DRUGS IN PREGNANCY: THE GOOD AND THE BAD
Highlights from Antepartum and Intrapartum Management, presented by the Department of Obstetrics, Gynecology, and
Reproductive Sciences, University of California, San Francisco, School of Medicine
Educational Objectives
| The goals of this program are to increase safety when prescribing antibiotics to pregnant patients and to improve
substance abuse screening in the pregnant population. After hearing and assimilating this program, the clinician
will be better able to:
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 | 1. Discuss physiologic changes of the pharmacokinetics of antibiotics in pregnancy.
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| 2. Safely prescribe medications for use during pregnancy and lactation.
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| 3. More appropriately treat common conditions seen during pregnancy.
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| 4. Discuss the rationale for universal screening for substance abuse in pregnancy.
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| 5. Identify patients at risk for substance abuse in pregnancy.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported
nothing to disclose.
Acknowledgments
Drs. Aziz and Bryant were recorded at Antepartum and Intrapartum Management, sponsored by the Department of Obstetrics,
Gynecology, and Reproductive Sciences at the University of California, San Francisco, School of Medicine,
held on June 7-9, 2007, in San Francisco. The Audio-Digest Foundation thanks the speakers and the University of
California, San Francisco, School of Medicine, for their cooperation in the production of this program.
| ANTIBIOTIC USE DURING PREGNANCY AND LACTATION —Natali Aziz, MD, MS, Clinical Assistant Professor,
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Stanford University School of
Medicine, Stanford, CA
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| Pharmacokinetics of antibiotics: poorly understood in pregnancy; lack of safety data limits use of newer antibiotics,
leaving provider with impression that few antibiotics safe in pregnancy; fall in plasma protein leads to decreased
drug binding (affects unbound drug availability); increase in intravascular volume causes increase in cardiac output
and glomerular filtration rate (increases drug clearance and lowers serum levels); lipid solubility and low molecular
weight of antibiotics facilitates ability to cross placenta (creates intrauterine and maternal compartment); with numerous
antibiotics, lower serum levels seen during pregnancy (lowered by 10%-50%); few antibiotics with unchanged serum
levels; higher range of dosing recommended for drugs with wider safety margin; standard dosing and periodic
check of therapeutic serum levels recommended for drugs with narrow safety margins; category A—safety established
by well-controlled human studies; category B—presumed safety in human pregnancies based on limited human data
or studies; no adverse effects in animal studies; category C—limited human studies; adverse effects in animal studies
(most antibiotics category B or C); safety in lactation—3 categories; 1) generally accepted as safe, 2) safety unknown
or controversial, or 3) generally regarded as unsafe
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| Antibiotic classifications: penicillins—lower serum levels in pregnancy, due to volume of distribution and increased
renal clearance in second and third trimesters; readily cross placenta; teratogenicity ranges from none to unlikely; studies
show no increased risk for congenital anomalies; potential association with necrotizing enterocolitis in preterm infants born
to mothers taking amoxicillin and potassium clavulanate (Augmentin) during third trimester; cephalosporins—
pharmacokinetics, placental transfer, and teratogenicity similar to penicillins; most studies show no increase in congenital
defects or toxicity to newborn; macrolides—pharmacokinetics similar to penicillins and cephalosporins; no association
with congenital anomalies, with exception of estolate salt formulation of erythromycin (associated with hepatotoxicity in
pregnant women; use not recommended in pregnancy); aminoglycosides—lower serum levels during pregnancy; clearance
decreased in patients with preeclampsia; teratogenicity undetermined; older aminoglycosides associated with ototoxicity;
newer case series involving streptomycin show variable ototoxicity in newborns; studies show no increase in
congenital anomalies, toxicity, or nephrotoxicity with gentamicin (even though class D drug); tetracyclines—
pharmacokinetics in pregnancy unknown; readily cross placenta; teratogenicity unlikely; may induce hepatic necrosis in
pregnant women; older tetracyclines associated with teeth staining, enamel hypoplasia, and reversible depression of fetal
bone growth; currently no study showing doxycycline associated with congenital anomalies or teeth staining;
quinolones—pharmacokinetics similar to other antibiotics; lower serum levels in pregnancy; teratogenicity unlikely; no
significant increase or trends in congenital anomalies in studies with ciprofloxacin (eg, Cipro) and ofloxacin
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| Antibiotics: chloramphenicol—pharmacokinetics in pregnancy unknown; crosses placenta; teratogenicity unlikely;
no risk for congenital anomalies; associated with bone marrow suppression in infant; do not use near term, during labor,
or in breast-feeding women; clindamycin—no increased risk for congenital anomalies; causative factor for development
of Clostridium difficile colitis; nitrofurantoin—lower serum levels; teratogenicity unlikely; no increased risk
for congenital anomalies; associated with pulmonary hypersensitivity; may induce hemolytic anemia in patient with
glucose-6-phosphate dehydrogenase deficiency; no reported cases of hemolytic anemia of newborn; safe to use
throughout pregnancy; rifampin—crosses placenta; no increased risk for congenital anomalies; vancomycin—
pharmacokinetics unchanged in pregnancy; no significant risk for congenital anomalies; studies do not show increase
in ototoxicity or nephrotoxicity in pregnant vs nonpregnant women; risk to fetus considered low
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| Breast-feeding: medication timing, bioavailability, and maternal clearance affect medication transfer into milk; drugs
most likely transferred include those that are nonionized or nonprotein bound, and those with low molecular weight, high
lipid solubility, and high pH; antibiotics do not affect breast milk supply; most antibiotics compatible with breast-feeding;
many used therapeutically in infants; adverse effects include changes in intestinal flora characterized by loose stools
or diarrhea; penicillins, cephalosporins, macrolides, and aminoglycosides considered safe; use of quinolones and metronidazole
controversial; ofloxacin associated with arthropathy in juvenile animals (low risk in infants); ofloxacin considered
compatible with breast-feeding; metronidazole—no significant increase in adverse events; compatible with breast-
feeding; women taking 2-g dose (eg, treatment of Trichomonas vaginalis) should express and discard breast milk for up
to 12 to 24 hr; contraindicated medications—chloramphenicol; concern for potential bone marrow suppression and
“gray-baby” syndrome; can decrease hepatic enzyme function; associated with hypotension, cyanosis, and death; long-
term use of tetracycline not recommended; potential for staining of immature teeth in infants; short-term use acceptable
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| Conditions: cystitis—adverse effects rare with nitrofurantoin (eg, risk for pulmonary hypersensitivity <1% [same as
for baseline population]); cephalosporins, penicillins, and trimethoprim-sulfamethoxazole (TMP-SMZ) also used for
cystitis; theoretic concern that sulfonamide component of TMP-SMZ (eg, Bactrim, Septra) displaces bilirubin, causing
kernicterus; no documented human cases of kernicterus and no association with birth defects; trimethoprim component
folic acid antagonist; if TMP-SMZ used in first trimester, make sure patient receives folic acid supplementation;
quinolones alternative for treating organisms resistant to other therapies; duration ranges from 3 to 7 days;
pyelonephritis—penicillins, cephalosporins, gentamicin, and quinolones; duration usually 48 hr of intravenous (IV)
antibiotics until patient afebrile; change to oral antibiotics for 10 to 14 days; consider outpatient management for patients
who are compliant, not acutely ill, and at <24-wk gestation; pneumonia—azithromycin, amoxicillin, amoxicillin
and potassium clavulanate, ceftriaxone, doxycycline, and quinolones; tuberculosis—isoniazid for preventive
therapy; crosses placenta; no increased toxicity to fetus; possible increase in hepatic toxicity; preventive therapy usually
postponed until delivery, except with HIV infection, recent tuberculosis skin test conversion, or known tuberculosis
contact; bacterial vaginosis—metronidazole 500 mg orally bid for 7 days (considered first-line treatment),
metronidazole 250 mg orally tid for 7 days, and clindamycin; oral preferable to vaginal therapy; single 2-g dose not effective
for bacterial vaginosis, but recommended for Trichomonas infection; clindamycin cream associated with low
birth weight and neonatal infection when used in second and third trimesters; syphilis—benzathine penicillin G; no
proven alternatives during pregnancy; recommended patient undergo skin testing to document penicillin allergy, followed
by penicillin desensitization; chlamydia—azithromycin (1 g, orally, single dose) and amoxicillin (500 mg,
orally, tid, for 7 days) first-line treatment; erythromycin second-line (gastrointestinal effects); doxycycline, quinolones,
and erythromycin estolate less favored or avoided; gonorrhea—third-generation cephalosporin; one-time dose of
spectinomycin recommended for patient allergic to penicillin; reserve azithromycin (2 g orally) for patients with anaphylactic
penicillin allergies; if chlamydia status unknown, treat presumptively for coinfection; quinolones no longer
recommended; mastitis—dicloxacillin for 10 to 14 days; change to broader spectrum regimen (eg, cephalexin [Keflex]
or amoxicillin and potassium clavulanate) if no response in 24 to 48 hr; cephalexin appropriate option; use in patients
with high-risk penicillin allergy; TMP-SMZ and clindamycin recommended if methicillin-resistant Staphylococcus
aureus (MRSA) suspected
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| SCREENING FOR SUBSTANCE ABUSE IN PREGNANCY —Allison S. Bryant, MD, MPH, Assistant Adjunct Professor
of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, School of Medicine
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| Scope of problem: ≈3.6 million Americans have dependency on illegal substances; ≈15% of pregnant women use alcohol;
20% use cigarettes, about 2% marijuana, and ≈1% use other illicit drugs; substance abuse in pregnancy correlated
with young age, single marital status, and less than high school education; not related to race or ethnicity; living
in underserved or poor neighborhood more predictive of use of illicit drugs than one’s race, ethnicity, or level of education;
age significant predictor; cigarette smoking in pregnancy more common among white women than most other
ethnicities; pregnant woman more likely to abstain from harmful substances during pregnancy for health and well-being
of unborn child; provides “teachable moment”; ≈28% of women who use illicit drugs before pregnancy likely abstain
in first trimester, 75% in second trimester, and 93% in third trimester (decreases to 24% postpartum)
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| Definitions: substance abuse—recurring pattern of use which substantially impairs functioning in important life areas
(eg, family, work, psychologic, social); substance dependence—primary chronic disease, with genetic, psychologic,
and environmental factors influencing development and manifestations; evidenced by subjective need for specific substance;
addiction—complex progressive behavior pattern with biologic, psychologic, sociologic, and behavioral components;
hallmark unhealthy seeking behaviors subject to compulsion, in which individual has reduced ability to exert
personal control over use
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| Universal screening: effort to eliminate bias; provides opportunity to talk with every patient about risks of alcohol,
tobacco, and other substances during pregnancy; increases likelihood of identifying substance abusers; allows for
early intervention; takes ≈30 sec for most patients, 5 to 10 min for patient actually using illicit substances; ethical rationale
for universal screening—as with other chronic diseases, addiction requires intervention; capacity for marked
improvement in health status; job as health care provider is to create climate of trust and respect for patient autonomy,
and to foster effective communication and intervention; respect patient’s autonomy to refuse screening; biases—4 to
5 times more common for charts of black or Hispanic patients to contain documentation of use or nonuse of illicit substances;
blacks, Hispanics, and women seen in clinics more likely to have toxicology screen than women seen in private
obstetric practices; women presenting with preterm labor or placental abruption more likely to have urine
toxicology screens
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| Screening: self-report—first-line; respectful and neutral questions; begin with legal substances, then illicit ones; behavior
patterns—inebriation, euphoria, agitation, prescription drug-seeking behavior; medical history—frequent hospitalizations,
unusual trauma, unusual infections, frequent falls, bruises, domestic violence, and diseases in which
alcohol plays role; physical examination—“normal” most common finding in users of illicit drugs; dilated or constricted
pupils (heroin or methamphetamine use); tremors; track marks; inflamed or eroded nasal mucosa; alterations
in vital signs; laboratory testing—only acceptable as follow-up to positive interview screen; time frames for presence
of metabolites—acute use of marijuana, 3 days; cocaine, 1 to 3 days; alcohol, 8 hr; heroin, 1 day; methadone, 3 days;
positive predictive value of any particular test somewhat dependent on prevalence of condition in population served;
obtain urine toxicology (for cocaine in particular) from all patients presenting with placental abruption; steps to
intervention—ask, advise, assess, assist, and arrange
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| Substances: alcohol—no safe level of prenatal alcohol consumption; risk for fetal alcohol syndrome (FAS) and stillbirth
varies among studies; FAS defined as having at least one structural, neurologic, or functional abnormality; no exact
dose-response relationship; binge drinking increases risk; older age, high parity, and black or American Indian ethnicity
increases risk; screening—T-ACE (tolerance, annoyed, cutdown, eye-opener) survey (questions developed for prenatal
use); includes measure of tolerance to inebriating effects of alcohol; sensitivity 69%, specificity 85%, positive predictive
value 23%; positive screen—assess current and past alcohol consumption; simply focusing patient’s attention on
drinking behavior can reduce antepartum alcohol consumption; opiates—≈2.4 million people report use sometime during
lifetime; signs and symptoms include runny nose, hyperventilation, restlessness, and impaired work or school performance;
data show substance abuse in 24% of women who did not present for prenatal care vs ≈4% incidence in those
seeking care in first trimester; perinatal effects include intrauterine growth restriction and low birth weight; probably no
increased risk for preterm delivery or fetal malformation; treatment principle to change from short-acting IV form to
long-acting oral form (reduces craving and withdrawal); methadone mainstay of therapy; blocks effects of heroin; no euphoria,
and long half-life; decreases maternal morbidity; associated with high risk for neonatal abstinence syndrome,
compared to heroin (usually started 2-3 days [≤1 wk] after birth); methadone maintenance believed preferable to detoxification
during pregnancy (concern for fetal distress); buprenorphine associated with lower risk for neonatal abstinence
syndrome; not well studied in pregnancy but believed safe; cocaine—produces sense of arousal and self-confidence;
long-term use produces irritability, paranoia, and decreased libido; associated with cardiac arrhythmias, left ventricular
hypertrophy, sudden death, myocardial infarction, and stroke; no definitive congenital anomalies; impaired fetal growth;
neonatal effects—include coarse tremor, increased risk for sudden infant death syndrome (SIDS), and hypertonia; some
studies show no difference in development long-term; help patient resist urge to restart compulsive use; group vs individual
counseling; cognitive behavioral therapy; methamphetamine—neurotoxic agent; enhances dopamine release,
which enhances mood and body movement; negative effects include irritability, insomnia, cardiovascular collapse and
death, hypothermia, disseminated intravascular coagulation, seizures, and central nervous system/intracranial hemorrhages;
increased risk of infant being born small for gestational age; treatment similar to that for cocaine abuse; no specific
pharmacologic therapies; marijuana—no clear association with adverse perinatal outcome; takes ≈5 to 10 min for
maternal ingestion to reach fetal bloodstream; tobacco—most important modifiable risk factor associated with adverse
birth outcomes; increased risk for SIDS, asthma, and neonatal mortality; self-report equivalent to underreport; women
with poor education, heavy smoking habits, and/or whose partners smoke in home at risk for continuation; only 50% of
health care providers involved in smoking intervention; American College of Obstetricians and Gynecologists (ACOG)
endorses use of nicotine replacement (transdermal systems [ie, patches] and gum category B drugs); bupropion (eg,
Wellbutrin) shown safe in pregnancy (probably first-line for women unable to stop with other modalities)
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Suggested Reading
ACOG Committee on Ethics: ACOG Committee Opinion. Number 294, May 2004. At-risk drinking and illicit
drug use: ethical issues in obstetric and gynecologic practice. Obstet Gynecol 103(5 Pt 1):1021, 2004; Chang G et al:
Alcohol use and pregnancy: improving identification. Obstet Gynecol 91:892, 1998; Ebrahim SH, Gfroerer J: Pregnancy-related
substance use in the United States during 1996-1998. Obstet Gynecol 101(2):374, 2003; Greenfield SF
et al: Epidemiology of substance use disorders in women. Obstet Gynecol Clin North Am 30:413, 2003; Heikkila
AM: Antibiotics in pregnancy—a prospective cohort study on the policy of antibiotic prescription. Ann Med 25:467,
1993; Pitsouni E et al: Single-dose azithromycin versus erythromycin or amoxicillin for Chlamydia trachomatis infection
during pregnancy: a meta-analysis of randomized controlled trials. Inter J Antimicrob Agents 30:213, 2007;
Nahum GG et al: Antibiotic use in pregnancy and lactation: what is and is not known about teratogenic and toxic
risks. Obstet Gynecol 107:1120, 2006.
Editor’s Note
University of California, San Francisco, Reproductive Infectious Disease Consult Service: Free 24-hr consultation service
for medical providers seeking assistance in management of reproductive infectious disease and perinatal HIV issues:
1-415-719-8726
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