1361
SECTION 9
GYNECOLOGIC AND OBSTETRIC DISORDERS
87
C H AP TER
Pregnancy and Lactation:
Therapeutic Considerations
KEY CONCEPTS
 Physiologic changes modify drug pharmacokinetics during
pregnancy, including changes in absorption, protein binding,
distribution, and elimination, requiring individualized drug
selection and dosing.
 Although drug-induced teratogenicity is a serious concern
during pregnancy, most drugs required by pregnant women
can be used safely. Informed selection of drug therapy is
essential.
 Healthcare practitioners must know where to find and how to
evaluate evidence related to the safety of drugs used during
pregnancy and lactation.
 Pregnancy-influenced health issues, such as constipation,
gastroesophageal reflux disease, and nausea/vomiting, can
be treated safely and effectively with nonpharmacologic
treatment or carefully selected drug therapy. Some acute
and chronic illnesses pose additional risks during pregnancy,
requiring treatment with appropriately selected and monitored
drug therapies to avoid harm to the woman and the fetus.
 Understanding the physiology of lactation and pharmacoki-
netic factors affecting drug distribution, metabolism, and elimi-
nation can assist the clinician in selecting safe and effective
medications during lactation.
Drug use in pregnancy and lactation is a topic often underempha-
sized in the education of health professionals. Drug use in preg-
nancy and lactation is a controversial and emotionally charged area
because of medicolegal and ethical implications.
Clinicians are responsible for ensuring safe and effective therapy
before conception, during pregnancy and parturition, and after
Learning objectives, review questions,
and other resources can be found at
www.pharmacotherapyonline.com.
KRISTINA E. WARD AND BARBARA M. OBRIEN
delivery. Active patient participation is essential. Optimal treat-
ments of illnesses during pregnancy sometimes differ from those
used in the nonpregnant patient. Principles of drug use during
lactation, although similar, are not the same as those applicable
during pregnancy.
In many cases, medication dosing recommendations for acute or
chronic illnesses in pregnant women are the same as for the gen-
eral population. However, some cases require different dosing and
selection of medications.
PHYSIOLOGY OF PREGNANCY
Fertilization and progression of pregnancy are complex, resulting
in survival of only approximately 50% of embryos.1 Because most
losses occur early, usually in the first 2 weeks after fertilization,
many women dont realize they were pregnant. Spontaneous loss
of pregnancy later in gestation occurs in about 15% of pregnancies
that survive the first 2 weeks after fertilization.2
Fertilization occurs when a sperm attaches to a receptor on the
outer protein layer of the egg, the zona pellucida, and renders the
egg nonresponsive to other sperm.3 The attached sperm releases
enzymes that cause the eggs chromosomes to mature, allowing the
sperm to fully penetrate the zona pellucida and contact the eggs
cell membrane. The membranes of the sperm and egg then com-
bine to create a new, single cell called a zygote. Male and female
chromosomes join in the zygote, fuse to create a single nucleus, and
organize for cell division.4
Fertilization usually occurs in the fallopian tube.4 The fertilized
egg travels down the fallopian tube over 2 days, with cell division
taking place. By day 3, the fertilized egg reaches the uterus. Cell
division continues for another 2 to 3 days in the uterine cavity
before implantation. Approximately 6 days after fertilization, the
cell mass is termed a blastocyst. Human chorionic gonadotropin
(hCG) now is produced in amounts detectable by commercial
laboratories. Implantation begins with the blastocyst sloughing
the zona pellucida to rest directly on the endometrium allowing
initiation of growth into the endometrial wall. By day 10 postfertil-
ization, the blastocyst is implanted under the endometrial surface
and receives nutrition from maternal blood.4 Now it is called an
embryo.4,5
1362
After the embryonic period (between weeks 2 and 8 postfertiliza-
tion), the conceptus is renamed a fetus.5 Most body structures are
SECTION 9
formed during the embryonic period, and they continue to grow
and mature during the fetal period. The fetal period continues until
the pregnancy reaches term, approximately 40 weeks after the last
menstrual period.6
Gravidity is the number of times that a woman is pregnant.5,7 A
multiple birth is counted as a single pregnancy. Parity refers to the
number of pregnancies exceeding 20 weeks gestation and relates
information regarding the outcome of each pregnancy. In sequence,
Gynecologic and Obstetric Disorders
the numbers reflect (1) term deliveries, (2) premature deliveries, (3)
aborted and/or ectopic pregnancies, and (4) number of living chil-
dren. A woman who has been pregnant four times; has experienced
two term deliveries, one premature delivery, and one ectopic preg-
nancy; and has three living children would be designated G4P2113.
PREGNANCY DATING
Pregnancy lasts approximately 280 days (about 40 weeks or
9 months); the time period is measured from the first day of the last
menstrual period to birth.5,7 Gestational age refers to the age of the
embryo or fetus beginning with the first day of the last menstrual
period, which is about 2 weeks prior to fertilization. When calcu-
lating the estimated due date, add 7 days to the first day of the last
menstrual period then subtract 3 months. Pregnancy is divided into
three periods of 3 calendar months, each called a trimester.
PREGNANCY SIGNS AND SYMPTOMS
Early symptoms of pregnancy include fatigue and increased fre-
quency of urination. At approximately 6 weeks gestation, nausea
and vomiting can occur. While commonly called morning sickness,
it can happen at any time of the day. Nausea and vomiting usually
resolve at 12 to 18 weeks gestation. A pregnant woman can feel fetal
movement in the lower abdomen at 16 to 20 weeks of gestation.
Signs of pregnancy include cessation of menses, change in cervi-
cal mucus consistency, bluish discoloration of the vaginal mucosa,
increased skin pigmentation, and anatomic breast changes.5,7
MATERNAL PHARMACOKINETIC
CHANGES IN PREGNANCY
 Normal physiologic changes that occur during pregnancy may
alter medication effects, resulting in the need to more closely moni-
tor and, sometimes, adjust therapy. Physiologic changes begin in
the first trimester and peak during the second trimester. For medi-
cations that can be monitored by blood or serum concentration
measurements, monitoring should occur throughout pregnancy.
During pregnancy, maternal plasma volume, cardiac output, and
glomerular filtration increase by 30% to 50% or higher, potentially
lowering the concentration of renally cleared drugs.8,9 As body fat
increases during pregnancy, the volume of distribution of fat-solu-
ble drugs may increase. Plasma albumin concentration decreases,
which increases the volume of distribution of drugs that are highly
protein bound. However, unbound drugs are more rapidly cleared
by the liver and kidney during pregnancy, resulting in little change
in concentration. Nausea and vomiting, as well as delayed gastric
emptying, may alter the absorption of drugs. Likewise, a pregnancy-
induced increase in gastric pH may affect the absorption of weak
acids and bases. Higher levels of estrogen and progesterone alter
liver enzyme activity and increase the elimination of some drugs but
result in accumulation of others.
TRANSPLACENTAL DRUG TRANSFER
Although once thought to be a barrier to drug transfer, the placenta
is the organ of exchange for a number of substances, including
drugs, between the mother and fetus. Most drugs move from the
maternal circulation to the fetal circulation by diffusion.10 Certain
chemical properties, such as lipid solubility, electrical charge,
molecular weight, and degree of protein binding of medications,
may influence the rate of transfer across the placenta.10
Drugs with molecular weights less than 500 Da readily cross
the placenta, whereas larger molecules (6001,000 Da) cross more
slowly.10 Drugs with molecular weights greater than 1,000 Da,
such as insulin and heparin, do not cross the placenta in signifi-
cant amounts.10 Lipophilic drugs, such as opiates and antibiotics,
cross the placenta more easily than do water-soluble drugs.10
Maternal plasma albumin progressively decreases while fetal albu-
min increases during the course of pregnancy, which may result in
higher concentrations of certain protein-bound drugs in the fetus.10
Fetal pH is slightly more acidic than maternal pH, permitting weak
bases to more easily cross the placenta. Once in the fetal circulation,
the molecule becomes more ionized and less likely to diffuse back
into the maternal circulation.10
DRUG SELECTION DURING PREGNANCY
 Although some drugs have the potential to cause teratogenic
effects, most medications required by pregnant women can be used
safely. There are many misconceptions about the association of
medications and birth defects.
The baseline risk for congenital malformations is approximately
3% to 6%, with approximately 3% considered severe.2 Medication
exposure is estimated to account for less than 1% of all birth
defects.2 Genetic causes are responsible for 15% to 25%, other envi-
ronmental issues (e.g., maternal conditions and infections) account
for 10%, and the remaining 65% to 75% of congenital malforma-
tions result from unknown causes.2
Factors such as the stage of pregnancy during exposure, route
of administration, and dose, can affect outcomes.2,11 In the first
2 weeks following conception, exposure to a teratogen may result
in an all-or-nothing effect, which could either destroy the embryo
or cause no problems.11 During organogenesis (18 to 60 days
postconception), organ systems are developing, and teratogenic
exposures may result in structural anomalies. For the remainder of
the pregnancy, exposure to teratogens may result in growth retar-
dation, central nervous system abnormalities, or death.2 Examples
of medications associated with teratogenic effects in the period of
organogenesis include chemotherapy drugs (e.g., methotrexate,
cyclophosphamide), sex hormones (e.g., diethylstilbestrol), lithium,
retinoids, thalidomide, certain antiepileptic drugs, and coumarin
derivatives. Other medications such as nonsteroidal antiinflamma-
tory drugs and tetracycline derivatives are more likely to exhibit
effects in the second or third trimester.
In summary, a small number of medications have the potential
to cause congenital malformations, and many can be avoided dur-
ing pregnancy. In situations where a drug may be teratogenic but
is necessary for maternal care, considerations related to route of
administration and dosing may lessen the risk.
METHODS OF DETERMINING
DRUG SAFETY IN PREGNANCY
 When assessing the safety of using medications during preg-
nancy, an important consideration for the clinician is how to evalu-
ate the quality of the evidence. Ideally, safety data from randomized,
controlled trials is most desirable, but pregnant women are not
usually eligible for participation in clinical trials. Other types of
data commonly used to estimate the risk associated with medication
use during pregnancy are animal studies, case reports, case-control

studies, prospective cohort studies, historical cohort studies, and
voluntary reporting systems.
Animal studies are a required component of drug testing,
but extrapolation of the results to humans is not always valid.12
Thalidomide was found to be safe in some animal models but
proved to have teratogenic effects in human offspring.
Case reports are usually of limited value because a birth defect
in the infant of a woman who used a medication during pregnancy
may have occurred by chance.12 Case-control studies identify an
outcome (congenital anomaly), match subjects with and without
that outcome, and report how often exposure to a suspected agent
occurred. Recall bias is a concern in case-control studies, as women
with an affected pregnancy may be more likely to remember drugs
used during the pregnancy than those who had a normal outcome.
Cohort studies evaluate the intervention (use of a particular
drug) in a group of persons and compare outcomes in a similar
group of subjects without the intervention.12,13 Prospective studies
eliminate some of the problems with recall bias but require time and
large numbers of participants. Despite these disadvantages, cohort
studies are often used for evaluating the effects of a drug exposure
on pregnancy outcomes.
Teratology information services provide pregnant women with
information about potential exposures during pregnancy and fol-
low these women throughout the pregnancy to assess the outcomes
of the pregnancy.12 The services may publish pooled data to facili-
tate information sharing about medications used during pregnancy.
Some pharmaceutical companies have organized voluntary report-
ing systems (also called pregnancy registries) for drugs used during
pregnancy.
RESOURCES
 Computerized databases (e.g., www.motherisk.org, LactMed
[www.toxnet.nlm.nih.gov]), tertiary compendia, and textbooks with
information from large cohorts of treated women offer valuable
assistance. New information regarding drug use in pregnancy and
lactation can be obtained from searches of the primary literature for
cohort and case-control studies.
The Food and Drug Administration (FDA) developed risk cat-
egories (i.e., A, B, C, D, X, with A considered safe and X considered
teratogenic) to guide clinicians regarding medication risk during
pregnancy. The FDA ranks very few as safe during pregnancy (cat-
egory A) because a controlled trial is required to establish safety;
this implies that few drugs are safe. Because of multiple limitations
of the risk categories, the FDA proposed a new system in 2008 to
replace the risk categories with a fetal risk summary and lactation
risk summary. Each section discusses clinical considerations and
summarizes available data.14
In summary, drug safety information from product labeling may
provide a rough estimate of risks for medication-related adverse
fetal outcomes but must be used in conjunction with other informa-
tion sources to make decisions about medication use in pregnant
women.
GENERAL RECOMMENDATIONS
FOR OPTIMIZING USE OF
MEDICATIONS IN PREGNANCY
 Medications are necessary during pregnancy for treatment of
acute and chronic conditions. Identifying patterns of medication
use before conception, eliminating nonessential medications and
discouraging self-medication, minimizing exposure to medications
known to be harmful, and adjusting medication doses are all strate-
gies to optimize the health of the mother while minimizing the risk
to the fetus.
1363
PRECONCEPTION PLANNING
CHAPTER 87
Pregnancy outcomes are influenced by maternal health status,
lifestyle, and history prior to conception.15 More than 60% of
pregnancies in the United States are unintended. Of women who
receive prenatal care, 18% seek it after the first trimester.16 The goal
of preconception care is health promotion, evidence-based screen-
ing, and intervention in all women of reproductive age to ensure
optimal health and improve pregnancy outcomes.15
The most common major congenital abnormalities are neural
Pregnancy and Lactation: Therapeutic Considerations
tube defects (NTDs), cleft palate and lip, and cardiac anomalies.
Each year in the United States approximately 1 in 1,000 infants
are born with NTDs.17 Folic acid supplementation substantially
reduces the incidence in offspring of women, including those with
a history of NTDs.16,17 Neural tube defects occur within the first
month of conception because neural tube closure occurs during
the first month of pregnancy. Folic acid supplementation is rec-
ommended throughout a womans reproductive years since many
pregnancies are unplanned and may not be recognized until after
the first month. Dietary intake of folic acid is not sufficient. For
all women of childbearing age, folic acid supplementation with
400 mcg/day is recommended.16 For women at high risk or those
who have a history of NTDs, folic acid 4 mg/day is recommended.
Multivitamins should not be used to achieve folic acid doses higher
than contained in the multivitamin product because of risk for
vitamin A toxicity.
Use of alcohol and recreational drugs during pregnancy is
associated with birth defects.15 Of births in the United States
in 2003, 10% of mothers smoked tobacco during pregnancy.15
Smoking can cause preterm birth, low birth weight, and other
adverse outcomes. In a systematic review of 72 trials of smoking
cessation and perinatal outcomes, incidences of low birth weight
and preterm birth were reduced, and birth weight increased by
54 g with smoking cessation.18 Cognitive behavioral therapy and
nicotine replacement therapy resulted in similar rates of smoking
cessation; however, offering incentives and social support resulted
in the highest rate of success. For women who cannot stop smok-
ing with behavioral interventions alone, nicotine replacement
therapies can be used with behavioral therapy. Use of nicotine
replacement during pregnancy is controversial since its use is not
supported by clinical trial data; however, nicotine replacement
theoretically imparts less risk than exposure to the over 4,000
chemicals found in cigarettes.19 Intermittent delivery formulations
are recommended because most users ingest a smaller total daily
dose than received from the topically applied patch.20 If patches
are necessary because of poor tolerability of other agents, they
should be applied for 16 rather than 24 hours per day. The initial
dose of the patch should be similar or higher than that used for
nonpregnant women because of nicotines rapid metabolism dur-
ing pregnancy. Bupropion is an alternative to nicotine replace-
ment for women who have not quit smoking with behavioral
therapy because the risk of its use appears to be less than that of
cigarette smoking. However, its efficacy for smoking cessation
in pregnancy has not been determined. Bupropion use during
pregnancy should be reported to the GlaxoSmithKline pregnancy
registry. Vareniclines safety and effectiveness during pregnancy
are unknown.
Prevention of infectious disease during pregnancy is important.
Vaccination against Rubella and hepatitis B as part of preconcep-
tion care reduces adverse pregnancy outcomes.15 Influenza vac-
cination is generally offered to women who will be in their second
or third trimester during influenza season. Women with comorbid
conditions that increase risks of complications from influenza
should receive vaccine regardless of time of gestation.
1364
PREGNANCY-INFLUENCED ISSUES
SECTION 9
 Pregnancy causes or exacerbates conditions that pregnant
women commonly experience, including constipation, gastroesoph-
ageal reflux, hemorrhoids, and nausea and vomiting. Gestational
diabetes, gestational hypertension, and venous thromboembolism
have the potential to cause adverse pregnancy consequences.
Gestational thyrotoxicosis is usually self-limiting.
Gynecologic and Obstetric Disorders
GASTROINTESTINAL TRACT
The prevalence of constipation during pregnancy ranges from
25% to 40%. Light physical exercise and increased intake of dietary
fiber and fluid should be instituted first.21 If additional treatment is
needed, supplemental fiber and/or a stool softener is appropriate.22
Osmotic laxatives (polyethylene glycol, lactulose, sorbitol, and mag-
nesium and sodium salts) are acceptable treatments but should be
reserved for occasional use only. Polyethylene glycol is considered
by some the ideal laxative for use in pregnancy.21,22 Senna and bisa-
codyl can be used occasionally. Castor oil and mineral oil should
be avoided.
Gastroesophageal reflux disease occurs in up to 80% of pregnant
women.21 An algorithm starting with lifestyle and dietary modifica-
tions (e.g., small, frequent meals; alcohol and tobacco avoidance;
food avoidance before bedtime; elevation of the head of the bed)
should be used. If symptoms are not relieved, use of antacids
(aluminum, calcium, or magnesium preparations) or sucralfate is
acceptable. Sodium bicarbonate and magnesium trisilicate should
be avoided. Evidence supports the use of ranitidine and cimetidine.
Literature evaluating the use of famotidine and nizatidine is lim-
ited, but they are likely safe. If a patient is unresponsive to lifestyle
changes and histamine-2 receptor blockers, metoclopramide is a
viable option. Relatively few data are available on the use of proton
pump inhibitors during pregnancy; use should be reserved for
women with complicated or intractable gastroesophageal reflux.
The prevalence of hemorrhoids during pregnancy is believed to
be higher than in the general population.23 Therapy during preg-
nancy is conservative (i.e., high intake of dietary fiber, adequate
oral fluid intake, and use of sitz baths) and may be helpful; however,
there is a paucity of supporting data for all management options.
Topical anesthetics, skin protectants, and astringents can be used.
Other options for refractory hemorrhoids include rubber band liga-
tion, sclerotherapy, and surgery.
Nausea and vomiting affect up to 90% of pregnant women,
usually beginning during the fifth week of gestation and lasting
through the first trimester; however, about 15% of women experi-
ence it throughout pregnancy.21,24 Hyperemesis gravidarum (HEG;
i.e., unrelenting vomiting causing weight loss of more than 5%
prepregnancy weight and ketonuria) occurs in about 1% to 3% of
women.24 Dietary modifications, such as eating frequent, small,
bland meals and avoiding fatty foods, may be helpful. Applying
pressure at acupressure point P6 on the volar aspect of the wrist
may be beneficial.
A number of pharmacotherapeutic approaches have been tried
for treatment of nausea and vomiting. Multivitamins, pyridoxine
(vitamin B6), and antihistamines (including doxylamine) have
shown efficacy.21,24 Phenothiazines and metoclopramide are widely
used and generally considered safe.21,24 Evidence of safety and
efficacy with ondansetron is limited, but ondansetron can be con-
sidered for HEG when other treatments fail. Corticosteroids are
effective for HEG but are associated with a small increase in the
risk of oral clefts when used during the first trimester.21,24 Ginger
has shown efficacy for hyperemesis in randomized, controlled trials
and is probably safe.21,24
GESTATIONAL DIABETES
Gestational diabetes mellitus (GDM) is glucose intolerance first
identified during pregnancy. It develops in about 4% of pregnant
women, although the prevalence may range from 1% to 14%.25
Screening for gestational diabetes is controversial.2527 The U.S.
Preventative Services Task Force Independent Expert Panel con-
cluded that there is a lack of evidence proving that screening for ges-
tational diabetes decreases adverse maternal and fetal outcomes.27
However, the American Diabetes Association recommends glucose
testing for women with risk factors of gestational diabetes (e.g.,
obesity, history of the condition, glycosuria, or strong family history
of diabetes) at the first prenatal visit.25 If normal, testing should be
repeated between weeks 24 and 28 of gestation. Pregnant women
considered to have average risk should undergo testing for GDM
between weeks 24 and 28 of gestation unless they are considered
low risk. To meet criteria for low risk, a woman must fulfill all the
following: (a) age younger than 25 years, (b) normal body weight,
(c) no known diabetes in first-degree relatives, (d) no history of
abnormal glucose tolerance, (e) no history of adverse obstetric out-
comes, and (f) not a member of an ethnic group with a high preva-
lence of GDM (e.g., African Americans, Native Americans, Asian
Americans, Hispanic Americans, Pacific Islanders). Initial screen-
ing for hyperglycemia in pregnancy is similar to that in the general
population and is described in the American Diabetes Association
practice guidelines.25
Dietary modification is considered first-line therapy for all
women who have GDM, with additional caloric restriction for
obese women.26,28 Daily self-monitoring of blood glucose is
required. Insulin therapy with recombinant human insulin should
be initiated if the following levels are not achieved with dietary
modification: fasting plasma glucose concentrations below 9099
mg/dL (5.05.5 mmol/L), 1-hour postprandial plasma glucose
concentration less than or equal to 140 mg/dL (7.8 mmol/L), or
2-hour postprandial plasma glucose concentration below 120127
mg/dL (6.77.0 mmol/L).26 Glyburide is an alternative because
it minimally crosses the placenta.26,28 Metformin may also be an
alternative, but it crosses the placenta and is less well studied than
insulin or glyburide.28 There are data, though limited, supporting
the use of postprandial over preprandial blood glucose monitoring
in women requiring insulin treatment.29 Recommended targets
for self-monitored blood glucose are preprandial plasma glucose
concentration between 80 and 110 mg/dL (4.46.1 mmol/L)
and 2-hour postprandial plasma glucose concentration below
155 mg/dL (8.6 mmol/L).30
Evidence supporting dietary modification, self-monitored blood
glucose, exercise, and pharmacologic interventions for women with
GDM is largely based on one randomized clinical trial that showed
reductions in perinatal morbidity (composite of death, nerve palsy,
bone fracture, and shoulder dystocia) with nutritional education,
blood glucose monitoring, and insulin treatment.31,32
HYPERTENSION
Approximately 10% of pregnancies are complicated by hyper-
tension at some time during the pregnancy. Hypertension in
pregnancy is divided into four categories: chronic hypertension
(preexisting hypertension), gestational hypertension (hypertension
without proteinuria), preeclampsia (hypertension with protein-
uria), and preeclampsia superimposed on chronic hypertension.33,34
Treatment of mild-to-moderate hypertension (defined as systolic
blood pressure 140169 mm Hg or diastolic blood pressure 90109
mm Hg) reduces the risk of severe hypertension by 50%, but does
not substantially affect fetal outcomes. However, severe hyperten-
sion (blood pressure greater than or equal to 160170 mm Hg

systolic or 110 mm Hg diastolic) can cause maternal complications,
hospital admission, and potential premature delivery. Preeclampsia
complicates 2%8% of pregnancies and can cause poorer outcomes,
including eclampsia (seizures in addition to preeclampsia), renal
failure, coagulopathy, preterm delivery, and intrauterine growth
restriction.33
Supplemental calcium 12 g/day decreases the relative risk of
hypertension by 30% (range 14%43%) and preeclampsia by 48%
(range 31%67%).35 High-risk patients (those with the lowest ini-
tial calcium intake) benefited most; however, even women with
adequate calcium intake at baseline had a 38% decrease in risk of
preeclampsia. Therefore, 1 g/day of supplemental calcium is recom-
mended for all pregnant women.
Nondrug managements center on activity restriction, psychosocial
therapy, and biofeedback; however, no evidence indicates that any
of these approaches improves pregnancy outcome, and prolonged
bed rest may increase the risk of venous thromboembolic disease.
Studies of antihypertensive drug therapy for mild-to-moderate
hypertension (less than or equal to 160/110 mm Hg) in pregnancy
have not conclusively shown a decrease in the risk of preeclampsia,
neonatal death, preterm birth, or small-for-gestational-age babies.
However, antihypertensives do prevent severe hypertension.34,36 No
evidence supports selection of one pharmacologic agent as first-line
therapy. Commonly used drugs include methyldopa, labetalol, and
calcium channel blockers.36 Agents affecting the renin-angiotensin
pathway (i.e., angiotensin-converting enzyme inhibitors, angio-
tensin receptor antagonists, and renin inhibitors) should probably
be avoided throughout pregnancy.36
Drug therapy is indicated for women with blood pressure
greater than or equal to 160/110 mm Hg. However, no consen-
sus exists on when to initiate treatment, and recommendations
vary from at least 140/90 mm Hg to 160/105 mm Hg.36 As with
mild-to-moderate hypertension in pregnancy, conclusive evidence
supporting one antihypertensive agent over another is lacking,
although agents to avoid include magnesium sulfate (unless indi-
cated for eclampsia prevention), high-dose diazoxide, nimodipine,
and chlorpromazine.37
Low-dose aspirin (7581 mg/day) started after 12 weeks gesta-
tion in women at risk for preeclampsia decreases the risk of its
development by 17%, which corresponds to prevention of one
preeclampsia case for every 72 at-risk women treated.33,38 Low-dose
aspirin also results in decreased rates of preterm birth (8% reduc-
tion) and fetal or neonatal death (14% reduction). In high-risk
women (i.e., previous severe preeclampsia, renal disease, autoim-
mune disease, diabetes, and chronic hypertension), use of low-dose
aspirin prevents one case for every 19 women treated. Features asso-
ciated with moderate risk for preeclampsia include first pregnancy,
adolescent maternal age, mild increase in blood pressure without
proteinuria, abnormal uterine artery Doppler scan, family history of
severe preeclampsia, and multiple fetuses; although some evidence
refutes young maternal age as a risk factor.33,38
Preeclampsia may progress rapidly to eclampsia, a medical emer-
gency, so signs and symptoms of preeclampsia must be monitored
carefully. Eclampsia is the occurrence of seizures superimposed
on preeclampsia.33,39 Signs and symptoms of preeclampsia include
blood pressure elevation; proteinuria; persistent severe headache;
persistent new epigastric pain; visual changes; vomiting; hyper-
reflexia; sudden and severe swelling of hands, face, or feet; low
platelet count; hemolytic anemia; increased serum creatinine; and
elevated liver enzyme tests. The only cure for preeclampsia is deliv-
ery of the fetus. Treatment of hypertension in women with preec-
lampsia is the same as mentioned previously (e.g., methyldopa,
labetalol, calcium channel blockers). Magnesium sulfate is recom-
mended to prevent eclampsia as well as treat eclamptic seizures.
Diazepam and phenytoin should be avoided.
1365
THYROID ABNORMALITIES
CHAPTER 87
During pregnancy, stimulation of the thyroid gland may occur
because of hCGs structural similarity to serum TSH (thyrotro-
pin).40 In women with HEG, gestational transient thyrotoxicosis
may result. Women are usually asymptomatic but may present with
vomiting, increased serum free thyroxine, and decreased thyrotro-
pin. Gestational transient thyrotoxicosis resolves as concentrations
of hCG decline toward the end of the first trimester. Treatment
with antithyroid medications is not usually needed. Nausea and
vomiting can be treated as for patients without this pseudohyper-
Pregnancy and Lactation: Therapeutic Considerations
thyroid state.
Postpartum thyroiditis occurs in approximately 4% of women
within 1 to 4 months after childbirth because of increased thyroid
hormone secretion.41 Most cases resolve spontaneously; however,
-blockers (propranolol or labetalol) can provide symptomatic
relief of adrenergic symptoms. Patients should be monitored since
2% to 5% of women go on to develop transient hypothyroidism 4 to
8 months postpartum; levothyroxine replacement is suggested for a
total of 6 to 12 months. Up to 30% of women develop permanent
hypothyroidism.
THROMBOEMBOLISM
Venous thromboembolism is estimated to occur in 0.06% to 0.13%
of pregnancies; a five- to tenfold increase in risk over nonpregnant
women.42
 Unfractionated heparin or adjusted-dose low-molecular
weight heparin are recommended for treatment of acute throm-
boembolism during pregnancy, although low-molecular-weight
heparin is preferred.42 Treatment should be continued through-
out pregnancy and for 6 weeks after delivery. Warfarin is not
used because it causes nasal hypoplasia, stippled epiphyses, limb
hypoplasia, and eye abnormalities; the risk period appears to be
between 6 and 12 weeks gestation. However, central nervous
system anomalies are associated with second- and third-trimester
exposure. Antepartum monitoring or anticoagulation plus post-
partum anticoagulation is recommended for women with a single
episode of thromboembolism and either (a) thrombophilia, (b) an
idiopathic cause without thrombophilia, or (c) a pregnancy- or
estrogen-related risk factor. Antepartum and postpartum antico-
agulation should be given to women with two or more episodes of
thromboembolism, women with antithrombin III deficiency, and
women receiving long-term anticoagulation. Pregnant women with
antiphospholipid antibodies and a history of pregnancy complica-
tions should receive antepartum aspirin in addition to unfraction-
ated heparin or low-molecular-weight heparin.
Women with prosthetic heart valves should receive low-
molecular-weight heparin or unfractionated heparin during preg-
nancy.42 After a discussion of potential risks, a heparin product
can be used until week 13 of gestation with subsequent substitu-
tion of warfarin until the middle of the third trimester when a
heparin product should again be used. High-risk women with
prosthetic heart valves (e.g., older-generation mitral valve, his-
tory of thromboembolism) may also receive low-dose aspirin
(75100 mg/day).
CONCLUSION
Women with pregnancy-influenced gastrointestinal issues can be
treated safely with lifestyle modification or medications, many of
them nonprescription. Gestational diabetes, hypertension, and thy-
rotoxicosis may or may not require drug therapy. Venous throm-
boembolism treatment or prevention usually requires therapy with
a low-molecular-weight heparin or unfractionated heparin.
1366
ACUTE CARE ISSUES IN PREGNANCY
SECTION 9
 In some cases, the risks associated with the acute illness are
magnified during pregnancy, and early screening and treatment
become critical. In other cases, such as during treatment of certain
sexually transmitted diseases, the urgency regarding treatment
comes from an increased likelihood of infection leading to preterm
labor. Occasionally, common acute care issues, such as migraine
headache, improve during pregnancy.
Gynecologic and Obstetric Disorders
URINARY TRACT INFECTION
 The most common infections in pregnant and nonpregnant
women are urinary tract infections.43 The incidence of asymptom-
atic bacteriuria ranges from 2% to 10% while estimates for acute
cystitis range from 1% to 4%. Untreated, bacteriuria progresses to
pyelonephritis in 20% to 40% of pregnant women compared with
1% to 2% of nonpregnant women. Complications of pyelonephritis
include premature delivery, low infant birth weight, hypertension,
anemia, bacteremia, and transient renal failure.44 A urine culture is
recommended to screen pregnant women for urinary tract infec-
tions between 12 and 16 weeks gestation.43 Use of other meth-
ods, such as dipsticks that measure nitrites or leukocyte esterase,
requires high bacterial concentrations for a positive result, leading
to false negatives and underdiagnosis.
Escherichia coli is the primary cause of infection in 80% to 90%
of cases.43 Other gram-negative rods, such as Proteus mirabilis and
Klebsiella pneumoniae, as well as Group B Streptococcus (GBS)
account for some infections. The presence of GBS in the urine indi-
cates heavy colonization of the genitourinary tract, increasing the
risk for GBS infection in the newborn.
To decrease the risk of pyelonephritis and its complications,
treatment of asymptomatic bacteriuria is necessary.44 -Lactams
are not known teratogens; however, the incidence of E. coli
resistance to ampicillin and amoxicillin limits their use as single
agents. Cephalexin is safe and effective. Nitrofurantoin is also
safe and effective, but it is not active against Proteus species.
It should not be used after week 37 in patients with glucose-6-
phosphate dehydrogenase deficiency because of a theoretical
risk for hemolytic anemia in the neonate; however, no cases are
reported. Sulfa-containing drugs can contribute to the develop-
ment of newborn kernicterus; use should be avoided during the
last weeks of gestation. Trimethoprim is a folate antagonist and is
relatively contraindicated during the first trimester because of asso-
ciations with cardiovascular malformations. Regionally, increased
rates of E. coli resistance to trimethoprim-sulfa may limit its use.
Fluoroquinolones and tetracyclines are contraindicated. The opti-
mal duration of therapy for asymptomatic bacteriuria in pregnancy
has not been determined. Courses of 7 to 14 days are common,
but shorter courses of 3 days may be sufficient.43 Repeat urine cul-
tures are recommended monthly for the remainder of gestation if
asymptomatic bacteriuria is diagnosed.
Signs and symptoms of acute cystitis include urgency, frequency,
hematuria, pyuria, and dysuria.43 Treatment of acute cystitis is
similar to that of asymptomatic bacteriuria. Using outcomes of cure
rates, recurrent infection, incidence of preterm delivery or rupture
of membranes, admission to neonatal intensive care, need for
change of antibiotic, or incidence of prolonged fever, antibiotic
treatment has demonstrated effectiveness in treating symptomatic
urinary tract infections (including pyelonephritis) in pregnancy.45
No specific treatment appeared superior to other commonly used
treatments.
Patients with pyelonephritis usually present with bacteriuria and
systemic symptoms of fever, flank pain, nausea, and vomiting.43
Hospitalization is the standard of care for pregnant women since
many require intravenous hydration. Inpatient therapy has included
parenteral administration of cephalosporins (e.g., cefazolin, ceftri-
axone), ampicillin plus gentamicin, or ampicillin-sulbactam.43,44
Switching to oral antibiotics can occur after the woman is afebrile
for 48 hours. Outpatient antibiotic therapy can be considered after
initial inpatient observation in women who are afebrile and less
than 24 weeks gestation. The total duration of antibiotic therapy
for acute pyelonephritis is 10 to 14 days. Suppression therapy
with nitrofurantoin 100 mg given nightly is recommended for the
remainder of gestation because of the 20% recurrence rate.
SEXUALLY TRANSMITTED DISEASES
 Sexually transmitted diseases in pregnant women range from
infections that may be transmitted across the placenta and infect
the infant prenatally (e.g., syphilis) to organisms that may be trans-
mitted during birth and cause neonatal infection (e.g., Chlamydia
trachomatis, Neisseria gonorrhoeae, or herpes simplex virus) to
infections that pose a threat for preterm labor (e.g., bacterial
vaginosis). Screening is essential for early detection of most sexually
transmitted diseases but may not be beneficial in other instances
(e.g., bacterial vaginosis in low-risk patients). Sexual partners
of women with certain infections (e.g., syphilis, N. gonorrhoeae,
C. trachomatis) also require treatment to prevent recurrence of
infection.
Syphilis
Serologic testing for syphilis should occur during the first prenatal
visit.46 For women who live in areas with a high prevalence of syphi-
lis, are at high risk, have not been previously tested, or had positive
serology in the first trimester, additional serologic testing during
the third trimester and at delivery is recommended. With the
exception of neurosyphilis, which is treated with aqueous penicillin
G, the drug of choice for all stages of syphilis is benzathine penicil-
lin G. Penicillin effectively prevents transmission to the fetus and
treats the fetus, if already infected. For pregnant women, the dose
and route of administration are determined by the stage of syphilis
and do not differ from recommendations for nonpregnant patients.
No alternatives for penicillin are acceptable for penicillin-allergic
pregnant women; therefore, penicillin skin testing and desensitiza-
tion are required.
Treatment during the second half of pregnancy may increase
the risk for preterm labor and fetal distress because a Jarisch-
Herxheimer reaction may occur; however, treatment should not
be withheld or delayed.46 All women should have serologic titers
repeated at 28 to 32 weeks gestation, at delivery, and as dictated by
recommendations for the stage of disease.
Neisseria gonorrhoeae
Perinatal gonococcal infection results from exposure to the infected
cervix during birth. Symptoms usually manifest within 2 to 5 days
after delivery.46 Milder manifestations include rhinitis, vaginitis,
urethritis, and infection at the site of fetal monitoring. More severe
presentations include ophthalmia neonatorum and sepsis.
Coinfection with C. trachomatis is common; treatment of most
N. gonorrhoeae infections includes treatment for C. trachomatis.46
Cotreatment regimens for presumptive or diagnosed C. trachomatis
infection are described in the following section. Ceftriaxone 125 mg
intramuscularly as a single dose or cefixime 400 mg orally in a single
dose is the treatment of choice for N. gonorrhoeae cervical infection.
Women with a cephalosporin allergy or intolerance should receive
a single dose of spectinomycin 2 g intramuscularly. Quinolones and
tetracyclines are contraindicated.

TABLE 87-1 Recommended Regimens for Treatment of Cervical
Infections Due to Chlamydia in Pregnancy
First-line treatment
Azithromycin 1 g orally in a single dose or
Amoxicillin 500 mg orally three times daily for 7 days
Alternative regimens
Erythromycin base 500 mg orally four times per day for 7 days or
Erythromycin base 250 mg orally four times per day for 14 days
Erythromycin ethylsuccinate 800 mg orally four times per day for 7 days or
Erythromycin ethylsuccinate 400 mg orally four times per day for 14 days
Data from Centers for Disease Control and Prevention, Workowski KA, Berman SM Sexually trans-
mitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006;55(RR-11):194.46
Chlamydia trachomatis
C. trachomatis infects the newborn through exposure to the infected
cervix during delivery.46 Perinatal infection most commonly causes
conjunctivitis that develops 5 to 12 days postpartum. A subacute,
afebrile pneumonia with an onset at ages 1 to 3 months may occur.
The treatment of choice for C. trachomatis cervicitis is azithromy-
cin 1 g orally as a single dose or amoxicillin 500 mg three times daily
for 7 days.46 Erythromycin base or ethylsuccinate regimens are alter-
natives, but gastrointestinal intolerance and the required frequency
of administration may limit patient acceptance. Erythromycin
estolate increases the risk for hepatotoxicity and should be avoided
(Table 871).
Genital Herpes
 Neonatal herpes often occurs in infants born to women lacking
clinical evidence of genital herpes.46 The risk of neonatal transmis-
sion is under 1% for women with a history of recurrent herpes at
term, but is 30% to 50% for women who initially acquire genital her-
pes during the first half of their pregnancy. However, because recur-
rent herpes is more common than initial episodes during pregnancy,
it remains the cause for most cases of neonatal transmission.
Prevention strategies include counseling uninfected women to
avoid intercourse during the third trimester with partners having
known or suspected genital herpes infection.46,47 Women with no
history of orolabial herpes should avoid receptive oral sex dur-
ing the third trimester with partners who have orolabial herpes.
Prevention of genital herpes transmission to pregnant women using
antiviral agents has not been studied.
All women should be asked about symptoms of genital herpes at
the time of delivery and should be examined for lesions.46,47 Women
who have no symptoms (including prodromal symptoms) or lesions
proceed with vaginal childbirth; however, those with evidence of an
outbreak undergo cesarean section to decrease the risk of neonatal
transmission.
Maternal use of acyclovir during the first trimester has not dem-
onstrated an increased risk for birth defects.46 Valacyclovir is an
alternative.47 Safety data with famciclovir are limited. For initial or
recurrent episodes, most women receive oral acyclovir therapy while
intravenous acyclovir is reserved for severe infections. Women with
an initial outbreak late in pregnancy may receive acyclovir, cesarean
section, or a combination of the two. Acyclovir use during the last
month of pregnancy may reduce the frequency of cesarean section
because of fewer recurrences. In women seropositive for herpes
simplex virus but who have not experienced an outbreak, no data
suggest a treatment benefit.
Bacterial Vaginosis
Bacterial vaginosis results from the lack of normal vaginal flora
(i.e., Lactobacillus species) and replacement with anaerobic bacte-
ria, mycoplasmas, and Gardnerella vaginalis.46 It is a risk factor for
1367
premature rupture of membranes, preterm labor, preterm birth,
spontaneous abortion, and postpartum endometritis. Women with
CHAPTER 87
a history of preterm delivery should undergo screening for asymp-
tomatic bacterial vaginosis at the first prenatal visit.
For symptomatic and asymptomatic women at high risk for
preterm delivery, the recommended treatment regimen is met-
ronidazole 500 mg orally twice daily for 7 days, metronidazole
250 mg orally three times daily for 7 days, or clindamycin 300 mg
twice daily for 7 days. Conflicting data exist with regard to treating
women at low risk for preterm labor. Vaginal preparations (e.g.,
Pregnancy and Lactation: Therapeutic Considerations
metronidazole gel, clindamycin cream) have not demonstrated
reductions in the risk of adverse pregnancy outcomes associated
with bacterial vaginosis. Use of intravaginal clindamycin cream
during the second half of pregnancy has caused low birth weight
and neonatal infections.
HEADACHE
 Primary headaches (e.g., tension, migraine) in pregnant women
are the most common types of headache.48 Secondary headaches can
also occur as a result of trauma, infection, preeclampsia, stroke, or
cerebral venous thrombosis.
The majority of pregnant women with a history of migraine head-
aches experience symptom improvement during pregnancy. Eighteen
percent to 86% of women improve, and the greatest improvements
occur during the second and third trimesters.48,49 Improvement is
more likely in women who have migraine without aura and less likely
in women with a history of menstrual migraine. Women with men-
strual migraine are more likely to have postpartum recurrence.
Relaxation, stress management, and biofeedback are all effective
nonpharmacologic treatment methods.48,49 Acetaminophen (with
or without codeine), codeine, or other narcotic analgesics can be
used to treat headaches that do not respond to nonpharmacologic
treatment. Aspirin should be avoided in the third trimester because
it can cause narrowing of the ductus arteriosus, maternal and
fetal bleeding, and decreased uterine contractility. Nonsteroidal
antiinflammatory drugs (NSAIDs) are considered safe but are also
contraindicated in the third trimester because of the potential for
closure of the ductus arteriosus. Caffeine may be added to any of
the foregoing treatments to improve response, but overuse may
cause withdrawal headaches. Use of sumatriptan is controversial
because of limited information about pregnancy outcomes with its
use, but some clinicians recommend it for women who have not
responded to other agents.49 Ergotamine and dihydroergotamine
are contraindicated. Metoclopramide can be used for patients who
have migraine-associated nausea. Chronic, preventive treatment
is reserved for women who have three to four severe episodes per
month that are not responsive to other treatments. -Blockers, such
as propranolol, are commonly used but may be associated with
side effects, including intrauterine growth retardation. Alternatives
include calcium channel blockers and antidepressants.48,49
Tension headaches are less studied.48,49 Most women report no
change in the frequency or intensity of tension headaches. Tension
headaches may be difficult to distinguish from secondary headaches.
Primary treatments for tension headache are nonpharmacologic
interventions, including exercise, biofeedback, and massage. Simple
analgesics such as acetaminophen, ibuprofen, or caffeine are used if
nonpharmacologic treatments fail. Opioids are rarely used.48
CHRONIC ILLNESSES IN PREGNANCY
 For the majority of women and their healthcare providers,
pregnancy is a new consideration for a previously diagnosed health
condition. Medications used to treat the chronic illness can often be
used throughout the pregnancy and during breast-feeding.
1368
ALLERGIC RHINITIS AND ASTHMA
SECTION 9
 Asthma and rhinitis are common chronic illnesses in preg-
nancy. During pregnancy, asthma control may change and worsen
maternal oxygenation resulting in significant health consequences
in the mother and fetus. Rhinitis itself is unlikely to cause harm
to the mother or fetus but may be associated with diminished
quality of life.
Asthma affects approximately 8% of pregnancies.50 During preg-
nancy almost equal proportions of patients have symptoms that
worsen, improve, or remain unchanged.51 Health consequences
Gynecologic and Obstetric Disorders
of untreated or poorly treated asthma include preterm labor, pre-
eclampsia, intrauterine growth restriction, premature birth, low birth
weight, and stillbirth; therefore, the treatment goal is symptom con-
trol.51,52 Asthma is controlled when there are no daytime symptoms,
limitations of activities, nocturnal symptoms, short-acting 2-agonist
use, or exacerbations, and there is normal pulmonary function.
Caring for patients with asthma should include (a) assessment
and monitoring (including measures of pulmonary function),
(b) identifying and controlling exposure to allergens and irritants
(e.g., tobacco smoke), (c) patient education, and (d) a stepped
approach to medication use.51 The risks of medication use to the
fetus are lower than the risks of untreated asthma.
Treatment recommendations are divided into six steps based on
symptom control.51,52 A short-acting 2-agonist is recommended
for all patients with asthma for quick relief of symptoms. For
mild intermittent asthma, Step 1 recommends only a short-acting,
inhaled 2-agonist; albuterol is preferred during pregnancy.
Initiation of treatment for persistent asthma should begin with
Step 2 unless the patient has severely uncontrolled asthma, in
which case treatment may start at Step 3.51,52 For persistent asthma,
step-appropriate doses (low, medium, high) of inhaled cortico-
steroids form the foundation of the controller medication regimen.
When possible, low-dose inhaled corticosteroids are the treatment
of choice for women with mild persistent asthma. Budesonide is
preferred during pregnancy, although other inhaled corticosteroids
that were effective before pregnancy can be continued. Long-acting
2-agonists are considered safe to use during pregnancy because
of the similar pharmacologic and safety profiles compared with
short-acting agents; use should follow the stepwise approach.5052
Cromolyn, leukotriene receptor antagonists, and theophylline are
considered alternative treatments but are not preferred because
they are less effective (cromolyn), there is less experience with them
(leukotriene receptor antagonists), and there is more potential tox-
icity (theophylline) than with inhaled corticosteroids. For patients
with the most severe disease, addition of systemic corticosteroids is
recommended to gain control of symptoms.51
Allergic rhinitis may also improve, worsen, or remain the same
during pregnancy.53 Treatment strategies include avoidance of
allergens, immunotherapy, and pharmacotherapy. Immunotherapy
is not contraindicated in pregnancy, but dose increases during preg-
nancy are not advised to lessen risk for anaphylaxis.
First-line medications to treat allergic rhinitis during preg-
nancy include intranasal corticosteroids, nasal cromolyn, and first-
generation antihistamines (e.g., chlorpheniramine, hydroxyzine).53
Intranasal corticosteroids are the most effective treatment and have
a low risk of systemic effect; beclomethasone and budesonide have
been most widely studied.53,54 Second-generation antihistamines
(i.e., loratadine and cetirizine) do not appear to increase fetal risk
but are less extensively studied than first-generation products. Oral
decongestants, such as pseudoephedrine, may be associated with
an increased risk for the rare birth defect gastroschisis. Use of an
external nasal dilator, short-term topical oxymetazoline, or inhaled
corticosteroids may be preferable to use of oral decongestants, espe-
cially during early pregnancy.
DERMATOLOGIC CONDITIONS
 Treatment of dermatologic conditions can often be delayed until
after the delivery.55 If treatment is required during gestation, topical
agents considered to have minimal pregnancy risk include baci-
tracin, benzoyl peroxide, ciclopirox, clindamycin, erythromycin,
metronidazole, mupirocin, permethrin, and terbinafine. Topical
corticosteroids are generally considered safe for use but should be
applied at the lowest possible dose for the shortest time. Systemic
agents considered safe include acyclovir, amoxicillin, azithromycin,
cephalosporins, cyproheptadine, dicloxacillin, diphenhydramine,
erythromycin (except estolate), nystatin, and penicillins. Lidocaine
and lidocaine with epinephrine can be used topically during preg-
nancy. Acitretin, fluorouracil, isotretinoin, methotrexate, and tha-
lidomide should be avoided because of teratogenic potential.
DIABETES
 Poorly controlled diabetes can cause fetal malformations and
fetal loss.30 Women with diabetes should use effective contracep-
tion until optimal glycemic control is achieved before attempting
pregnancy. Additionally, diabetic retinopathy may worsen, hyper-
tension may develop, and renal function may deteriorate during
pregnancy, requiring enhanced monitoring for these target-organ
problems.56
For patients with both type 1 and type 2 diabetes, insulin is the
drug treatment of choice.56 However, glyburide and metformin may
be alternatives.26,28 Medical nutrition therapy and supervised physi-
cal activity programs should continue. Goals for self-monitored
blood glucose are the same as for gestational diabetes.30,56
EPILEPSY
 Seizure frequency does not change for most pregnant women
with epilepsy. Studies have demonstrated no frequency change in
54% to 80% of women with epilepsy, while decreased frequency
ranges between 3% and 24% and increased frequency ranges from
14% to 32%.57,58 Seizures may become more frequent because of
changes in maternal hormones, sleep deprivation, and medica-
tion adherence problems (because of perceived teratogenic risk).
Another potential cause is changes in free serum concentrations
of antiepileptic drugs resulting from increased maternal volume
of distribution, decreased protein binding from hypoalbumi-
nemia, increased hepatic drug metabolism, and increased renal
drug clearance. A womans clinical condition and her free serum
concentrations of antiepileptic drug should be the basis for dose
adjustments.
The risks of untreated epilepsy to the fetus are considered to be
greater than those associated with the antiepileptic drugs.58 Major
malformations are two to three times more likely to occur in chil-
dren born to women taking antiepileptic drugs than to those who
do not. Major malformations with valproic acid are dose related and
range from 6.2% to 10.7%; use of valproic acid should be avoided if
possible during pregnancy to minimize the risk of NTDs (e.g., spina
bifida), facial clefts, and cognitive teratogenicity.59,60 Rates of major
malformation for monotherapy with antiepileptic drugs other than
valproic acid range between 2.9% and 3.6%. Carbamazepine and
lamotrigine appear to be safest based on available data. However,
individual antiepileptic drugs are associated with malformations.
Phenytoin, lamotrigine, and carbamazepine may cause cleft pal-
ate, while phenobarbital is associated with cardiac malformations.
Polytherapy with antiepileptic drugs is associated with a greater rate
of major malformation than monotherapy.59,60
When possible, antiepileptic drug monotherapy is recom-
mended with medication regimen optimization occurring before

conception.59 Medication change solely to minimize teratogenic
risk is not recommended. If drug withdrawal is planned, it should
be attempted at least 6 months before attempting to conceive.59
While vitamin K administration during the last month of gestation
was previously recommended to decrease the risk of hemorrhagic
complications in newborns, evidence to support this practice is
lacking. The American Academy of Pediatrics recommends that all
neonates receive vitamin K at delivery. All women taking antiepi-
leptic drugs should receive folic acid supplementation; 4 to 5 mg
daily starting before pregnancy and continuing through at least the
first trimester.58
HUMAN IMMUNODEFICIENCY
VIRUS INFECTION
 Pregnant women newly diagnosed with HIV, with or without
prior treatment, should receive highly active antiretroviral therapy
(HAART). The treatment regimen should be selected from those
suggested for nonpregnant adults, with special consideration given
to the teratogenic profile of each drug.61 Women currently receiv-
ing antiretroviral treatment should be continued on their regimen
when possible. If antiretroviral drugs are being used exclusively to
prevent mother-to-child transmission, prophylaxis may be delayed
until after the first trimester.
Zidovudine is the mainstay of antiretroviral therapy and is
recommended for use during pregnancy, labor, and delivery, as
well as during the postpartum period.61 Lamivudine should be
used along with zidovudine as the nucleoside reverse transcriptase
inhibitor (NRTI) backbone of therapy when feasible. For HAART,
two NRTIs plus either a nonnucleoside reverse transcriptase
inhibitor (NNRTI) or a protease inhibitor is recommended; cur-
rent guidelines recommend nevirapine or lopinavir/ritonavir.
Efavirenz should be avoided during the first trimester and the
entire pregnancy if possible. If therapy is discontinued during the
first trimester, reintroduction of all medications should occur only
when the ability to tolerate drug therapy is certain. All medications
should be restarted at the same time to decrease risk of resistance.
Zidovudine dosing recommendations during pregnancy are 300
mg twice daily or 200 mg three times a day. Intravenous zidovu-
dine is recommended during labor, and the infant should receive
the drug beginning 6 to 12 hours after birth and continuing for the
first 6 weeks of life.
HYPERTENSION
 Treatment of stage 1 or 2 chronic hypertension (blood pres-
sure 140179 mm Hg systolic or 90109 mmHg diastolic) during
pregnancy is controversial because the physiologic drop in blood
pressure during the first half of pregnancy may result in improved
blood pressure control without drug treatment.36,62 However, treat-
ment may decrease uteroplacental blood flow and impair fetal
development. Additionally, most of the increases in adverse fetal
and maternal outcomes are caused by preeclampsia superimposed
on chronic hypertension. Women should be monitored closely if
treatment is discontinued, and therapy should be reinstituted if
blood pressure exceeds 150 to 160 mm Hg systolic or 100 to 110
mm Hg diastolic or if target-organ damage occurs. Alternatively,
antihypertensive drugs may be continued (except for angiotensin-
converting enzyme inhibitors and angiotensin II receptor blockers)
at the lowest effective dose. Use of diuretics (excluding spironolac-
tone) is controversial but may be considered for chronic hyper-
tension. Women with severe hypertension (blood pressure above
170 mmHg systolic or above 110 mmHg diastolic) should receive
drug therapy to prevent occurrence of cerebrovascular hemor-
rhage or other target-organ damage.37 Available evidence does not
1369
support superior efficacy of one agent versus another for blood
pressure reduction.34,36,37
CHAPTER 87
MENTAL HEALTH CONDITIONS
 Psychiatric illness affects approximately 500,000 pregnancies
each year.63,64 Anxiety disorders, including panic disorder, obses-
sivecompulsive disorder, generalized anxiety disorder, posttrau-
matic stress disorder, social anxiety disorder, and phobias, can
cause adverse maternal and fetal outcomes such as spontaneous
abortion, preterm delivery, prolonged labor, and fetal distress.63
Pregnancy and Lactation: Therapeutic Considerations
Depression occurs in 10% to 16% of pregnant women.63,64
Maternal depression is associated with greater risk for premature
birth, low birth weight, and fetal growth restriction. In addition to
the potential impact of maternal depression on obstetric complica-
tions, untreated depression may have long-term implications for
normal infant development.63 Up to 6.4% of Americans have bipolar
disorder, with men and women equally affected, but the incidence
in pregnancy is unknown. Patients with bipolar disorder may be
more likely to relapse during pregnancy, especially with rapid dis-
continuation of drug therapy.64
Schizophrenia occurs in 1% to 2% of women, however the inci-
dence in pregnancy is unknown.63,64 Drug therapy is usually neces-
sary, although some women refuse treatment because of concerns
about teratogenicity or paranoid or delusional thinking. Maternal
schizophrenia is associated with increased risk of perinatal death,
low birth weight, small-for-gestational-age infants, cardiovascular
malformations, preterm delivery, stillbirth, and infant death.63
Nonpharmacologic therapies may be tried in pregnant women
with psychiatric illnesses who fail to respond or inadequately
respond to drug therapy and in those who refuse drug therapy.
Cognitive behavioral therapy and interpersonal psychotherapy have
been shown beneficial in the treatment of anxiety disorders and
depression.64 Light therapy has also been effective for treatment of
seasonal depression. Electroconvulsive therapy is considered safe
and effective treatment of major depression, bipolar disorder, and
schizophrenia.
Because most psychotropic medications are used to treat more
than one condition, the reader should refer to other sources for
information about treatment of specific mental health diagnoses. In
general, monotherapy is preferred over polytherapy even if higher
doses are required.64
Neither the selective serotonin reuptake inhibitors (SSRIs) nor
the tricyclic antidepressants are considered major teratogens.63 The
SSRIs are the drugs of first choice for several mental health condi-
tions in the general population and are widely used by pregnant
women. Data suggest that paroxetine may cause a 1.5- to 2-fold
increased risk of cardiac malformations; this finding has not been
replicated for other SSRIs. About 1 two 2 newborns per 1,000
develop persistent pulmonary hypertension. Infants exposed to
SSRIs in utero after 20 weeks gestation developed persistent pul-
monary hypertension at a rate 6 times greater than the background
rate; this finding needs further confirmation.65 Overall, the absolute
risk of major malformations with SSRIs is small; approximately
2 in 1,000 births are affected.63 Use of SSRIs late in pregnancy can
precipitate neonatal withdrawal symptoms consisting of irritability
and difficulty with feeding and breathing. There are concerns about
adverse effects in infants born to women who use SSRIs during
pregnancy. However, women who stop taking antidepressants are
more likely to relapse, and this can also have implications for the
well-being of the infant.
Studies completed over 30 years ago showed an increased risk
of oral clefts with diazepam use during pregnancy; these findings
were not confirmed in a subsequent study.63 A recent meta-analysis
found the absolute risk of oral cleft changed from 6 cases to 7 cases
1370
per 10,000 exposures (0.01%). Another large case-control study
found no association between benzodiazepine use and congenital
SECTION 9
anomalies. Benzodiazepine use in the third trimester can cause
infant sedation and withdrawal symptoms (i.e., restlessness, hyper-
tonia, hyperreflexia, tremulousness, apnea, diarrhea, vomiting).
Floppy baby syndrome, consisting of low Apgar scores, hypo-
thermia, poor muscle tone, feeding difficulties, and poor tempera-
ture adaptation, has also been described.
Mood stabilizers, such as lithium, lamotrigine, carbamazepine,
and valproic acid, are often used to treat bipolar disorder.63 The
Gynecologic and Obstetric Disorders
reader can find information related to the use of the seizure medica-
tions used for mood stabilization in the section on epilepsy.
Lithiums place in the treatment of bipolar disorder is controver-
sial because of concerns about cardiovascular anomalies, especially
Ebstein anomaly, in exposed infants.63 A meta-analysis calculated
that the relative risk for cardiac malformations was between 1.2
and 7.7 and for all congenital malformations was between 1.5 and
3. Stated differently, the risk for Ebstein anomaly after prenatal lith-
ium exposure would rise from 1:20,000 to 1:1,000.66 Other reported
neonatal side effects include floppy baby syndrome, nephrogenic
diabetes insipidus, hypoglycemia, cardiac arrhythmias, thyroid
dysfunction, polyhydramnios, and premature delivery.63,66 Lithium
may cause lethargy, hypotonia, hypothermia, cyanosis, and changes
in electrocardiogram in infants exposed through breast-feeding.
If breastfeeding, the infants lithium levels, thyroid function, and
complete blood count should be monitored.
Chlorpromazine, haloperidol, and perphenazine have long his-
tories of use during pregnancy, with no reported significant
teratogenic effect.63 Atypical antipsychotics are considered first-line
treatment for schizophrenia because of their more favorable side-
effect profiles and potential increased efficacy for treating negative
symptoms compared with the older agents. However, use of atypical
antipsychotics in pregnant women is controversial because of the
limited data regarding teratogenic potential. Although olanzapine
and clozapine have not been associated with increased risk for con-
genital malformations, they do cause weight gain and glucose intol-
erance, which have implications for poorer obstetric outcomes.66
One study found a higher rate (10% vs. 2%) of low-birth-weight
infants with olanzapine, clozapine, quetiapine, and risperidone
compared with nonexposed infants.63 At present, atypical antipsy-
chotics do not appear to be safer than the typical agents.
THYROID DISORDERS
 Hypothyroidism affects 0.1 to 0.3% of pregnancies.40 Untreated
hypothyroidism increases the risk of preeclampsia, premature birth,
miscarriage, and growth restriction; impaired neurological develop-
ment in the fetus may also occur. Causes of hypothyroidism include
autoimmune diseases (e.g., Hashimoto thyroiditis), iodine defi-
ciency (uncommon in the United States), and thyroid dysfunction
following surgery or ablative therapy for previous hyperthyroidism.
Thyroid replacement therapy should be instituted with levothy-
roxine 0.1 to 0.15 mg/day in hypothyroid patients; the goal is to
attain normal thyrotropin concentration. Women receiving thyroid
replacement therapy before pregnancy may have an increased dos-
age requirement during pregnancy; any dose change should follow
thyroid function testing. Laboratory follow-up of thyrotropin con-
centrations and free T4 should occur every 8 weeks.
Hyperthyroidism affects approximately 0.2% of pregnancies and
is associated with fetal death, low birth weight, intrauterine growth
restriction, and preeclampsia.40 Graves disease accounts for 95% of
hyperthyroidism in pregnancy. Therapy includes the thioamides
(initial doses are propylthiouracil 100150 mg or methimazole
520 mg). Either agent is given three times daily with dose reduc-
tion after becoming euthyroid. Surgery is reserved for the most
severe cases. The risks of uncontrolled hyperthyroidism outweigh
the risks of the thioamides. Iodine-131 is contraindicated because
of the risk of thyroid damage in the fetus. The goal of therapy is to
attain free thyroxine concentrations near the upper limit of nor-
mal to allow for dose minimization and to limit fetal or neonatal
hypothyroidism.
LABOR AND DELIVERY
Management of the pregnant woman during the perinatal period
often requires drug therapy for pain and for potential complications.
PRETERM LABOR
Preterm labor occurs when there are cervical changes and uterine
contractions between 20 and 37 weeks gestation.67,68 Preterm birth
is the leading cause of infant morbidity and mortality in the United
States, with an incidence of 12.8%. Risk factors for preterm deliv-
ery include previous preterm delivery, infections, multiple gesta-
tion, poverty, nonwhite race, maternal complication factors (e.g.,
smoking and use of illicit drugs or alcohol), and uterine functional
causes (e.g., incompetent cervix); previous history and prior second
trimester loss confer a higher risk.67,68
No adequate tests are available for monitoring and preventing
preterm labor. Monitoring of uterine activity along with inten-
sive surveillance does not minimize risk.68 The presence of fetal
fibronectin, a glycoprotein found in cervicovaginal secretions,
indicates a high risk of preterm birth. Cervical shortening is also
associated with preterm delivery. Fetal fibronectin determinations
and cervical ultrasound have not helped to prevent preterm labor
but have been useful for their negative predictive value.68
Tocolytic Therapy
The purposes of tocolytic therapy are threefold: (a) postpone
delivery long enough to allow for the maximum effect of antenatal
steroid administration; (b) allow for transportation of the mother
to a facility equipped to deal with high-risk deliveries; and (c)
prolongation of pregnancy when there are underlying, self-limited
conditions that can cause labor, such as pyelonephritis or abdomi-
nal surgery, that are unlikely to cause recurrent preterm labor.6870
Tocolytics have not reduced the number of premature deliveries.
The criteria for starting tocolysis are regular uterine contractions
with cervical change. Tocolytic therapy should not be used in cases
of intrauterine fetal demise, a lethal fetal anomaly, intrauterine
infection, fetal distress, severe preeclampsia, vaginal bleeding, or
maternal hemodynamic instability.
Four classes of tocolytics are available in the United States:
-agonists, magnesium, calcium channel blockers, and NSAIDs.71
All four therapies have similar effectiveness in prolonging preg-
nancy from 48 hours to 1 week. However, this prolongation of preg-
nancy was not associated with a statistically significant reduction in
overall rates of respiratory distress syndrome or neonatal death.
The -agonists terbutaline and ritodrine have been used for toco-
lytic therapy.69 Ritodrine is no longer available in the United States.
Relative to other agents, -agonists have a higher incidence of
maternal side effects, including hyperkalemia, arrhythmias, hyper-
glycemia, hypotension, and pulmonary edema. Recommended
terbutaline doses range from 250 to 500 mcg subcutaneously every
3 to 4 hours.70
Intravenous magnesium sulfate has been used for tocolysis;
however, a Cochrane review does not support its effectiveness.72
Heterogeneity of study designs and results along with small treat-
ment arms in included studies may partially explain this finding;

however, its use remains controversial.69 The incidence of cerebral
palsy is increased in premature infants. In one study, intravenous
magnesium use (6 g load followed by 2 g per hour continuous
infusion) decreased the occurrence of moderate or severe cerebral
palsy.73 Although not the primary end point, the study suggests that
women at risk for imminent delivery (up to 34 weeks gestation)
should receive intravenous magnesium. Maternal side effects are
rare but can include pulmonary edema. At toxic levels, hypotension,
muscle paralysis, tetany, cardiac arrest, and respiratory depression
may occur.70 Magnesium undergoes renal excretion; dose adjust-
ment is required in women with impaired renal function.
CURRENT CONTROVERSY
Intravenous magnesium sulfate is commonly used in the
United States for tocolysis. Some advocate cessation of its use
because a Cochrane review found no difference in preterm
delivery in the 48 hours after administration and an increase
in perinatal death.69,72
Nifedipine is associated with fewer side effects than magnesium
or -agonist therapy.69 Several studies have suggested that calcium
channel blockers are superior to -agonists for prolonging labor.
One concern with the use of nifedipine is its hypotensive effect
and corresponding change in uteroplacental blood flow. However,
a meta-analysis showed reduced neonatal morbidity with calcium
channel blocker use. With the initial diagnosis of preterm labor, 5
to 10 mg nifedipine can be administered sublingually every 15 to
20 minutes for three doses. After patient stabilization, if no evidence
of continuing cervical dilation is seen, 10 to 20 mg nifedipine can be
administered orally every 4 to 6 hours for preterm contractions.70
Nonsteroidal antiinflammatory drugs such as indomethacin have
been used for tocolysis.69,70 Oral or rectal doses of 50 to 100 mg, fol-
lowed by an oral dose of 25 to 50 mg every 6 hours, have been used.
An increased rate of premature constriction of the ductus arteriosus
has been noted in infants with indomethacin use after 32 weeks
gestation and with use exceeding 48 hours.69 Indomethacin may be
used when tocolysis is needed despite treatment with magnesium
for neuroprotection because other agents, such as calcium channel
blockers, can cause hypotension when administered concurrently
with magnesium.
Other Drug Therapies for Preterm Labor Prevention
Infection is a potential cause of preterm labor. Antibiotics have been
used, in addition to tocolytics and corticosteroids, to improve the
outcome of preterm labor; however, a Cochrane review showed no
reduction in the incidence of preterm delivery but a trend toward
increased neonatal mortality. Therefore, routine use of antibiotics
is not recommended. However, if a patient experiences preterm
premature rupture of membranes (PPROM) before 34 weeks gesta-
tion, prophylactic antibiotics should be initiated. The combination
of initial intravenous therapy (48 hours) with ampicillin and eryth-
romycin, followed by 5 days of oral therapy with the same antibiot-
ics, decreased the likelihood of chorioamnionitis and delivery for
3 weeks. Additionally, a reduction in major morbidities (i.e., death,
respiratory distress syndrome, early sepsis, severe intraventricular
hemorrhage, and necrotizing enterocolitis) was demonstrated.74
Progesterone administration in the setting of prior preterm birth
is much debated. Two large randomized, controlled trials produced
significant findings. First, the administration of intramuscular
17-alpha-hydroxyprogesterone weekly (250 mg) starting between
weeks 16 and 20 and continued through week 36 in high-risk
1371
women decreased the incidence of recurrent preterm birth.75 The
second study replicated the findings using vaginal progesterone
CHAPTER 87
suppositories (100 mg).76 However, progesterone supplementation
in women whose previous preterm birth occurred beyond 34 weeks
produced similar rates of preterm delivery compared with placebo.77
The American College of Obstetrics and Gynecology currently rec-
ommends that progesterone supplementation be limited to women
with a singleton pregnancy and a previous history of spontaneous
preterm birth.78
Pregnancy and Lactation: Therapeutic Considerations
Antenatal Corticosteroids
 Use of antenatal corticosteroids for fetal lung maturation to
prevent respiratory distress syndrome, intraventricular hemor-
rhage, and death in infants delivered prematurely is supported by
a Cochrane review.79 The current clinical recommendation is to
administer betamethasone 12 mg intramuscularly every 24 hours
for two doses or dexamethasone 6 mg intramuscularly every 12
hours for four doses to pregnant women between 26 and 34 weeks
gestation who are at risk for preterm delivery within the next 7 days.
Benefits from antenatal corticosteroids are believed to begin within
24 hours.
Salvage (rescue) treatment is administered to women who are
at risk of delivering within 7 days but who have received a previous
course of therapy. The incidence of respiratory distress syndrome
was lower with the administration of rescue steroids compared with
placebo (41.4% with betamethasone vs. 61.6% with placebo).80
GROUP B STREPTOCOCCUS INFECTION
 Maternal infection with group B Streptococcus (GBS) is associ-
ated with invasive disease in the newborn.81,82 Women colonized
with GBS have an increased risk for pregnancy loss, premature
delivery, and transmission of the bacteria to the infant during
delivery. Between 10% and 30% of pregnant women are colonized
with GBS. The rate of invasive infection (defined as isolation of GBS
from blood or other sterile body site excluding urine) in pregnant
women is 0.12 per 1000 live births (range 0.11 to 0.14 per 1,000
births). The incidence of early-onset disease in neonates, although
higher than in pregnant women, has declined steadily from 1.8 per
1,000 live births in 1990 to approximately 0.34 cases per 1,000 live
births during 2003 to 2005. The consequences of neonatal infections
include bacteremia, pneumonia, meningitis, and fatality in the new-
born.82 The case-fatality rate is approximately 4%.
Recommendations for prevention of GBS infection were updated
in 2002.82 Universal prenatal screening for GBS colonization is
recommended. Antibiotics are given if the woman previously gave
birth to an infant with invasive GBS disease or in the presence of
GBS bacteriuria. All other pregnant women should have a vaginal/
rectal culture at 35 to 37 weeks gestation. If negative, antibiotics
are not indicated. If a woman presents in labor and no screening
information is available, antibiotics are given for fever greater than
100.4F (38C), membrane rupture at least 18 hours prior, or gesta-
tion under 37 weeks.
Penicillin G 5 million units given intravenously, followed by
2.5 million units given every 4 hours until delivery is the recom-
mended treatment regimen.82 Alternatively, ampicillin 2 g can be
given intravenously, followed by 1 g every 4 hours. For women
with penicillin allergy but not at risk for anaphylaxis, cefazolin 2 g
intravenously, followed by 1 g every 8 hours, is recommended. In
women at high risk for anaphylaxis, clindamycin 900 mg intrave-
nously every 8 hours or erythromycin 500 mg intravenously every
6 hours is recommended. For penicillin-allergic women, GBS cul-
tures should be sent for sensitivities. If resistant to clindamycin or
erythromycin, vancomycin 1 g intravenously every 12 hours until
delivery is appropriate.
1372
CERVICAL RIPENING AND LABOR INDUCTION
SECTION 9
Throughout gestation the cervix is closed and firm. During the last
few weeks of pregnancy, the cervix softens and thins to facilitate
labor.83,84 This process is mediated by hormonal changes, including
final mediation by prostaglandins E2 and F2, which increase col-
lagenase activity in the cervix leading to thinning and dilation.
The rate of pregnancy induction ranges from 9.5% to 33.5%; the
most common indications for induction are postdatism (beyond
42 weeks) and pregnancy-induced hypertension, which account for
80% of inductions.83,84 Other reasons for induction include suspected
Gynecologic and Obstetric Disorders
fetal growth retardation, maternal hypertension, premature rupture
of membranes with no active onset of labor, and social factors.
Contraindications include placenta previa, oblique or transverse lie,
pelvic structure abnormality, prolapsed umbilical cord, and active
herpes. Concerns with induction of labor are ineffective labor and
side effects, such as uterine hyperstimulation, that may adversely
affect the infant and increase the likelihood of cesarean section.
Scoring systems have been used to determine the likelihood of
successful labor induction. The Bishop scoring system is most com-
monly used and is based on five parameters: cervical dilation, cervi-
cal effacement (thinning), station of the babys head, consistency
of the cervix, and position of the cervix.83,84 A Bishop score under
6 indicates the need for cervical ripening while a score above 8 cor-
responds to a likely successful vaginal delivery.
A number of nonpharmacologic methods are used for cervi-
cal ripening. Castor oil, hot baths, sexual intercourse, and nipple
stimulation all have been suggested for labor induction.83 Minimal
evidence supports the efficacy of these methods. Use of a Foley
catheter placed in an unfavorable cervix for ripening has been
found as effective as prostaglandin E2. Membrane stripping is safe
and inexpensive.83,84
Prostaglandin E2 analogs (e.g., dinoprostone [Prepidil gel, Cervidil
vaginal insert]) are commonly used for cervical ripening. Prepidil 500
mcg is administered intracervically.84 The dose may be repeated after
6 hours to a maximum of three doses in 24 hours. After administra-
tion, the patient remains supine for 30 minutes. Cervidil contains
10 mg dinoprostone with a slower, more constant release of medica-
tion than the gel. The insert is removed when labor begins or after
12 hours. Patients must be attached to a fetal heart rate monitor for
the duration of Cervidil use and for 15 minutes after its removal.83
Misoprostol, a prostaglandin E1 analog, is an effective and
inexpensive drug for cervical ripening and labor induction.84
Intravaginal administration of misoprostol is more effective than
other prostaglandin agents and results in a shorter time to delivery.
Oral misoprostol has been used successfully for cervical ripening
and labor induction, but the evidence of safety is more extensive
with intravaginal use. The most commonly encountered side effects
are uterine hyperstimulation and meconium-stained amniotic fluid.
Use of misoprostol is contraindicated in women with a previous
uterine scar because of its association with uterine rupture, a cata-
strophic medical event.
CURRENT CONTROVERSY
Despite its efficacy and comparatively reasonable cost, some
health systems have decided not to use misoprostol as an
induction agent because of concerns about uterine rupture
and lack of FDA indication for cervical ripening.84
Progesterone inhibits uterine contractions. Preliminary studies
show that mifepristone, an antiprogesterone agent, compared with
placebo results in a shorter time to delivery and fewer cesarean
sections.85 Limited information on fetal and maternal outcomes is
available because of the small sample sizes.
Oxytocin is the most commonly used agent for labor induction
after cervical ripening. By the end of pregnancy, the number of
oxytocin receptors has increased by 300-fold.83,84 A solution of 10
milliunits/mL is used for infusion. Oxytocin is effective in both low-
dose (physiologic) and high-dose (pharmacologic) regimens.
LABOR ANALGESIA
In the first phase of labor, women perceive visceral pain caused by
uterine contractions. Pain in the second phase of labor is associated
with perineal stretching.86
Nonpharmacologic Approaches to Analgesia
Women who receive continuous support from nurses, midwives,
childbirth educators, or doulas [laywomen trained in labor sup-
port], have fewer operative vaginal deliveries, cesarean deliveries,
and requests for pain medication.87 Warm water baths provide
temporary pain relief but have not been shown to decrease the
use of pharmacologic pain treatments. Intradermal injections of
sterile water in the sacral area decrease back pain during labor
for 45 to 120 minutes. However, requests for pain medication
did not decrease in studies. Acupuncture has also been used for
pain relief. Three randomized, controlled trials have shown that
acupuncture decreases the need for analgesia, but more method-
ologically sound studies are needed. Use of audioanalgesia (music
or white noise), relaxation and breathing techniques, application
of heat and cold, aromatherapy, acupressure, and hypnosis have
little to no evidence of effectiveness derived from randomized,
controlled trials.
Pharmacologic Approaches
to Labor Pain Management
The American College of Obstetricians and Gynecologists supports
the concept that maternal request alone is a sufficient medical indi-
cation for labor analgesia.88 The two main types of pharmacologic
approaches in the United States are parenteral opioids and epidural
analgesia.
Parenteral opioids are commonly used to alleviate labor pain.89 In
comparison with epidural analgesia, parenteral opioids have lower
rates of oxytocin augmentation, result in shorter stages of labor, and
require fewer instrumental deliveries.
Approximately 60% of women in the United States choose an
epidural for pain relief during labor and report better pain relief
than with other analgesic modalities.89 With epidural analgesia, a
catheter is introduced into the epidural space and an opioid and/
or an anesthetic (e.g., fentanyl and/or bupivacaine) is administered.
Combined spinalepidural analgesia consists of injecting a single
opioid bolus into the subarachnoid space to provide instant pain
relief with additional use of a local anesthetic epidural. Patient-
controlled epidural analgesia allows the patient to control the
amount and timing of the anesthetic; it results in a lower total dose
of local anesthetics used over the course of labor compared with
continuous epidural infusions.90
Side effects of the regional anesthesia include hypotension, pru-
ritus, and inability to void.89 Epidural analgesia is associated with
prolongation of the first and second stages of labor, higher numbers
of instrumental deliveries, and maternal fever. A rare complication
of epidural anesthesia is puncture of the subarachnoid space leading
to a severe headache, which occurs in approximately 1% of women.
Other complications include hypotension, nausea, vomiting, itch-
ing, and urinary retention. Low back pain has not been associated
with the use of epidural analgesia.

POSTPARTUM HEMORRHAGE
The placenta is delivered after the delivery of the baby and is
referred to as the third stage of labor. Postpartum hemorrhage is
an obstetrical emergency and is a major cause of morbidity and
mortality.91 In the United States, the postpartum hemorrhage rate
is approximately 1%5% for vaginal deliveries.92 The traditional
definition of postpartum hemorrhage is more than 500 mL of blood
within 24 hours of a vaginal delivery or 1,000 mL after a cesarean
section; however, other definitions have also been suggested. Risk
factors include retained placenta, failure to progress during the
second stage of labor, placenta previa, placenta accreta, lacerations,
instrumental delivery, large for gestational newborn, hypertensive
disorders, induction of labor, augmentation of labor with oxytocin,
prior history, obesity, and high parity.93
The most common cause of postpartum hemorrhage is uter-
ine atony.91,92 Initial management should include oxytocin. Early
clamping and cutting of the umbilical cord as well as controlled
traction of the cord also decrease the incidence.91 Administration
of a uterotonic medication (intramuscular oxytocin, ergotamine, or
combination) before placental delivery and instituting active man-
agement of labor after all uncomplicated vaginal deliveries results
in reduced maternal blood loss, fewer cases of postpartum hemor-
rhage, and less prolongation of the third stage of labor. Other utero-
tonic agents should be used if an inadequate response is attained
with oxytocin alone. Methylergonovine, carboprost, misoprostol,
and dinoprostone have all been used; less evidence is available for
misoprostol and dinoprostone.
POSTPARTUM ISSUES
DRUG USE DURING LACTATION
 Most drugs transfer into breast milk, but breast-feeding may
be continued in most circumstances. Healthcare providers should
encourage breast-feeding women who require medications to
continue breast-feeding whenever possible. Medications that are
contraindicated or require the mother to pump and discard milk
are few.
A wide variety of benefits (health, nutritional, immunologic, psy-
chological, economic, developmental, and social) are imparted by
breast-feeding to infants, mothers, and the family.94,95 Women should
breast-feed exclusively for 6 months and continue until at least
12 months of age while other foods are introduced.95 Healthy People
2010 set a target of 75% of neonates being breast-fed at the time of
birth and 50% of infants being breast-fed at 6 months of age.
Most drugs reach breast milk through passive diffusion, but other
drug-related factors influence drug transfer from maternal circula-
tion into breast milk, including (a) degree of protein binding in
maternal plasma, (b) molecular weight, (c) lipid solubility (and cor-
responding fat content of milk), (d) maternal plasma concentration,
(e) drug half-life, and (f) drug pH.94,96 The degree of protein binding
to maternal plasma proteins is one of the most significant factors
affecting drug transfer to breast milk; highly bound medications
transfer in low amounts. Low-molecular-weight drugs passively dif-
fuse into breast milk, but larger molecules are not likely to transfer
in large amounts. Higher lipid solubility of drugs also increases
the likelihood of transfer. Colostrum is secreted in the first couple
of days after birth and has high quantities of immunoglobulins,
maternal lymphocytes, and maternal macrophages. Compared with
mature milk, colostrum is lower in fat content, so highly lipid soluble
drugs achieve higher concentrations in mature milk. The higher the
concentration of drug in the mothers serum, the higher the con-
centration will be in the breast milk. As the drug is metabolized and
1373
excreted by the mother, the mothers serum concentration drops,
and drug in the breast milk may redistribute back into the mothers
CHAPTER 87
bloodstream. Maternal plasma pH is 7.4, while the pH of breast milk
ranges between 6.8 and 7.96 Weak bases are not ionized in the mater-
nal circulation and easily transfer to breast milk. In the lower pH of
breast milk, molecules become ionized and are less likely to diffuse
back into maternal circulation (ion trapping). Likewise, drugs with
longer half-lives are more likely to maintain higher levels in breast
milk, resulting in greater exposure to the infant.
Infant-related factors may also influence the amount of drug
Pregnancy and Lactation: Therapeutic Considerations
ingested through breastfeeding.94 Both the frequency of feedings
and the amount of milk ingested are important considerations.
Exclusively breast-fed infants are more likely to ingest larger amounts
of drugs than older infants who receive other foods. Drugs unstable
in gastric acid (aminoglycosides, omeprazole, heparin, insulin) are
less likely to be absorbed by infants. Finally, infants may vary in their
ability to metabolize and excrete ingested medication. Premature
and full-term infants may not have full renal and liver function.
Strategies for reducing the risk to the infant include selection of
medications that would be considered safe for use in the infant.96
Drugs with shorter half-lives accumulate less, and those that are
more protein bound do not cross into breast milk as well as those
that are less protein bound. Drugs with lower oral bioavailability
and lower lipid solubility are good choices. If the mother is using
a once-daily medication, administration before the infants longest
sleep period may be advised to increase the interval to the next feed-
ing. For medications taken multiple times per day, administration
immediately after breast-feeding provides the longest interval for
back diffusion of drug from the breast milk to the mothers serum.
During short-term drug therapy, the mother can pump and discard
milk to preserve her milk-producing capability if the medication is
not considered compatible with breast-feeding.94
Industry-based research on transfer of drugs into breast milk
is scarce.94 Information from expert committees (e.g., American
Academy of Pediatrics Committee on Drugs) and evidence-based
textbooks or Web sites may be of assistance in providing reassur-
ance regarding the safe use of medications in the lactating mother.
MASTITIS
Mastitis is inflammation in one breast.97 It can be infectious or
noninfectious; the most common cause is milk stasis. About 10%
of women in the United States experience mastitis during the
first 3 months postpartum. Signs and symptoms include breast
tenderness, redness, warmth, and flulike symptoms.98 Risk factors
for developing mastitis include breast engorgement, plugged milk
ducts, and cracked nipples.
Staphylococcus aureus is the most common bacterial cause of
mastitis; E. coli and Streptococcus have also been implicated.97,98 A
10- to 14-day course of antibiotics is usually given for treatment
of mastitis; penicillinase-resistant penicillins (e.g., dicloxacillin,
oxacillin) and cephalosporins (e.g., cephalexin) are frequently pre-
scribed. Antiinflammatory drugs, such as ibuprofen, may provide
some pain relief. Application of heat may also be helpful. Affected
women should be counseled to continue breast-feeding from both
breasts throughout treatment and to pump if breasts are not emp-
tied completely with feedings.
POSTPARTUM DEPRESSION
Mood disorders in the postpartum period may include postpar-
tum blues, postpartum depression, and postpartum psychosis.99
Postpartum blues is common, usually affecting 15% to 85% of new
mothers within the first 10 days of delivery, and generally does not
require treatment. Symptoms include anxiety, anger, and sadness.
1374
Postpartum psychosis is more severe but is rare, affecting less than
1% of new mothers.
SECTION 9
Postpartum depression affects up to 15% of women.99 Symptoms
may develop during pregnancy or up to 6 months after deliv-
ery, although the strict definition for major depressive disorder
after delivery specifies symptom occurrence within 1 month.
Psychotherapy, including interpersonal psychotherapy, cognitive
behavioral therapy, and group/family therapy, has been shown
effective for treatment of postpartum depression.
In cases where pharmacotherapy is warranted, selection of medi-
Gynecologic and Obstetric Disorders
cation with low transfer to breast milk is desirable. Sertraline is
generally considered a first-line treatment because of its minimal
transfer into breast milk and lack of reported adverse events in
infants.94,99 Paroxetine and nortriptyline are considered second-line.
CURRENT CONTROVERSY
Treatment of postpartum depression in the breast-feeding
mother poses challenges since all antidepressants transfer
into breast milk, and long-term effects on cognitive, behav-
ioral, motor, and neurologic development are unknown.99
Postpartum depression poses significant risks to both mother
and infant. Benefits and risks of pharmacologic and nonphar-
macologic therapy must be weighed in selecting treatments for
women with postpartum depression.
RELACTATION
Adequate milk removal from the breast by breastfeeding or pumping
is necessary to maintain or increase milk production.100 Relactation
is the process of increasing the breast milk supply for women who
have failed lactogenesis II, who have inadequate milk production
despite appropriate breastfeeding frequency or pumping, or who
have weaned or never breast-fed after delivery. Lactation can also
be induced in women who have not recently delivered a baby, such
as adoptive mothers. The mainstay of therapy for this condition
involves nipple stimulation either by the infants nursing or by
pumping of the breast with a mechanical pump or the hand.
Metoclopramide can be used for relactation if nonpharmacologic
measures are ineffective because of its stimulation of prolactin
secretion.100 The most common dose is 10 mg orally three times
daily for 7 to 14 days. Breast milk production can be increased up
to 100% or more in women, although many of the studies have
inadequate designs. Breast milk production may decrease after
metoclopramide therapy is stopped, but production will continue if
lactation has been established successfully.
CONCLUSION
Many women perceive a high inherent risk of birth defects with
drug exposure during pregnancy. This perception, linked with a
high rate of unplanned pregnancies, may create anxiety because of
drug exposure prior to the discovery of pregnancy.
Some medications are considered safe for use in pregnancy
because of frequent use with no apparent increase in the rate of con-
genital problems. In some cases, ensuring the health of the mother
and the fetus will require selection or continuation of medications
that have been associated with a higher risk of adverse effects to the
fetus. In these instances, realistic information about the types and
likelihood of adverse effects will aid the patient and her family in
making decisions.
Healthcare providers who care for pregnant women must
work in collaboration to seek, evaluate, and present the most
contemporary and accurate information to their patients. Use of
technology to access evidence-based resources, databases related
to drug use in pregnancy, and primary and secondary literature
may assist healthcare practitioners in accessing relevant medica-
tion information to manage drug therapy needs during pregnancy
and lactation.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the work of Denise L. Walbrandt
Pigarelli, Connie K. Kraus, and Beth E. Potter, who served as
authors in the 7th edition of Pharmacotherapy: A Pathophysiologic
Approach.
ABBREVIATIONS
FDA: Food and Drug Administration
GBS: group B Streptococcus
GDM: gestational diabetes mellitus
HAART: highly active antiretroviral therapy
hCG: human chorionic gonadotropin
HEG: hyperemesis gravidarum
HIV: human immunodeficiency virus
NNRTI: nonnucleoside reverse transcriptase inhibitor
NRTI: nucleoside reverse transcriptase inhibitor
NSAIDs: nonsteroidal antiinflammatory drugs
NTDs: neural tube defects
PPROM: preterm premature rupture of the membranes
SSRIs: selective serotonin reuptake inhibitors
TSH: thyroid stimulating hormone
REFERENCES
1. Ord T. The scourge: Moral implications of natural embryo loss. Am
J Bioeth 2008;8:129.
2. Brent RL. Environmental causes of human congenital malformations:
The pediatricians role in dealing with these complex clinical prob-
lems caused by a multiplicity of environmental and genetic factors.
Pediatrics 2004;113(4 suppl):957968.
3. Talbot P, Shur BD, Myles DG. Cell adhesion and fertilization: Steps in
oocyte transport, sperm-zona pellucida interactions, and sperm-egg
fusion. Biol Reprod 2003;68:19.
4. Cunningham FG, Leveno KJ, Bloom SL, et al. Implantation, embryo-
genesis, and placental development. In: Cunningham FG, Leveno KJ,
Bloom SL, et al. Williams Obstetrics, Chap. 3, 22nd ed., http://www.
accessmedicine.com/content.aspx?aID=728347.
5. Bernstein HB, Weinstein M. Normal pregnancy and prenatal
care. In: DeCherney AH, Nathan L, eds. Current Diagnosis and
Treatment Obstetrics and Gynecology, Chap. 9, 10th ed.: http://www.
accessmedicine.com/content.aspx?aID=2384287.
6. Cunningham FG, Leveno KJ, Bloom SL, et al. Fetal growth and devel-
opment. In: Cunningham FG, Leveno KJ, Bloom SL, et al. Williams
Obstetrics, Chap. 4, 22nd ed.: http://www.accessmedicine.com/
content.aspx?aID=733548.
7. Cunningham FG, Leveno KJ, Bloom SL, et al. Prenatal care. In:
Cunningham FG, Leveno KJ, Bloom SL, et al. Williams Obstetrics,
Chap. 8, 22nd ed.: http://www.accessmedicine.com/content.
aspx?aID=742204.

8. McCarter-Spaulding DE. Medications in pregnancy and lactation.
MCN Am J Matern Child Nurs 2005;30:1017.
9. Kahn DA, Koos BJ. Maternal physiology during pregnancy. In:
DeCherney AH, Nathan L, eds. Current Diagnosis and Treatment
Obstetrics and Gynecology, Chap. 7, 10th ed.: http://www.
accessmedicine.com/content.aspx?aID=2383850.
10. Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the
human placenta. Clin Pharmacokinet 2004;43:487514.
11. Polifka JE, Friedman JM. Medical genetics, I: Clinical teratology in the
age of genomics. CMAJ 2002;167:265273.
12. Irl C, Hasford J. Assessing the safety of drugs in pregnancy: The role of
prospective cohort studies. Drug Saf 2000;22:169177.
13. Schaefer C, Ornoy A, Clementi M, et al. Using observational cohort
data for studying drug effects on pregnancy outcomeMethodologi-
cal considerations. Reprod Toxicol 2008;26:3641.
14. Content and format of labeling for human prescription drug and
biological products: Requirements for pregnancy and lactation
labeling (proposed rules). Federal Register 73:104 (May 29, 2008):
3083130868.
15. Johnson K, Posner SF, Biermann J, et al. Recommendations to improve
preconception health and health careUnited States. A report of the
CDC/ATSDR Preconception Care Work Group and the Select Panel
on Preconception Care. MMWR Recomm Rep 2006;55(RR-6):123.
16. Korenbrot CC, Steinberg A, Bender C, Newberry S. Preconception
care: A systematic review. Matern Child Health J 2002;6:7588.
17. Folic acid for the prevention of neural tube defects: U.S. Preventive
Services Task Force recommendation statement. Ann Intern Med
2009;150:626631.
18. Lumley J, Chamberlain C, Dowswell T, et al. Interventions for promot-
ing smoking cessation during pregnancy. Cochrane Database Syst Rev
2009(3):CD001055.
19. Coleman T. Recommendations for the use of pharmacological smok-
ing cessation strategies in pregnant women. CNS Drugs 2007;21:
983993.
20. Benowitz N, Dempsey D. Pharmacotherapy for smoking cessation
during pregnancy. Nicotine Tob Res 2004;6(suppl 2):S189202.
21. Keller J, Frederking D, Layer P. The spectrum and treatment of gas-
trointestinal disorders during pregnancy. Nat Clin Pract Gastroenterol
Hepatol 2008;5:430443.
22. Mahadevan U, Kane S. American gastroenterological association
institute technical review on the use of gastrointestinal medications in
pregnancy. Gastroenterology 2006;131:283311.
23. Quijano CE, Abalos E. Conservative management of symptomatic
and/or complicated haemorrhoids in pregnancy and the puerperium.
Cochrane Database Syst Rev 2005(3):CD004077.
24. Badell ML, Ramin SM, Smith JA. Treatment options for nausea and
vomiting during pregnancy. Pharmacotherapy 2006;26:12731287.
25. Diagnosis and classification of diabetes mellitus. Diabetes Care
2009;32(suppl 1):S6267.
26. Serlin DC, Lash RW. Diagnosis and management of gestational diabe-
tes mellitus. Am Fam Physician 2009;80:5762.
27. Screening for gestational diabetes mellitus: U.S. Preventive Services
Task Force recommendation statement. Ann Intern Med 2008;148:
759765.
28. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and rec-
ommendations of the Fifth International Workshop-Conference
on Gestational Diabetes Mellitus. Diabetes Care 2007;30(suppl 2):
S251260.
29. de Veciana M, Major CA, Morgan MA, et al. Postprandial versus pre-
prandial blood glucose monitoring in women with gestational diabetes
mellitus requiring insulin therapy. N Engl J Med 1995;333:12371241.
30. Reece EA, Homko CJ. Prepregnancy care and the prevention of fetal
malformations in the pregnancy complicated by diabetes. Clin Obstet
Gynecol 2007;50:990997.
31. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of ges-
tational diabetes mellitus on pregnancy outcomes. N Engl J Med
2005;352:24772486.
32. Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes.
Cochrane Database Syst Rev 2009(3):CD003395.
33. Leeman L, Fontaine P. Hypertensive disorders of pregnancy. Am Fam
Physician 2008;78:93100.
1375
34. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive
drug therapy for mild to moderate hypertension during pregnancy.
CHAPTER 87
Cochrane Database Syst Rev 2007(1):CD002252.
35. Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation
for prevention of pre-eclampsia and related problems: A systematic
review and commentary. BJOG 2007;114:933943.
36. Podymow T, August P. Update on the use of antihypertensive drugs in
pregnancy. Hypertension 2008;51:960969.
37. Duley L, Henderson-Smart DJ, Meher S. Drugs for treatment of very
high blood pressure during pregnancy. Cochrane Database Syst Rev
2006(3):CD001449.
Pregnancy and Lactation: Therapeutic Considerations
38. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents
for preventing pre-eclampsia and its complications. Cochrane Database
Syst Rev 2007(2):CD004659.
39. Duley L, Meher S, Abalos E. Management of pre-eclampsia. BMJ
2006;332:463468.
40. Neale DM, Cootauco AC, Burrow G. Thyroid disease in pregnancy.
Clin Perinatol 2007;34:543557.
41. Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynecol
2006;108:12831292.
42. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism,
thrombophilia, antithrombotic therapy, and pregnancy: American
College of Chest Physicians Evidence-Based Clinical Practice
Guidelines, 8th ed. Chest 2008;133(6 suppl):844S886S.
43. Mittal P, Wing DA. Urinary tract infections in pregnancy. Clin
Perinatol 2005;32:749764.
44. Schnarr J, Smaill F. Asymptomatic bacteriuria and symptomatic uri-
nary tract infections in pregnancy. Eur J Clin Invest 2008;38(suppl 2):
5057.
45. Vazquez JC, Villar J. Treatments for symptomatic urinary
tract infections during pregnancy. Cochrane Database Syst Rev
2003(4):CD002256.
46. Workowski KA, Berman SM. Sexually transmitted diseases treatment
guidelines, 2006. MMWR Recomm Rep 2006;55(RR-11):194.
47. ACOG Practice Bulletin. Clinical management guidelines for obste-
trician-gynecologists. No. 82 June 2007. Management of herpes in
pregnancy. Obstet Gynecol 2007;109:14891498.
48. Menon R, Bushnell CD. Headache and pregnancy. Neurologist
2008;14:108119.
49. Martin SR, Foley MR. Approach to the pregnant patient with head-
ache. Clin Obstet Gynecol 2005;48:211.
50. Schatz M, Dombrowski MP. Clinical practice: Asthma in pregnancy.
N Engl J Med 2009;360:18621869.
51. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and
Management of AsthmaSummary Report 2007. J Allergy Clin
Immunol 2007;120(5 suppl):S94138.
52. Global Strategy for Asthma Management and Prevention. Update
from NHLB/WHO Workshop Report 1995. Global Initiative for
Asthma (GINA), revised 2006: updated 2008.
53. Gilbert C, Mazzotta P, Loebstein R, Koren G. Fetal safety of drugs
used in the treatment of allergic rhinitis: A critical review. Drug Saf
2005;28:707719.
54. Piette V, Daures JP, Demoly P. Treating allergic rhinitis in pregnancy.
Curr Allergy Asthma Rep 2006;6:232238.
55. Leachman SA, Reed BR. The use of dermatologic drugs in pregnancy
and lactation. Dermatol Clin 2006;24:167197.
56. Preconception care of women with diabetes. Diabetes Care
2004;27(suppl 1):S7678.
57. Harden CL, Hopp J, Ting TY, et al. Management issues for women
with epilepsy-Focus on pregnancy (an evidence-based review), I:
Obstetrical complications and change in seizure frequency: Report of
the Quality Standards Subcommittee and Therapeutics and Technology
Assessment Subcommittee of the American Academy of Neurology
and the American Epilepsy Society. Epilepsia 2009;50:12291236.
58. Tomson T, Battino D. Pregnancy and epilepsy: What should we tell
our patients? J Neurol 2009;256:856862.
59. Harden CL, Sethi NK. Epileptic disorders in pregnancy: an overview.
Curr Opin Obstet Gynecol 2008;20:557562.
60. Harden CL, Meador KJ, Pennell PB, et al. Management issues
for women with epilepsy-Focus on pregnancy (an evidence-based
review), II: Teratogenesis and perinatal outcomes: Report of the
1376
Quality Standards Subcommittee and Therapeutics and Technology
Subcommittee of the American Academy of Neurology and the
SECTION 9
American Epilepsy Society. Epilepsia 2009;50:12371246.
61. Perinatal HIV Guidelines Working Group. Public Health Service Task
Force Recommendations for Use of Antiretroviral Drugs in Pregnant
HIV-Infected Women for Maternal Health and Interventions to
Reduce Perinatal HIV Transmission in the United States. April 29,
2009:190, http://aidsinfo.nih.gov/contentfiles/perinatalgl.pdf.
62. Karthikeyan VJ, Lip GY. Hypertension in pregnancy: Pathophysiology
and management strategies. Curr Pharm Des 2007;13:25672579.
63. ACOG Practice Bulletin: Clinical management guidelines for obstetri-
Gynecologic and Obstetric Disorders
cian-gynecologists number 92, April 2008 (replaces practice bulletin
number 87, November 2007). Use of psychiatric medications during
pregnancy and lactation. Obstet Gynecol 2008;111:10011020.
64. Van Mullem C, Tillett J. Psychiatric disorders in pregnancy. J Perinat
Neonatal Nurs 2009;23:124130.
65. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective
serotonin-reuptake inhibitors and risk of persistent pulmonary hyper-
tension of the newborn. N Engl J Med 2006;354:579587.
66. Levey L, Ragan K, Hower-Hartley A, et al. Psychiatric disorders in
pregnancy. Neurol Clin 2004;22:863893.
67. Damus K. Prevention of preterm birth: A renewed national priority.
Curr Opin Obstet Gynecol 2008;20:590596.
68. Chandiramani M, Shennan A. Preterm labour: update on predic-
tion and prevention strategies. Curr Opin Obstet Gynecol 2006;18:
618624.
69. Giles W, Bisits A. Preterm labour: The present and future of tocolysis.
Best Pract Res Clin Obstet Gynaecol 2007;21:857868.
70. Weismiller DG. Preterm labor. Am Fam Physician 1999;59:593602.
71. Haas DM, Imperiale TF, Kirkpatrick PR, et al. Tocolytic therapy:
A meta-analysis and decision analysis. Obstet Gynecol 2009;113:
585594.
72. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for prevent-
ing preterm birth in threatened preterm labour. Cochrane Database
Syst Rev 2002(4):CD001060.
73. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of
magnesium sulfate for the prevention of cerebral palsy. N Engl J Med
2008;359:895905.
74. American College of Obstetricians and Gynecologists. Premature rup-
ture of membranes. Practice Bulletin No. 80. Washington, DC: ACOG;
2007a.
75. Meis PJ, Connors N. Progesterone treatment to prevent preterm birth.
Clin Obstet Gynecol 2004;47:784795; discussion 881882.
76. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic
administration of progesterone by vaginal suppository to reduce the
incidence of spontaneous preterm birth in women at increased risk:
A randomized placebo-controlled double-blind study. Am J Obstet
Gynecol 2003;188:419424.
77. Spong CY, Meis PJ, Thom EA, et al. Progesterone for prevention of
recurrent preterm birth: Impact of gestational age at previous delivery.
Am J Obstet Gynecol 2005;193(3 Pt 2):11271131.
78. ACOG Committee Opinion no. 419 October 2008 (replaces no. 291,
November 2003). Use of progesterone to reduce preterm birth. Obstet
Gynecol 2008;112:963965.
79. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal
lung maturation for women at risk of preterm birth. Cochrane
Database Syst Rev 2006(3):CD004454.
80. Garite TJ, Kurtzman J, Maurel K, Clark R. Impact of a rescue course
of antenatal corticosteroids: A multicenter randomized placebo-
controlled trial. Am J Obstet Gynecol 2009;200:248 e19.
81. Phares CR, Lynfield R, Farley MM, et al. Epidemiology of invasive
group B streptococcal disease in the United States, 19992005. JAMA
2008;299:20562065.
82. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of peri-
natal group B streptococcal disease. Revised guidelines from CDC.
MMWR Recomm Rep 2002;51(RR-11):122.
83. Tenore JL. Methods for cervical ripening and induction of labor. Am
Fam Physician 2003;67:21232128.
84. Sanchez-Ramos L. Induction of labor. Obstet Gynecol Clin North Am
2005;32:181200.
85. Hapangama D, Neilson JP. Mifepristone for induction of labour.
Cochrane Database Syst Rev 2009(3):CD002865.
86. Kuczkowski KM. Labor pain and its management with the combined
spinal-epidural analgesia: What does an obstetrician need to know?
Arch Gynecol Obstet 2007;275:183185.
87. Simkin P, Bolding A. Update on nonpharmacologic approaches to
relieve labor pain and prevent suffering. J Midwifery Womens Health
2004;49:489504.
88. ACOG Committee Opinion no. 295: Pain relief during labor. Obstet
Gynecol 2004;104:213.
89. Anim-Somuah M, Smyth R, Howell C. Epidural versus non-
epidural or no analgesia in labour. Cochrane Database Syst Rev
2005(4):CD000331.
90. van der Vyver M, Halpern S, Joseph G. Patient-controlled epidural
analgesia versus continuous infusion for labour analgesia: a meta-
analysis. Br J Anaesth 2002;89:459465.
91. Chong YS, Su LL, Arulkumaran S. Current strategies for the preven-
tion of postpartum haemorrhage in the third stage of labour. Curr
Opin Obstet Gynecol 2004;16:143150.
92. Mousa HA, Alfirevic Z. Treatment for primary postpartum haemor-
rhage. Cochrane Database Syst Rev 2007(1):CD003249.
93. Sheiner E, Sarid L, Levy A, et al. Obstetric risk factors and outcome of
pregnancies complicated with early postpartum hemorrhage: A popu-
lation-based study. J Matern Fetal Neonatal Med 2005;18:149154.
94. Ilett KF, Kristensen JH. Drug use and breastfeeding. Expert Opin Drug
Saf 2005;4:745768.
95. Gartner LM, Morton J, Lawrence RA, et al. Breastfeeding and the use
of human milk. Pediatrics 2005;115:496506.
96. Della-Giustina K, Chow G. Medications in pregnancy and lactation.
Emerg Med Clin North Am 2003;21:585613.
97. Jahanfar S, Ng CJ, Teng CL. Antibiotics for mastitis in breastfeeding
women. Cochrane Database Syst Rev 2009(1):CD005458.
98. Walker M. Conquering common breast-feeding problems. J Perinat
Neonatal Nurs 2008;22:267274.
99. Pearlstein T, Howard M, Salisbury A, Zlotnick C. Postpartum depres-
sion. Am J Obstet Gynecol 2009;200:357364.
100. Betzold CM. Galactagogues. J Midwifery Womens Health 2004;49:
151154.