, Toft
Sorensen H, The Euromap group. Drug use in first pregnancy and lactation: a population-
based survey among Danish women. Eur J Clin Pharmacol 1999; 55: 139–44.
84. Patterson EC, Staszak DJ. Effects of geophagia (kaolin ingestion) on the maternal blood and
embryonic development in the pregnant rat. J Nutr 1977;107:2020.
85. Pinn G, Pallett L. Herbal medicine in pregnancy. Complement Ther Nurs Midwifery
2002;8:77-80.
86. Practice guideline for the treatment of patients with bipolar disorder. Am J Psychiatry
2002;159(Suppl 4):1-50.
87. Public Affairs Committee of the Teratology Society. Teratology public affairs committee
positon paper: pregnancy labeling for prescription drugs: ten years later. Birth Defects Res.
A Clin. Mol. Teratol. 79, 627–630 (2007).
88. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement
use by US adults: data from the National Health and Nutrition Examination Survey, 1999-
2000. Am J Epidemiol 2004;160:339-49.
89. Rutledge JC. Developmental toxicity induced during early stages of mammalian
embryogenesis. Mutat Res 1997;396:113-27.
90. Schwarz EB, Jaselli J, Norton M, Gonzales R. Prescription of teratogenic medications in
United States ambulatory practices. Am J Med 2005;118:1240-9.
91. Sharma R., Kapoor B., Verma U. — Drug utilization pattern during pregnancy in North
India. J Med Sci. 60:277-287, 2006.
- 434 - | P a g e International Standard Serial Number (ISSN): 2319-8141
Full Text Available On www.ijupbs.com
92. Shaw GM, Todoroff K, Velie EM, Lammer EJ. Maternal illness, including fever and
medication use as risk factors for neural tube defects. Teratology 1998;57:1-7.
93. Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol 2002;100:369-77.
94. Sorensan M.K., Phillips B.B., Mutnick A.H. — Drug use in specific patient populations:
Pediatric, Pregnant, Geriatric. In: Shargel L, Mutnick A, editors.
95. Comprehensive Pharmacy Review. 5th ed. Philadelphia: Lippincott William Wilkins; p. 673-
682, 2004.
96. Splinter MY, Sagraves R, Nightengale B, Rayburn WF. Pre-natal use of medications by
women giving birth at a university hospital. South Med J 1997;90:498-502.
97. The use of newer asthma and allergy medications during pregnancy. The American College
of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma,
and Immunology (ACAAI). Ann Allergy Asthma Immunol 2000;84: 475-80.
98. Tisonova J., Magulova L., Goboova M., Wawruch M., Lassanova M., Bozekova L., et al.
Consultation activity of two Slovak centres for pharmacotherapy during pregnancy and
lactation. Cas Lek Cesk. 2006;145:154-159.
99. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1-77.
100. Uhl K. Conducting clinical pharmacology studies in pregnant and lactating women. In:
Sahajwalla CG, ed. New drug development: regulatory paradigms for clinical pharmacology
and biopharmaceutics. New York: Marcel Dekker, Inc; 2004:267-96.
101. United States Department of Health and Human Services, Health Research Services
Administration, Maternal and Child Health Bureau. Women’s Health USA 2002. Rockville,
Md: 2004.
102. US Department of Health and Human Services; Food and Drug Administration, CDER and
CBER. Guidance for Industry Establishing Pregnancy Exposure Registries. August 2002.
103. Werler MM, Mitchell AA, Shapiro S. First trimester maternal medication use in relation to
gastroschisis. Teratology 1992;45:361-7.
104. Wilson JG. Current status of teratology. In: Wilson JG, Fraser FC, eds. Handbook of
teratology. New York: Plenum, 1977:47.
105. World Health Organization Collaborating Centre for Drug Utilization Research and Clinical
Pharmacological Services. Introduction to Drug Utilization Research, 2003.
http://apps.who.int/medicinedocs/en/d/Js4876e/ (accessed September 7, 2009).
106. Young GL, Jewell D. Topical treatment for vaginal candidiasis (thrush) in pregnancy.
Cochrane Database Syst Rev 2001;CD000225.