Académique Documents
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SECTION 9
GYNECOLOGIC AND OBSTETRIC DISORDERS
87
C H AP TER
formed during the embryonic period, and they continue to grow chemical properties, such as lipid solubility, electrical charge,
and mature during the fetal period. The fetal period continues until molecular weight, and degree of protein binding of medications,
the pregnancy reaches term, approximately 40 weeks after the last may influence the rate of transfer across the placenta.10
menstrual period.6 Drugs with molecular weights less than 500 Da readily cross
Gravidity is the number of times that a woman is pregnant.5,7 A the placenta, whereas larger molecules (6001,000 Da) cross more
multiple birth is counted as a single pregnancy. Parity refers to the slowly.10 Drugs with molecular weights greater than 1,000 Da,
number of pregnancies exceeding 20 weeks gestation and relates such as insulin and heparin, do not cross the placenta in signifi-
information regarding the outcome of each pregnancy. In sequence, cant amounts.10 Lipophilic drugs, such as opiates and antibiotics,
Gynecologic and Obstetric Disorders
the numbers reflect (1) term deliveries, (2) premature deliveries, (3) cross the placenta more easily than do water-soluble drugs.10
aborted and/or ectopic pregnancies, and (4) number of living chil- Maternal plasma albumin progressively decreases while fetal albu-
dren. A woman who has been pregnant four times; has experienced min increases during the course of pregnancy, which may result in
two term deliveries, one premature delivery, and one ectopic preg- higher concentrations of certain protein-bound drugs in the fetus.10
nancy; and has three living children would be designated G4P2113. Fetal pH is slightly more acidic than maternal pH, permitting weak
bases to more easily cross the placenta. Once in the fetal circulation,
PREGNANCY DATING the molecule becomes more ionized and less likely to diffuse back
into the maternal circulation.10
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 DRUG SELECTION DURING PREGNANCY
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 Although some drugs have the potential to cause teratogenic
menstrual period then subtract 3 months. Pregnancy is divided into effects, most medications required by pregnant women can be used
three periods of 3 calendar months, each called a trimester. safely. There are many misconceptions about the association of
medications and birth defects.
PREGNANCY SIGNS AND SYMPTOMS The baseline risk for congenital malformations is approximately
3% to 6%, with approximately 3% considered severe.2 Medication
Early symptoms of pregnancy include fatigue and increased fre- exposure is estimated to account for less than 1% of all birth
quency of urination. At approximately 6 weeks gestation, nausea defects.2 Genetic causes are responsible for 15% to 25%, other envi-
and vomiting can occur. While commonly called morning sickness, ronmental issues (e.g., maternal conditions and infections) account
it can happen at any time of the day. Nausea and vomiting usually for 10%, and the remaining 65% to 75% of congenital malforma-
resolve at 12 to 18 weeks gestation. A pregnant woman can feel fetal tions result from unknown causes.2
movement in the lower abdomen at 16 to 20 weeks of gestation. Factors such as the stage of pregnancy during exposure, route
Signs of pregnancy include cessation of menses, change in cervi- of administration, and dose, can affect outcomes.2,11 In the first
cal mucus consistency, bluish discoloration of the vaginal mucosa, 2 weeks following conception, exposure to a teratogen may result
increased skin pigmentation, and anatomic breast changes.5,7 in an all-or-nothing effect, which could either destroy the embryo
or cause no problems.11 During organogenesis (18 to 60 days
MATERNAL PHARMACOKINETIC postconception), organ systems are developing, and teratogenic
CHANGES IN PREGNANCY exposures may result in structural anomalies. For the remainder of
Normal physiologic changes that occur during pregnancy may the pregnancy, exposure to teratogens may result in growth retar-
alter medication effects, resulting in the need to more closely moni- dation, central nervous system abnormalities, or death.2 Examples
tor and, sometimes, adjust therapy. Physiologic changes begin in of medications associated with teratogenic effects in the period of
the first trimester and peak during the second trimester. For medi- organogenesis include chemotherapy drugs (e.g., methotrexate,
cations that can be monitored by blood or serum concentration cyclophosphamide), sex hormones (e.g., diethylstilbestrol), lithium,
measurements, monitoring should occur throughout pregnancy. retinoids, thalidomide, certain antiepileptic drugs, and coumarin
During pregnancy, maternal plasma volume, cardiac output, and derivatives. Other medications such as nonsteroidal antiinflamma-
glomerular filtration increase by 30% to 50% or higher, potentially tory drugs and tetracycline derivatives are more likely to exhibit
lowering the concentration of renally cleared drugs.8,9 As body fat effects in the second or third trimester.
increases during pregnancy, the volume of distribution of fat-solu- In summary, a small number of medications have the potential
ble drugs may increase. Plasma albumin concentration decreases, to cause congenital malformations, and many can be avoided dur-
which increases the volume of distribution of drugs that are highly ing pregnancy. In situations where a drug may be teratogenic but
protein bound. However, unbound drugs are more rapidly cleared is necessary for maternal care, considerations related to route of
by the liver and kidney during pregnancy, resulting in little change administration and dosing may lessen the risk.
in concentration. Nausea and vomiting, as well as delayed gastric
emptying, may alter the absorption of drugs. Likewise, a pregnancy- METHODS OF DETERMINING
induced increase in gastric pH may affect the absorption of weak DRUG SAFETY IN PREGNANCY
acids and bases. Higher levels of estrogen and progesterone alter
When assessing the safety of using medications during preg-
liver enzyme activity and increase the elimination of some drugs but
nancy, an important consideration for the clinician is how to evalu-
result in accumulation of others.
ate the quality of the evidence. Ideally, safety data from randomized,
controlled trials is most desirable, but pregnant women are not
TRANSPLACENTAL DRUG TRANSFER usually eligible for participation in clinical trials. Other types of
Although once thought to be a barrier to drug transfer, the placenta data commonly used to estimate the risk associated with medication
is the organ of exchange for a number of substances, including use during pregnancy are animal studies, case reports, case-control
1363
studies, prospective cohort studies, historical cohort studies, and
voluntary reporting systems. PRECONCEPTION PLANNING
CHAPTER 87
Animal studies are a required component of drug testing,
Pregnancy outcomes are influenced by maternal health status,
but extrapolation of the results to humans is not always valid.12
lifestyle, and history prior to conception.15 More than 60% of
Thalidomide was found to be safe in some animal models but
pregnancies in the United States are unintended. Of women who
proved to have teratogenic effects in human offspring.
receive prenatal care, 18% seek it after the first trimester.16 The goal
Case reports are usually of limited value because a birth defect
of preconception care is health promotion, evidence-based screen-
in the infant of a woman who used a medication during pregnancy
ing, and intervention in all women of reproductive age to ensure
may have occurred by chance.12 Case-control studies identify an
optimal health and improve pregnancy outcomes.15
outcome (congenital anomaly), match subjects with and without
The most common major congenital abnormalities are neural
GASTROINTESTINAL TRACT obesity, history of the condition, glycosuria, or strong family history
The prevalence of constipation during pregnancy ranges from of diabetes) at the first prenatal visit.25 If normal, testing should be
25% to 40%. Light physical exercise and increased intake of dietary repeated between weeks 24 and 28 of gestation. Pregnant women
fiber and fluid should be instituted first.21 If additional treatment is considered to have average risk should undergo testing for GDM
needed, supplemental fiber and/or a stool softener is appropriate.22 between weeks 24 and 28 of gestation unless they are considered
Osmotic laxatives (polyethylene glycol, lactulose, sorbitol, and mag- low risk. To meet criteria for low risk, a woman must fulfill all the
nesium and sodium salts) are acceptable treatments but should be following: (a) age younger than 25 years, (b) normal body weight,
reserved for occasional use only. Polyethylene glycol is considered (c) no known diabetes in first-degree relatives, (d) no history of
by some the ideal laxative for use in pregnancy.21,22 Senna and bisa- abnormal glucose tolerance, (e) no history of adverse obstetric out-
codyl can be used occasionally. Castor oil and mineral oil should comes, and (f) not a member of an ethnic group with a high preva-
be avoided. lence of GDM (e.g., African Americans, Native Americans, Asian
Gastroesophageal reflux disease occurs in up to 80% of pregnant Americans, Hispanic Americans, Pacific Islanders). Initial screen-
women.21 An algorithm starting with lifestyle and dietary modifica- ing for hyperglycemia in pregnancy is similar to that in the general
tions (e.g., small, frequent meals; alcohol and tobacco avoidance; population and is described in the American Diabetes Association
food avoidance before bedtime; elevation of the head of the bed) practice guidelines.25
should be used. If symptoms are not relieved, use of antacids Dietary modification is considered first-line therapy for all
(aluminum, calcium, or magnesium preparations) or sucralfate is women who have GDM, with additional caloric restriction for
acceptable. Sodium bicarbonate and magnesium trisilicate should obese women.26,28 Daily self-monitoring of blood glucose is
be avoided. Evidence supports the use of ranitidine and cimetidine. required. Insulin therapy with recombinant human insulin should
Literature evaluating the use of famotidine and nizatidine is lim- be initiated if the following levels are not achieved with dietary
ited, but they are likely safe. If a patient is unresponsive to lifestyle modification: fasting plasma glucose concentrations below 9099
changes and histamine-2 receptor blockers, metoclopramide is a mg/dL (5.05.5 mmol/L), 1-hour postprandial plasma glucose
viable option. Relatively few data are available on the use of proton concentration less than or equal to 140 mg/dL (7.8 mmol/L), or
pump inhibitors during pregnancy; use should be reserved for 2-hour postprandial plasma glucose concentration below 120127
women with complicated or intractable gastroesophageal reflux. mg/dL (6.77.0 mmol/L).26 Glyburide is an alternative because
The prevalence of hemorrhoids during pregnancy is believed to it minimally crosses the placenta.26,28 Metformin may also be an
be higher than in the general population.23 Therapy during preg- alternative, but it crosses the placenta and is less well studied than
nancy is conservative (i.e., high intake of dietary fiber, adequate insulin or glyburide.28 There are data, though limited, supporting
oral fluid intake, and use of sitz baths) and may be helpful; however, the use of postprandial over preprandial blood glucose monitoring
there is a paucity of supporting data for all management options. in women requiring insulin treatment.29 Recommended targets
Topical anesthetics, skin protectants, and astringents can be used. for self-monitored blood glucose are preprandial plasma glucose
Other options for refractory hemorrhoids include rubber band liga- concentration between 80 and 110 mg/dL (4.46.1 mmol/L)
tion, sclerotherapy, and surgery. and 2-hour postprandial plasma glucose concentration below
Nausea and vomiting affect up to 90% of pregnant women, 155 mg/dL (8.6 mmol/L).30
usually beginning during the fifth week of gestation and lasting Evidence supporting dietary modification, self-monitored blood
through the first trimester; however, about 15% of women experi- glucose, exercise, and pharmacologic interventions for women with
ence it throughout pregnancy.21,24 Hyperemesis gravidarum (HEG; GDM is largely based on one randomized clinical trial that showed
i.e., unrelenting vomiting causing weight loss of more than 5% reductions in perinatal morbidity (composite of death, nerve palsy,
prepregnancy weight and ketonuria) occurs in about 1% to 3% of bone fracture, and shoulder dystocia) with nutritional education,
women.24 Dietary modifications, such as eating frequent, small, blood glucose monitoring, and insulin treatment.31,32
bland meals and avoiding fatty foods, may be helpful. Applying
pressure at acupressure point P6 on the volar aspect of the wrist
HYPERTENSION
may be beneficial.
A number of pharmacotherapeutic approaches have been tried Approximately 10% of pregnancies are complicated by hyper-
for treatment of nausea and vomiting. Multivitamins, pyridoxine tension at some time during the pregnancy. Hypertension in
(vitamin B6), and antihistamines (including doxylamine) have pregnancy is divided into four categories: chronic hypertension
shown efficacy.21,24 Phenothiazines and metoclopramide are widely (preexisting hypertension), gestational hypertension (hypertension
used and generally considered safe.21,24 Evidence of safety and without proteinuria), preeclampsia (hypertension with protein-
efficacy with ondansetron is limited, but ondansetron can be con- uria), and preeclampsia superimposed on chronic hypertension.33,34
sidered for HEG when other treatments fail. Corticosteroids are Treatment of mild-to-moderate hypertension (defined as systolic
effective for HEG but are associated with a small increase in the blood pressure 140169 mm Hg or diastolic blood pressure 90109
risk of oral clefts when used during the first trimester.21,24 Ginger mm Hg) reduces the risk of severe hypertension by 50%, but does
has shown efficacy for hyperemesis in randomized, controlled trials not substantially affect fetal outcomes. However, severe hyperten-
and is probably safe.21,24 sion (blood pressure greater than or equal to 160170 mm Hg
1365
systolic or 110 mm Hg diastolic) can cause maternal complications, THYROID ABNORMALITIES
hospital admission, and potential premature delivery. Preeclampsia
CHAPTER 87
complicates 2%8% of pregnancies and can cause poorer outcomes, During pregnancy, stimulation of the thyroid gland may occur
including eclampsia (seizures in addition to preeclampsia), renal because of hCGs structural similarity to serum TSH (thyrotro-
failure, coagulopathy, preterm delivery, and intrauterine growth pin).40 In women with HEG, gestational transient thyrotoxicosis
restriction.33 may result. Women are usually asymptomatic but may present with
Supplemental calcium 12 g/day decreases the relative risk of vomiting, increased serum free thyroxine, and decreased thyrotro-
hypertension by 30% (range 14%43%) and preeclampsia by 48% pin. Gestational transient thyrotoxicosis resolves as concentrations
(range 31%67%).35 High-risk patients (those with the lowest ini- of hCG decline toward the end of the first trimester. Treatment
tial calcium intake) benefited most; however, even women with with antithyroid medications is not usually needed. Nausea and
vomiting can be treated as for patients without this pseudohyper-
CHAPTER 87
Infections Due to Chlamydia in Pregnancy
a history of preterm delivery should undergo screening for asymp-
First-line treatment
tomatic bacterial vaginosis at the first prenatal visit.
Azithromycin 1 g orally in a single dose or
Amoxicillin 500 mg orally three times daily for 7 days
For symptomatic and asymptomatic women at high risk for
preterm delivery, the recommended treatment regimen is met-
Alternative regimens
Erythromycin base 500 mg orally four times per day for 7 days or
ronidazole 500 mg orally twice daily for 7 days, metronidazole
Erythromycin base 250 mg orally four times per day for 14 days 250 mg orally three times daily for 7 days, or clindamycin 300 mg
Erythromycin ethylsuccinate 800 mg orally four times per day for 7 days or twice daily for 7 days. Conflicting data exist with regard to treating
Erythromycin ethylsuccinate 400 mg orally four times per day for 14 days women at low risk for preterm labor. Vaginal preparations (e.g.,
Asthma and rhinitis are common chronic illnesses in preg- Treatment of dermatologic conditions can often be delayed until
nancy. During pregnancy, asthma control may change and worsen after the delivery.55 If treatment is required during gestation, topical
maternal oxygenation resulting in significant health consequences agents considered to have minimal pregnancy risk include baci-
in the mother and fetus. Rhinitis itself is unlikely to cause harm tracin, benzoyl peroxide, ciclopirox, clindamycin, erythromycin,
to the mother or fetus but may be associated with diminished metronidazole, mupirocin, permethrin, and terbinafine. Topical
quality of life. corticosteroids are generally considered safe for use but should be
Asthma affects approximately 8% of pregnancies.50 During preg- applied at the lowest possible dose for the shortest time. Systemic
nancy almost equal proportions of patients have symptoms that agents considered safe include acyclovir, amoxicillin, azithromycin,
worsen, improve, or remain unchanged.51 Health consequences cephalosporins, cyproheptadine, dicloxacillin, diphenhydramine,
Gynecologic and Obstetric Disorders
of untreated or poorly treated asthma include preterm labor, pre- erythromycin (except estolate), nystatin, and penicillins. Lidocaine
eclampsia, intrauterine growth restriction, premature birth, low birth and lidocaine with epinephrine can be used topically during preg-
weight, and stillbirth; therefore, the treatment goal is symptom con- nancy. Acitretin, fluorouracil, isotretinoin, methotrexate, and tha-
trol.51,52 Asthma is controlled when there are no daytime symptoms, lidomide should be avoided because of teratogenic potential.
limitations of activities, nocturnal symptoms, short-acting 2-agonist
use, or exacerbations, and there is normal pulmonary function.
DIABETES
Caring for patients with asthma should include (a) assessment
and monitoring (including measures of pulmonary function), Poorly controlled diabetes can cause fetal malformations and
(b) identifying and controlling exposure to allergens and irritants fetal loss.30 Women with diabetes should use effective contracep-
(e.g., tobacco smoke), (c) patient education, and (d) a stepped tion until optimal glycemic control is achieved before attempting
approach to medication use.51 The risks of medication use to the pregnancy. Additionally, diabetic retinopathy may worsen, hyper-
fetus are lower than the risks of untreated asthma. tension may develop, and renal function may deteriorate during
Treatment recommendations are divided into six steps based on pregnancy, requiring enhanced monitoring for these target-organ
symptom control.51,52 A short-acting 2-agonist is recommended problems.56
for all patients with asthma for quick relief of symptoms. For For patients with both type 1 and type 2 diabetes, insulin is the
mild intermittent asthma, Step 1 recommends only a short-acting, drug treatment of choice.56 However, glyburide and metformin may
inhaled 2-agonist; albuterol is preferred during pregnancy. be alternatives.26,28 Medical nutrition therapy and supervised physi-
Initiation of treatment for persistent asthma should begin with cal activity programs should continue. Goals for self-monitored
Step 2 unless the patient has severely uncontrolled asthma, in blood glucose are the same as for gestational diabetes.30,56
which case treatment may start at Step 3.51,52 For persistent asthma,
step-appropriate doses (low, medium, high) of inhaled cortico-
EPILEPSY
steroids form the foundation of the controller medication regimen.
When possible, low-dose inhaled corticosteroids are the treatment Seizure frequency does not change for most pregnant women
of choice for women with mild persistent asthma. Budesonide is with epilepsy. Studies have demonstrated no frequency change in
preferred during pregnancy, although other inhaled corticosteroids 54% to 80% of women with epilepsy, while decreased frequency
that were effective before pregnancy can be continued. Long-acting ranges between 3% and 24% and increased frequency ranges from
2-agonists are considered safe to use during pregnancy because 14% to 32%.57,58 Seizures may become more frequent because of
of the similar pharmacologic and safety profiles compared with changes in maternal hormones, sleep deprivation, and medica-
short-acting agents; use should follow the stepwise approach.5052 tion adherence problems (because of perceived teratogenic risk).
Cromolyn, leukotriene receptor antagonists, and theophylline are Another potential cause is changes in free serum concentrations
considered alternative treatments but are not preferred because of antiepileptic drugs resulting from increased maternal volume
they are less effective (cromolyn), there is less experience with them of distribution, decreased protein binding from hypoalbumi-
(leukotriene receptor antagonists), and there is more potential tox- nemia, increased hepatic drug metabolism, and increased renal
icity (theophylline) than with inhaled corticosteroids. For patients drug clearance. A womans clinical condition and her free serum
with the most severe disease, addition of systemic corticosteroids is concentrations of antiepileptic drug should be the basis for dose
recommended to gain control of symptoms.51 adjustments.
Allergic rhinitis may also improve, worsen, or remain the same The risks of untreated epilepsy to the fetus are considered to be
during pregnancy.53 Treatment strategies include avoidance of greater than those associated with the antiepileptic drugs.58 Major
allergens, immunotherapy, and pharmacotherapy. Immunotherapy malformations are two to three times more likely to occur in chil-
is not contraindicated in pregnancy, but dose increases during preg- dren born to women taking antiepileptic drugs than to those who
nancy are not advised to lessen risk for anaphylaxis. do not. Major malformations with valproic acid are dose related and
First-line medications to treat allergic rhinitis during preg- range from 6.2% to 10.7%; use of valproic acid should be avoided if
nancy include intranasal corticosteroids, nasal cromolyn, and first- possible during pregnancy to minimize the risk of NTDs (e.g., spina
generation antihistamines (e.g., chlorpheniramine, hydroxyzine).53 bifida), facial clefts, and cognitive teratogenicity.59,60 Rates of major
Intranasal corticosteroids are the most effective treatment and have malformation for monotherapy with antiepileptic drugs other than
a low risk of systemic effect; beclomethasone and budesonide have valproic acid range between 2.9% and 3.6%. Carbamazepine and
been most widely studied.53,54 Second-generation antihistamines lamotrigine appear to be safest based on available data. However,
(i.e., loratadine and cetirizine) do not appear to increase fetal risk individual antiepileptic drugs are associated with malformations.
but are less extensively studied than first-generation products. Oral Phenytoin, lamotrigine, and carbamazepine may cause cleft pal-
decongestants, such as pseudoephedrine, may be associated with ate, while phenobarbital is associated with cardiac malformations.
an increased risk for the rare birth defect gastroschisis. Use of an Polytherapy with antiepileptic drugs is associated with a greater rate
external nasal dilator, short-term topical oxymetazoline, or inhaled of major malformation than monotherapy.59,60
corticosteroids may be preferable to use of oral decongestants, espe- When possible, antiepileptic drug monotherapy is recom-
cially during early pregnancy. mended with medication regimen optimization occurring before
1369
conception.59 Medication change solely to minimize teratogenic support superior efficacy of one agent versus another for blood
risk is not recommended. If drug withdrawal is planned, it should pressure reduction.34,36,37
CHAPTER 87
be attempted at least 6 months before attempting to conceive.59
While vitamin K administration during the last month of gestation MENTAL HEALTH CONDITIONS
was previously recommended to decrease the risk of hemorrhagic
complications in newborns, evidence to support this practice is Psychiatric illness affects approximately 500,000 pregnancies
lacking. The American Academy of Pediatrics recommends that all each year.63,64 Anxiety disorders, including panic disorder, obses-
neonates receive vitamin K at delivery. All women taking antiepi- sivecompulsive disorder, generalized anxiety disorder, posttrau-
leptic drugs should receive folic acid supplementation; 4 to 5 mg matic stress disorder, social anxiety disorder, and phobias, can
daily starting before pregnancy and continuing through at least the cause adverse maternal and fetal outcomes such as spontaneous
abortion, preterm delivery, prolonged labor, and fetal distress.63
anomalies. Benzodiazepine use in the third trimester can cause of the risk of thyroid damage in the fetus. The goal of therapy is to
infant sedation and withdrawal symptoms (i.e., restlessness, hyper- attain free thyroxine concentrations near the upper limit of nor-
tonia, hyperreflexia, tremulousness, apnea, diarrhea, vomiting). mal to allow for dose minimization and to limit fetal or neonatal
Floppy baby syndrome, consisting of low Apgar scores, hypo- hypothyroidism.
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 LABOR AND DELIVERY
Gynecologic and Obstetric Disorders
reader can find information related to the use of the seizure medica-
Management of the pregnant woman during the perinatal period
tions used for mood stabilization in the section on epilepsy.
often requires drug therapy for pain and for potential complications.
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 PRETERM LABOR
that the relative risk for cardiac malformations was between 1.2
Preterm labor occurs when there are cervical changes and uterine
and 7.7 and for all congenital malformations was between 1.5 and
contractions between 20 and 37 weeks gestation.67,68 Preterm birth
3. Stated differently, the risk for Ebstein anomaly after prenatal lith-
is the leading cause of infant morbidity and mortality in the United
ium exposure would rise from 1:20,000 to 1:1,000.66 Other reported
States, with an incidence of 12.8%. Risk factors for preterm deliv-
neonatal side effects include floppy baby syndrome, nephrogenic
ery include previous preterm delivery, infections, multiple gesta-
diabetes insipidus, hypoglycemia, cardiac arrhythmias, thyroid
tion, poverty, nonwhite race, maternal complication factors (e.g.,
dysfunction, polyhydramnios, and premature delivery.63,66 Lithium
smoking and use of illicit drugs or alcohol), and uterine functional
may cause lethargy, hypotonia, hypothermia, cyanosis, and changes
causes (e.g., incompetent cervix); previous history and prior second
in electrocardiogram in infants exposed through breast-feeding.
trimester loss confer a higher risk.67,68
If breastfeeding, the infants lithium levels, thyroid function, and
No adequate tests are available for monitoring and preventing
complete blood count should be monitored.
preterm labor. Monitoring of uterine activity along with inten-
Chlorpromazine, haloperidol, and perphenazine have long his-
sive surveillance does not minimize risk.68 The presence of fetal
tories of use during pregnancy, with no reported significant
fibronectin, a glycoprotein found in cervicovaginal secretions,
teratogenic effect.63 Atypical antipsychotics are considered first-line
indicates a high risk of preterm birth. Cervical shortening is also
treatment for schizophrenia because of their more favorable side-
associated with preterm delivery. Fetal fibronectin determinations
effect profiles and potential increased efficacy for treating negative
and cervical ultrasound have not helped to prevent preterm labor
symptoms compared with the older agents. However, use of atypical
but have been useful for their negative predictive value.68
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- Tocolytic Therapy
genital malformations, they do cause weight gain and glucose intol- The purposes of tocolytic therapy are threefold: (a) postpone
erance, which have implications for poorer obstetric outcomes.66 delivery long enough to allow for the maximum effect of antenatal
One study found a higher rate (10% vs. 2%) of low-birth-weight steroid administration; (b) allow for transportation of the mother
infants with olanzapine, clozapine, quetiapine, and risperidone to a facility equipped to deal with high-risk deliveries; and (c)
compared with nonexposed infants.63 At present, atypical antipsy- prolongation of pregnancy when there are underlying, self-limited
chotics do not appear to be safer than the typical agents. 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.
THYROID DISORDERS The criteria for starting tocolysis are regular uterine contractions
Hypothyroidism affects 0.1 to 0.3% of pregnancies.40 Untreated with cervical change. Tocolytic therapy should not be used in cases
hypothyroidism increases the risk of preeclampsia, premature birth, of intrauterine fetal demise, a lethal fetal anomaly, intrauterine
miscarriage, and growth restriction; impaired neurological develop- infection, fetal distress, severe preeclampsia, vaginal bleeding, or
ment in the fetus may also occur. Causes of hypothyroidism include maternal hemodynamic instability.
autoimmune diseases (e.g., Hashimoto thyroiditis), iodine defi- Four classes of tocolytics are available in the United States:
ciency (uncommon in the United States), and thyroid dysfunction -agonists, magnesium, calcium channel blockers, and NSAIDs.71
following surgery or ablative therapy for previous hyperthyroidism. All four therapies have similar effectiveness in prolonging preg-
Thyroid replacement therapy should be instituted with levothy- nancy from 48 hours to 1 week. However, this prolongation of preg-
roxine 0.1 to 0.15 mg/day in hypothyroid patients; the goal is to nancy was not associated with a statistically significant reduction in
attain normal thyrotropin concentration. Women receiving thyroid overall rates of respiratory distress syndrome or neonatal death.
replacement therapy before pregnancy may have an increased dos- The -agonists terbutaline and ritodrine have been used for toco-
age requirement during pregnancy; any dose change should follow lytic therapy.69 Ritodrine is no longer available in the United States.
thyroid function testing. Laboratory follow-up of thyrotropin con- Relative to other agents, -agonists have a higher incidence of
centrations and free T4 should occur every 8 weeks. maternal side effects, including hyperkalemia, arrhythmias, hyper-
Hyperthyroidism affects approximately 0.2% of pregnancies and glycemia, hypotension, and pulmonary edema. Recommended
is associated with fetal death, low birth weight, intrauterine growth terbutaline doses range from 250 to 500 mcg subcutaneously every
restriction, and preeclampsia.40 Graves disease accounts for 95% of 3 to 4 hours.70
hyperthyroidism in pregnancy. Therapy includes the thioamides Intravenous magnesium sulfate has been used for tocolysis;
(initial doses are propylthiouracil 100150 mg or methimazole however, a Cochrane review does not support its effectiveness.72
520 mg). Either agent is given three times daily with dose reduc- Heterogeneity of study designs and results along with small treat-
tion after becoming euthyroid. Surgery is reserved for the most ment arms in included studies may partially explain this finding;
1371
however, its use remains controversial.69 The incidence of cerebral women decreased the incidence of recurrent preterm birth.75 The
palsy is increased in premature infants. In one study, intravenous second study replicated the findings using vaginal progesterone
CHAPTER 87
magnesium use (6 g load followed by 2 g per hour continuous suppositories (100 mg).76 However, progesterone supplementation
infusion) decreased the occurrence of moderate or severe cerebral in women whose previous preterm birth occurred beyond 34 weeks
palsy.73 Although not the primary end point, the study suggests that produced similar rates of preterm delivery compared with placebo.77
women at risk for imminent delivery (up to 34 weeks gestation) The American College of Obstetrics and Gynecology currently rec-
should receive intravenous magnesium. Maternal side effects are ommends that progesterone supplementation be limited to women
rare but can include pulmonary edema. At toxic levels, hypotension, with a singleton pregnancy and a previous history of spontaneous
muscle paralysis, tetany, cardiac arrest, and respiratory depression preterm birth.78
may occur.70 Magnesium undergoes renal excretion; dose adjust-
Throughout gestation the cervix is closed and firm. During the last Oxytocin is the most commonly used agent for labor induction
few weeks of pregnancy, the cervix softens and thins to facilitate after cervical ripening. By the end of pregnancy, the number of
labor.83,84 This process is mediated by hormonal changes, including oxytocin receptors has increased by 300-fold.83,84 A solution of 10
final mediation by prostaglandins E2 and F2, which increase col- milliunits/mL is used for infusion. Oxytocin is effective in both low-
lagenase activity in the cervix leading to thinning and dilation. dose (physiologic) and high-dose (pharmacologic) regimens.
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 LABOR ANALGESIA
80% of inductions.83,84 Other reasons for induction include suspected
Gynecologic and Obstetric Disorders
CHAPTER 87
The placenta is delivered after the delivery of the baby and is bloodstream. Maternal plasma pH is 7.4, while the pH of breast milk
referred to as the third stage of labor. Postpartum hemorrhage is ranges between 6.8 and 7.96 Weak bases are not ionized in the mater-
an obstetrical emergency and is a major cause of morbidity and nal circulation and easily transfer to breast milk. In the lower pH of
mortality.91 In the United States, the postpartum hemorrhage rate breast milk, molecules become ionized and are less likely to diffuse
is approximately 1%5% for vaginal deliveries.92 The traditional back into maternal circulation (ion trapping). Likewise, drugs with
definition of postpartum hemorrhage is more than 500 mL of blood longer half-lives are more likely to maintain higher levels in breast
within 24 hours of a vaginal delivery or 1,000 mL after a cesarean milk, resulting in greater exposure to the infant.
section; however, other definitions have also been suggested. Risk Infant-related factors may also influence the amount of drug
factors include retained placenta, failure to progress during the
Postpartum depression affects up to 15% of women.99 Symptoms contemporary and accurate information to their patients. Use of
may develop during pregnancy or up to 6 months after deliv- technology to access evidence-based resources, databases related
ery, although the strict definition for major depressive disorder to drug use in pregnancy, and primary and secondary literature
after delivery specifies symptom occurrence within 1 month. may assist healthcare practitioners in accessing relevant medica-
Psychotherapy, including interpersonal psychotherapy, cognitive tion information to manage drug therapy needs during pregnancy
behavioral therapy, and group/family therapy, has been shown and lactation.
effective for treatment of postpartum depression.
In cases where pharmacotherapy is warranted, selection of medi-
Gynecologic and Obstetric Disorders
CURRENT CONTROVERSY
Treatment of postpartum depression in the breast-feeding ABBREVIATIONS
mother poses challenges since all antidepressants transfer
into breast milk, and long-term effects on cognitive, behav- FDA: Food and Drug Administration
ioral, motor, and neurologic development are unknown.99 GBS: group B Streptococcus
Postpartum depression poses significant risks to both mother GDM: gestational diabetes mellitus
and infant. Benefits and risks of pharmacologic and nonphar-
macologic therapy must be weighed in selecting treatments for HAART: highly active antiretroviral therapy
women with postpartum depression. hCG: human chorionic gonadotropin
HEG: hyperemesis gravidarum
HIV: human immunodeficiency virus
RELACTATION NNRTI: nonnucleoside reverse transcriptase inhibitor
Adequate milk removal from the breast by breastfeeding or pumping NRTI: nucleoside reverse transcriptase inhibitor
is necessary to maintain or increase milk production.100 Relactation NSAIDs: nonsteroidal antiinflammatory drugs
is the process of increasing the breast milk supply for women who
NTDs: neural tube defects
have failed lactogenesis II, who have inadequate milk production
despite appropriate breastfeeding frequency or pumping, or who PPROM: preterm premature rupture of the membranes
have weaned or never breast-fed after delivery. Lactation can also SSRIs: selective serotonin reuptake inhibitors
be induced in women who have not recently delivered a baby, such TSH: thyroid stimulating hormone
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
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