TRIPASS XR تري باس

 

lower rates of chorioamnionitis.201 Their newborns experienced

decreased mortality, as well as decreased morbidity including

RDS and necrotizing enterocolitis. These effects were not owing

to tocolytics or corticosteroids because these were exclusionary factors. These results were confirmed by the results of a

large meta-analysis including more than 6,000 women, although

information on the best choice of antibiotics was less clear.202

Therefore, women with PPROM benefit from antibiotic therapy with a broad-spectrum regimen, and IV ampicillin plus

erythromycin for 48 hours followed by 5 days of oral amoxicillin

plus erythromycin for a total of 7 days treatment is a reasonable

choice.203

B.B. should not be started on any PPROM antibiotic regimens

because her membranes are not ruptured. Antibiotics have not

been proved to prevent premature births in the setting of acute

preterm labor.164,168 There is currently no role for antibiotic use

to prolong pregnancy or reduce neonatal morbidity in preterm

labor with intact membranes, and it may be associated with

long-term harm.164,203 There may be a role for treatment of bacterial vaginosis antenatally to reduce the risk of preterm birth in

women with a past history of spontaneous preterm birth.

BACTERIAL VAGINOSIS

Some, but not all, studies have demonstrated that screening

and treating asymptomatic women who are at high risk for

preterm delivery for bacterial vaginosis (BV) may reduce the risk

of preterm birth.165,167 A polymicrobial overgrowth of mostly

anaerobic bacteria, BV is one of the most common genital infections in pregnancy, and it is associated with an increased risk of

preterm delivery.200 Treatment of women with BV who had a

prior preterm delivery with oral metronidazole in combination

with erythromycin decreased the risk of recurrent preterm delivery in one randomized clinical trial, but there was no difference

for women without a history of recurrent preterm birth.204,205

In addition, a meta-analysis including 622 women with prior

preterm birth found no reduction in the risk of preterm birth

before 37 weeks’ gestation after treatment of BV with antibiotics, but did find a reduction in PPROM. In addition, in women

with BV who were treated with oral antibiotics before 20 weeks’

gestation, there was a reduction in preterm birth at less than

37 weeks.205 B.B. does not have BV; therefore, treatment with

metronidazole is unnecessary.

GROUP B STREPTOCOCCUS INTRAPARTUM

PROPHYLAXIS

Antibiotics should be given to women if delivery is anticipated

resulting either from preterm labor with intact membranes or

after PPROM to prevent group B streptococcal (GBS) infection

in the newborn. Other broad-spectrum antibiotic therapy to prevent preterm delivery should not be given routinely to women

in preterm labor with intact membranes.

Approximately 10% to 30% of pregnant women are colonized

with GBS or Streptococcus agalactiae in the vagina or rectum,

and 1% to 2% of neonates born to colonized women experience

early-onset invasive GBS disease in the absence of IV intrapartum

antibiotic prophylaxis.206 One-fourth of all cases of neonatal GBS

infections occur in preterm newborns. B.B.’s fetus, therefore,

is at risk for invasive GBS infection from vertical transmission

(mother to infant) of bacteria during labor or delivery. The mortality rate for GBS is reported to be between 5% and 20%. Fortunately, the incidence of GBS has declined to a rate of 0.34

to 0.37 cases per 1,000 live births in recent years owing to prevention efforts.206 During pregnancy, GBS infection can cause

maternal urinary tract infection, amnionitis, endometritis, and

wound infection. Antibiotics given to the mother during preterm

labor and delivery help to prevent neonatal GBS disease, which

may lead to sepsis, pneumonia, and meningitis. In the past

decade, the routine administration of intrapartum antibiotic prophylaxis to certain subsets of pregnant women has led to a 70%

reduction in the overall incidence of GBS disease.206 The decision

to treat women with intrapartum antibiotics has been based on

either a positive vaginal and rectal GBS culture routinely obtained

at 35 to 37 weeks’ gestation or one or more of the following risk

factors without culture screening: (a) previous infant with invasive GBS disease; (b) GBS bacteriuria during any trimester of the

current pregnancy; (c) unknown GBS status at onset of labor and

any of the following: delivery at less than 37 weeks’ gestation,

amniotic membrane rupture at 18 hours or more, intrapartum

temperature of 38◦C (100.4◦F) or greater.206 This treatment algorithm prevents an estimated 85% of all early-onset GBS disease

(Fig. 49-5).

Obtain GBS culture

results

GBS prophylaxis at

onset of true labor

Positive Negative

Patient entering true labor?¶

Not available before labor

onset and patient still preterm

Continue GBS prophylaxis

until delivery**

Discontinue GBS

prophylaxis

Yes No

No GBS prophylaxis at onset

of true labor;††

repeat vaginal-rectal culture if

patient reaches 35–37 weeks’

gestation and has not yet

delivered§§

Obtain vaginal-rectal swab for GBS culture†

and start GBS prophylaxis§

Patient admitted with signs and symptoms of preterm labor

FIGURE 49-5 Sample algorithm for group B streptococcus (GBS)

prophylaxis for women with threatened preterm delivery.

∗At <37 weeks and 0 days’ gestation. †If patient has undergone

vaginal-rectal GBS culture within the preceding 5 weeks, the results

of that culture should guide management. GBS-colonized women

should receive intrapartum antibiotic prophylaxis. No antibiotics are

indicated for GBS prophylaxis if a vaginal-rectal screen within

5 weeks was negative. §See Figure 49-6 for recommended antibiotic

regimens. ¶Patient should be regularly assessed for progression to

true labor; if the patient is considered not to be in true labor,

discontinue GBS prophylaxis. ∗∗If GBS culture results become

available prior to delivery and are negative, then discontinue GBS

prophylaxis. ††Unless subsequent GBS culture prior to delivery is

positive. §§A negative GBS screen is considered valid for 5 weeks. If a

patient with a history of PTL is readmitted with signs and symptoms

of PTL and had a negative GBS screen >5 weeks prior, she should be

rescreened and managed according to this algorithm at that time.

(Reprinted from Verani JR et al. Prevention of perinatal group B

streptococcal disease—revised guidelines from CDC, 2010. MMWR

Recomm Rep. 2010;59(RR-10):1.)

1139Obstetric Drug Therapy Chapter 49

Vaginal and rectal GBS cultures should be obtained from

B.B., and she should be given a loading dose of penicillin

G injection 5 million units, followed by 2.5 to 3.0 million

units IV every 4 hours until delivery, while awaiting success of

tocolysis and culture results. The Centers for Disease Control and

Prevention guidelines recommend that the benchmark for optimal prophylaxis should be antibiotics given at least 4 or more

hours before delivery. Penicillin G is preferred over ampicillin

because it has a narrower spectrum of antimicrobial activity. If

B.B. had a severe allergy to penicillin, sensitivities to clindamycin

and erythromycin should be requested at the time of culture

in the event GBS is found because of increasing resistance to

these drugs. If the isolate is susceptible to both clindamycin and

erythromycin, then clindamycin 900 mg IV every 8 hours should

be used until delivery. Erythromycin is no longer recommended

as an option for treatment because it is often associated with

inducible resistance to clindamycin. If the isolate is not susceptible to both clindamycin and erythromycin or if sensitivities

are not available, penicillin-allergic women at high risk for anaphylaxis should receive vancomycin 1 g IV every 12 hours until

delivery. Penicillin-allergic women at low risk for anaphylaxis

should receive cefazolin 2 g IV initially, then 1 g IV every 8 hours

until delivery.206 Antibiotic regimens for intrapartum antimicrobial prophylaxis are listed in Figure 49-6. Because B.B is only at

29 weeks’ gestation and is in preterm labor, she has not yet had her

GBS culture obtained, which normally occurs at 35 to 37 weeks.

Until the results of her rapid testing for GBS culture returns, she

should receive penicillin G, 3 million units IV every 4 hours until

delivery to prevent perinatal GBS infection (Fig. 49-4).

CASE 49-7, QUESTION 9: B.B.’s culture results are negative

for GBS growth. She is still at high risk for imminent delivery.

Should penicillin G administration be discontinued?

Penicillin should be discontinued at this time. Vaginal and

rectal cultures need not be repeated if B.B. delivers within the

next 4 weeks. If tocolysis is successful and delivery is delayed for

more than 4 weeks, obtaining cultures and starting penicillin G

pre-emptively should be repeated at that time. Intrapartum prophylaxis is effective only if antibiotics can be given immediately

before and during delivery.

CASE 49-7, QUESTION 10: B.B.’s contractions are gone, and

her cervical examination remains unchanged for 48 hours.

She is able to be discharged home undelivered, but is counseled to stay on bed rest for the duration of the pregnancy.

Vancomycin, 1 g IV every 12

hours until delivery

Clindamycin, 900 mg IV

every 8 hours until delivery

Patient with a history of any of

the following after receiving

penicillin or a cephalosporin?§

• Anaphylaxis

• Angioedema

• Respiratory distress

• Urticaria

Penicillin G, 5 million units IV initial

dose, then 2.5–3.0 million units†

 every

4 hours until delivery

or

Ampicillin, 2 g IV initial dose, then 1 g

IV every 4 hours until delivery

Cefazolin, 2 g IV initial dose,

then 1 g IV every 8 hours

until delivery

Isolate susceptible to

clindamycin¶

 and

erythromycin**?

No Yes

No Yes

Patient allergic to penicillin?

No Yes

FIGURE 49-6 Intrapartum antibiotic prophylaxis to prevent perinatal group B streptococcus (GBS) disease. Indications for

intrapartum antibiotic prophylaxis to prevent perinatal group B streptococcus (GBS) disease under a universal prenatal screening

strategy based on combined vaginal and rectal cultures collected at 35–37 weeks’ gestation from all pregnant women. IV,

intravenously. ∗Broader-spectrum agents, including an agent active against GBS, might be necessary for treatment of

chorioamnionitis. †Doses ranging from 2.5 to 3.0 million units are acceptable for the doses administered every 4 hours following

the initial dose. The choice of dose within that range should be guided by which formulations of penicillin G are readily available

to reduce the need for pharmacies to specially prepare doses. §Penicillin-allergic patients with a history of anaphylaxis,

angioedema, respiratory distress, or urticaria following administration of penicillin or a cephalosporin are considered to be at

high risk for anaphylaxis and should not receive penicillin, ampicillin, or cefazolin for GBS intrapartum prophylaxis. For

penicillin-allergic patients who do not have a history of those reactions, cefazolin is the preferred agent because pharmacologic

data suggest it achieves effective intraamniotic concentrations. Vancomycin and clindamycin should be reserved for

penicillin-allergic women at high risk for anaphylaxis. ¶If laboratory facilities are adequate, clindamycin and erythromycin

susceptibility testing should be performed on prenatal GBS isolates from penicillin-allergic women at high risk for anaphylaxis. If

no susceptibility testing is performed, or the results are not available at the time of labor, vancomycin is the preferred agent for

GBS intrapartum prophylaxis for penicillin-allergic women at high risk for anaphylaxis. ∗∗Resistance to erythromycin is often but

not always associated with clindamycin resistance. If an isolate is resistant to erythromycin, it might have inducible resistance to

clindamycin, even if it appears susceptible to clindamycin. If a GBS isolate is susceptible to clindamycin, resistant to

erythromycin, and testing for inducible clindamycin resistance has been performed and is negative (no inducible resistance), then

clindamycin can be used for GBS intrapartum prophylaxis instead of vancomycin. (Reprinted from Verani JR et al. Prevention of

perinatal group B streptococcal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010;59(RR-10):1.)

1140 Section 10 Women’s Health

B.B. has a significant history of a prior preterm delivery at

32 weeks’ gestation. What medication should be recommended to B.B. now and in her next pregnancy, to decrease

her risk and prevent another preterm delivery from occurring?

Recent studies have shown that progesterone supplementation can help to reduce preterm births, but should only be used

in women who have had a prior documented history of a spontaneous preterm birth before 37 weeks’ gestation.207 The optimal progesterone product is not known (vaginal suppositories,

oral capsules, or IM injectables). Progesterone should be offered

to women like B.B. who have had a prior history of spontaneous preterm delivery.207 A recent randomized, double-blinded,

placebo-controlled trial found a significant reduction in the rate

of preterm deliveries in these high-risk women with a prior

documented history of preterm delivery with the use of 17-α

hydroxyprogesterone (17-OHP).208 The rate of preterm delivery

in the treatment group was 6.3% versus 54.9% in the placebo

group.208 17-OHP is given as an IM injection prepared as 250 mg/

mL once weekly. Therapy should be initiated at 16 to 20 weeks’

gestation and continued until 37 weeks’ gestation.207 17-OHP

is widely available from compounding pharmacies, and most

recently, a commercially marketed FDA-approved drug called

Makena has been released into the market.209 Although B.B. is

already 29 weeks pregnant, she should be started on 17-OHP therapy at 250 mg/mL injected IM once weekly until 37 weeks. She

should be counseled that progesterone should be started earlier

at 16 weeks in her next pregnancies. The compounded 17-OHP

is more affordable, cost-effective, and equally as effective as the

marketed Makena product.209

Chorioamnionitis

CASE 49-7, QUESTION 11: B.B. returns to labor and delivery at 36 5/7 weeks’ gestation with spontaneous rupture of

the membranes and is found to be 4 cm dilated and 80%

effaced. Her vital signs currently are a BP of 106/79 mm Hg,

heart rate of 80 beats/minute, and respiratory rate of 12

breaths/minute with 99% oxygenation on room air. Intrapartum fetal monitoring shows a reassuring reactive fetal

heart rate with variability. After being in labor for about 16

hours, her temperature spikes up to 101.1◦F. What are the

risks of an elevated fever during labor, and how should B.B.

be treated?

Chorioamnionitis is an infection of the amniotic fluid, membranes, and placenta occurring before, during, or immediately

after birth.210 Intra-amniotic infections occur in approximately

1% to 5% of term pregnancies and may complicate up to 15%

of cases of preterm labor.211 Maternal fevers are usually the

most common clinical presentation in many patients. Diagnosis is based on the presence of fever, defined as 100.4◦F (38◦C)

or greater measured twice at least 4 hours apart, or a temperature of 101◦F (38.3◦C) measured once. Patients may also present

with maternal tachycardia (>100 beats/minute), fetal tachycardia

(160 beats/minute), uterine tenderness, foul odor from amniotic

fluid, and maternal leukocytosis.210,211 The exclusion of other

sources of infection such as urinary tract infection, viral illness,

abscesses, and drug-induced fever (i.e., epidural, misoprostol)

must be made. Common organisms ascending from vaginal flora

causing polymicrobial intra-amniotic infections include genital

mycoplasmas such as U. urealyticum and Mycoplasma hominis,

anaerobes including G. vaginalis, enteric gram-negative bacilli,

and GBS.211,212 The two most prominent risk factors of intraamniotic infections are the number of digital examinations and

duration of labor.210

Maternal complications from intra-amniotic infections

include bacteremia, suboptimal uterine contractility, and risk for

postpartum hemorrhage.211 Increases in rates of neonatal sepsis, pneumonia, meningitis, and mortality have been shown in

infants whose mothers had chorioamnionitis.213 Furthermore,

inflammation, intrapartum fever, and infection increases the risk

of long-term neurodevelopmental delay and cerebral palsy in

these neonates.214 The risk of cerebral palsy is at least twofold

to fourfold higher in infants who were exposed to intra-amniotic

infection in utero.214

Early administration of broad-spectrum antibiotics immediately after the diagnosis of chorioamnionitis has been shown

to have both maternal and neonatal benefit versus postpartum

antibiotic administration. A common regimen implemented is

ampicillin 2 g IV every 6 hours in addition to gentamicin dosed

to a target peak of 8 mcg/mL and trough of 1 mcg/mL.211 Standard dosing of gentamicin dosed every 8 hours is preferred

over once-daily dosing to prevent elevated fetal serum peak

levels, although no adverse effects of high-dose therapy were

noted.215 Clindamycin 900 mg IV every 8 hours may be added

to the regimen to cover anaerobic organisms. If fevers persist for

longer than 24 hours on triple antibiotics with ampicillin, gentamicin, and clindamycin, metronidazole can be substituted for

clindamycin to help broaden anaerobic coverage.211 Other

options for antibiotic coverage include extended-spectrum

penicillins (i.e., piperacillin-tazobactam, ampicillin-sulbactam)

or second-generation cephalosporins (i.e., cefoxitin and

cefotetan).211 Intrapartum antibiotics administered about 1 hour

after infusion produce adequate bactericidal concentrations in

the fetus and placental membranes.

With a fever of 101.1◦F, B.B. meets criteria for a clinical diagnosis of chorioamnionitis. However, she does not exhibit any other

symptoms of systemic infection such as tachycardia, uterine tenderness, or fetal tachycardia, which is quite common. Gentamicin and ampicillin should be started promptly after diagnosis

to decrease the risk of neonatal sepsis and to avoid possible neurodevelopment sequelae. In addition, clindamycin can be added

to cover anaerobic organisms. B.B.’s risk for chorioamnionitis

includes multiple digital examinations, preterm labor, spontaneous labor, and long duration of labor. Antibiotics should be

continued until B.B. is afebrile for at least 24 to 48 hours or

until delivery. Ultimately, immediate antibiotic administration

and delivery of the offending source is paramount to ensure fetal

health and safety.

Human Immunodeficiency Virus in Labor

and Breast-Feeding

CASE 49-8

QUESTION 1: S.L. is a 23-year-old G1, P0 at 38 weeks’ gestation and is positive for human immunodeficiency virus (HIV).

She is presenting to labor and delivery with spontaneous

rupture of membranes and is having regular contractions

every 5 minutes. Her last HIV RNA levels were undetectable,

and her CD4 count was 400 cells/μL. Her current antiretroviral therapy (ART) consists of zidovudine (AZT), lamivudine,

and lopinavir/ritonavir, which was started 2 years ago. What

are the risks of HIV perinatal transmission in S.L., and what

medications must be started while she is in labor?

Current recommendations state that all HIV-infected pregnant women should receive intrapartum AZT, and their infants

should receive neonatal AZT immediately after delivery for

1141Obstetric Drug Therapy Chapter 49

TABLE 49-6

Intrapartum Maternal and Neonatal Zidovudine Dosing for Prevention of Perinatal Human Immunodeficiency Virus Transmission

Drug Dose Duration

Maternal zidovudine (intravenous) Load: 2 mg/kg (actual body weight) intravenously for 1 hour

Maintenance: Continuous infusion of 1 mg/kg/h

Onset of labor until delivery of infant

Neonatal zidovudine (oral syrup)a Greater than 35 weeks’ gestation:

4 mg/kg per dose orally every 12 hours

Start within 6–12 hours of birth and

continue for 6 weeks

Greater than 30 weeks’ but less than 35 weeks’ gestation:

2 mg/kg per dose orally every 12 hours, then after 2 weeks,

advanced to every 8 hours

Start within 6–12 hours of birth and

continue for 6 weeks

Less than 30 weeks’ gestation:

2 mg/kg per dose orally every 12 hours, then after 4 weeks,

advanced to every 8 hours

Start within 6–12 hours of birth and

continue for 6 weeks

Neonatal combination therapy

(zidovudine + nevirapine)b

Zidovudine 4 mg/kg per dose orally every 12 hours

Nevirapine (total of 3 doses given orally in first week of life: at

birth, at 48 hours, and 96 hours after second dose)

Birthweight 1.5–2 kg: 8 mg per dose

Birthweight: Greater than 2 kg: 12 mg per dose

Start within 6–12 hours of birth and

continue AZT for 6 weeks.

Nevirapine given only during first

week of life.

a Intravenous neonatal zidovudine dose of 1.5 mg/kg/dose every 6 hours if oral zidovudine cannot be given.

b In mothers who have not received antepartum ARV medication, infants will need combination ARV therapy.

Source: Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant

HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Sep. 14, 2011; pp. 1–207. http://aidsinfo.nih.gov/

ContentFiles/PerinatalGL.pdf. Accessed November 7, 2011.

6 weeks regardless of the ART regimen taken during the pregnancy (Table 49-6).216 Many factors must be taken into consideration, including cost, ease of administration for compliance,

individual ART resistance patterns, and risks of side effects with

the possibility of teratogenicity.217 Generally, if a woman on ART

becomes pregnant, she should continue on therapy throughout

the pregnancy, including the first trimester.216 Women who did

not require ART before becoming pregnant should start ART prophylaxis after the first trimester but not later than 28 weeks of

gestation.216 ART is more effective in preventing perinatal HIV

transmission if it is started earlier, before 28 weeks’ gestation

versus 36 weeks’ gestation.216 All HIV-infected women should

be counseled and offered ART during pregnancy to prevent perinatal transmission regardless of HIV RNA levels.216 Avoiding the

use of efavirenz or combination of stavudine and didanosine

in women of childbearing age and during the first trimester,

if possible, may be prudent owing to possible teratogenicity

reported with these agents.216 Three ART regimens, in particular,

have been shown to decrease mother-to-child HIV transmission,

including (a) zidovudine/lamivudine/nevirapine, (b) zidovudine/

lamivudine/lopinavir-ritonavir, and (c) zidovudine/lamivudine/

abacavir.217 Further studies are needed to help identify the effectiveness and safety of other ART regimens.

Antepartum ART provides maternal virologic suppression,

reducing HIV RNA levels in blood and genital secretions and

limiting the potential for exposure. These medications cross the

placenta and produce systemic levels in the fetus, which are vital

during labor and delivery when the infant is at the highest risk of

virus exposure through genital secretions, maternal-fetal transfusion, or accidental ingestion.216

S.L. should continue on her ART (AZT, lamivudine, and

lopinavir-ritonavir) during labor without missing any doses. She

should also be started on intrapartum IV AZT therapy. A loading

dose of AZT 2 mg/kg (actual body weight) should be administered IV for 1 hour, followed by a continuous infusion of 1 mg/kg

(actual body weight) per hour. If S.L. were having a cesarean

section, the infusion must be started 3 hours before surgery to

ensure adequate systemic levels. After S.L. delivers, the infusion

should be discontinued. Prophylactic neonatal AZT should be

administered to the infant at a dose of 4 mg/kg (actual weight)

PO every 12 hours, within 6 to 12 hours of birth, for a total duration of 6 weeks.216 In the event that S.L. failed to receive any

antepartum ARV medications, her infant would be started on a

combination ARV therapy including neonatal AZT and nevirapine immediately after delivery.

CASE 49-8, QUESTION 2: Should S.L. breast-feed her infant

if her HIV RNA levels are undetectable and her CD4 counts

are 400 cells/μL?

Although S.L. is currently on effective ART to suppress her

HIV RNA levels and maintain her CD4 levels, she should not

breast-feed. Breast-feeding is not recommended for HIV-infected

women in the United States because of safer and affordable alternatives such as formula. Prophylactic ART in the infant and

mother does not entirely eliminate the risk of perinatal transmission through breast milk.216

POSTPARTUM HEMORRHAGE

Prevention

CASE 49-8, QUESTION 3: S.L. successfully has a normal

spontaneous vaginal delivery with an estimated blood loss

of 400 mL. Which medications should be given to S.L. routinely after delivery?

Oxytocin is administered routinely after the delivery of the

placenta to promote uterine contraction and vasoconstriction.

Meta-analysis of randomized clinical trials demonstrates that the

use of oxytocin preventatively in the third stage of labor reduces

the risk of hemorrhage and need for medical therapy for uterine atony.218 Uterine atony, the condition in which the uterus

fails to contract after delivery of the placenta, is the most common cause of postpartum hemorrhage.219 Risks for uterine atony

include induction and augmentation of labor, prolonged labor,

an overdistended uterus such as with twins or polyhydramnios,

and previous postpartum hemorrhage.219 Oxytocin 10 to 20 units

IM or diluted in 0.5 to 1 L of parenteral fluid and given as an IV

infusion of 200 milli-units/minute until the uterus is firmly contracted reduces the risk for postpartum hemorrhage secondary

1142 Section 10 Women’s Health

to uterine atony.220 Oxytocin should never be administered undiluted as a bolus dose because it can cause severe hypotension and

cardiac dysrhythmias.220

MISOPROSTOL

Misoprostol 400 to 600 mcg can be administered orally in the

third stage of labor to prevent postpartum hemorrhage.221,222 In

a comparison of 600 mcg of oral misoprostol with parenteral

oxytocin for prevention of postpartum hemorrhage, oxytocin

was marginally but statistically more effective and had fewer

side effects.223 Misoprostol also can be administered rectally.

Rectal administration is associated with a lower incidence of

fever and shivering, which is common with orally administered

misoprostol during the third stage of labor.223 The rectal route

of administration also is associated with lower maximal serum

concentrations and lower time to maximal concentrations than

when the drug is administered orally. Although not as effective as

oxytocin in preventing postpartum hemorrhage, misoprostol,

which is inexpensive, stable at room temperature, and not administered parenterally, may be preferred in settings of meager

resources for management of the third stage of labor.

S.L. should receive an infusion of oxytocin 20 units in 1 L of

lactated Ringer solution at 125 mL/hour.

Treatment

CASE 49-8, QUESTION 4: Within a few hours of delivering her baby, S.L. has visible vaginal bleeding. She has a

distended uterus, and the hemorrhage is attributed to uterine atony. Uterine massage, which is standard treatment,

does not control the bleeding. What other pharmacologic

options are available to treat her postpartum hemorrhage

in addition to the infusion of more oxytocin at this time?

ERGOT ALKALOIDS

If the postpartum hemorrhaging does not respond to oxytocin

administration, ergonovine maleate (Ergotrate) and its semisynthetic derivative, methylergonovine maleate (Methergine), can

be used because of their potent uterotonic effects. IM administration is associated with less frequent adverse effects (nausea,

vomiting, hypertension, headache, chest pain, dizziness, tinnitus, diaphoresis) than the IV route.220 Ergot alkaloids should be

avoided in hypertensive and eclamptic patients because of the

potential for arrhythmias, seizures, cerebrovascular accidents,

and rarely myocardial infarction. The dose of both drugs is

0.2 mg administered IM every 2 hours as needed. This may be

followed by 0.2 to 0.4 mg administered PO two to four times daily

for 2 to 7 days to promote involution of the uterus (Table 49-7).220

15-METHYL PROSTAGLANDIN F2α (CARBOPROST

TROMETHAMINE)

Bleeding caused by uterine atony that is unresponsive to oxytocin

can be treated with 15-methyl prostaglandin F2α-tromethamine,

also known as carboprost tromethamine (Hemabate).219 Carboprost tromethamine, as with naturally occurring prostaglandins,

stimulates uterine contraction and decreases postpartum hemorrhage; it is more potent and has a longer duration of effect than

its parent compound, prostaglandin F2α.

Carboprost tromethamine is approved for IM use, but

also has been also administered through direct myometrial

injection.220,224 Intramyometrial administration has been associated with severe hypotension and pulmonary edema.225 An initial

dose of 0.25 mg IM is given followed by 0.25 mg every 15 to 90

minutes.220,224 The total cumulative dose should not exceed 2 mg

(eight doses maximum).224 Carboprost tromethamine is effective

in treating 60% to 85% of women with uterine atony who have

failed standard treatment.220 Improvement in bleeding typically

occurs after one to two injections.

The most common adverse effects of carboprost tromethamine are GI, including nausea, vomiting, and diarrhea. Flushing

and fever also occur frequently. Many of the adverse effects are

related to the contractile effect of this drug on smooth muscle.224

Hypertension, although rare, typically occurs in women with

pre-existing hypertension or pre-eclampsia. The potent vasoconstricting and bronchoconstricting properties of carboprost can

cause uterine rupture, as well as pulmonary and cardiac problems. Carboprost must be used with caution in women with

asthma, and is relatively contraindicated in the presence of pulmonary, cardiac, renal, or hepatic disease.219,224

MISOPROSTOL

Several case series and small randomized trials have reported

that misoprostol might be useful in the treatment of postpartum hemorrhage caused by uterine atony. The available data are

very limited, however, and large randomized trials are needed to

clarify the efficacy of misoprostol compared with standard therapies, as well as the optimal dose and route of administration.226

A recent double-blind, randomized, placebo-controlled clinical

trial was performed to clarify the role of misoprostol for the

treatment of postpartum hemorrhage.227 Treatment was either

800 mcg of sublingual misoprostol or 40 international units of

oxytocin in 1 L of IV fluid given for 15 minutes. Resolution

of active bleeding occurred within 20 minutes in 89% to 90% of

women in each study arm, demonstrating no advantage to misoprostol over standard IV therapy with oxytocin. Furthermore,

women who received misoprostol had significantly more shivering and fever greater than 40◦C. In areas with meager resources,

misoprostol may offer advantages (low cost, prolonged stability,

TABLE 49-7

Uterotonic Medications Used for Postpartum Obstetric Hemorrhage

Drug Dose Comments

Oxytocin (Pitocin) 40 international units in 1 L NS or lactated

Ringer solution

10 international units IM if no IV site available

Do not give as undiluted IV bolus, can cause

hypotension.

Methylergonovine maleate (Methergine) 0.2 mg IM every 2–4 hours Contraindicated in hypertensive patients.

Carboprost tromethamine (Hemabate) 0.25 mg IM every 15–90 minutes, not to exceed

eight doses

Caution in use with patients with asthma, can cause

bronchoconstriction.

Misoprostol 1,000 mcg rectally given once Can be also be given orally or sublingually, but PR is

preferred route.

IM, intramuscular; IV, intravenous; NS, normal saline; PR, per rectum.

Source: Cunningham FG et al. Obstetrical hemorrhage. In: Williams Obstetrics. 23rd ed. New York, NY: McGraw-Hill; 2010:757.

1143Obstetric Drug Therapy Chapter 49

and oral formulation), but the role for misoprostol as an

adjunctive therapy when oxytocin is already available remains

uncertain.220

S.L. does not have any contraindications (i.e., asthma or hypertension) to any of the postpartum hemorrhage medications. She

should be given oxytocin 40 international units in 1 L of lactated Ringer solution given for 15 minutes. Methylergonovine

maleate 0.2 mg IM and misoprostol 1,000 mcg rectally can be

given in succession after oxytocin if bleeding does not subside.

Lastly, carboprost tromethamine 0.25 mg IM is an option if those

medications fail to control bleeding.

PREVENTION OF RH D

ALLOIMMUNIZATION

Maternal–Fetal Rh Incompatibility

CASE 49-9

QUESTION 1: G.G., a 34-year-old primigravida, had her

ABO blood group and Rh status determined during her

initial prenatal visit. She is found to be type O, Rh negative. Her husband is type O, Rh positive. What are the risks

associated with Rh incompatibility that could affect G.G.’s

unborn?

Blood group incompatibility between a pregnant woman and

her fetus can result in alloimmunization of the mother and

hemolytic anemia in the fetus. When a woman is exposed during

pregnancy, labor, or delivery to an antigen found on the fetus’s

red blood cells (i.e., AB, Rh complex) that is not found on her

own red blood cells (RBCs), she forms antibodies against fetus’s

antigen. This is referred to as alloimmunization. These antibodies,

particularly immunoglobulin (Ig) G antibodies, cross the placenta

and can interact with the fetal RBC antigens. The pregnancy in

which the alloimmunization has occurred usually results in an

unaffected child. The risk is carried on in subsequent pregnancies when maternal antibodies from a tiny amount of blood (less

than 0.1 mL) can cross from the mother to child, which can result

in the destruction of RBCs and lead to hemolytic disease of the

newborn (HDN). Most serious cases of HDN are caused by Rh

alloimmunization involving the D antigen. The other four alleles of the Rh gene complex code for the antigens C, c, E, and e.

They are also serious, but less common, causes of alloimmunization.228

An Rh D-negative mother becomes immunized after exposure to fetal erythrocytes that carry the D antigen. The likelihood

of having an Rh D-positive offspring is determined by whether

an Rh D-positive father is homozygous or heterozygous for the

D antigen. If the father is homozygous for the D antigen, all of

his offspring will be D positive (Rh positive). If he is heterozygous

for the D antigen, then there is a 50% chance that his offspring

will be Rh positive.

Pregnant women can produce detectable IgG antibodies to

Rh antigens within 6 weeks to 6 months.229 These antibodies can

cross the placenta during subsequent pregnancies and destroy

fetal Rh D-positive RBCs. Of Rh D-negative women who do

not receive Rho(D) immune globulin during pregnancy, 17%

will become alloimmunized during a term pregnancy, with most

cases occurring at the time of delivery.230

The severity of Rh-associated HDN or erythroblastosis fetalis

depends on the concentration of maternal antibodies. The placental transfer of large amounts of antibody can cause substantial RBC destruction. This initially results in anemia and

hyperbilirubinemia with compensatory extramedullary erythropoiesis (e.g., liver, spleen). In severe hemolytic diseases, the fetus

might develop hepatosplenomegaly, portal hypertension, edema,

ascites, and hepatic and cardiac failure. The clinical presentation

of profound anemia, anasarca, hepatosplenomegaly, cardiac failure, and circulatory collapse is termed hydrops fetalis.229

The severity of Rh-associated HDN generally worsens with

each pregnancy in the alloimmunized mother if her fetus is Rh

positive. Thus, it is important to discuss the consequences of

alloimmunization with any woman who is known to be alloimmunized and wishes to have more children in the future.230

Rho(D) Immunoglobulin

CASE 49-9, QUESTION 2: What interventions should be

undertaken to prevent G.G. from becoming alloimmunized?

ANTEPARTUM PROPHYLAXIS

G.G. should have antibody screens at the beginning of each pregnancy and postpartum. Although the American Association of

Blood Banks recommends that an antepartum screen should also

be obtained at 28 weeks’ gestation, the cost-effectiveness of such

screening has not been studied, and it is estimated that sensitization before 28 weeks occurs at a rate of less than 0.18%.

Therefore, the ACOG has suggested that the decision to obtain a

third-trimester antibody screen should be dictated by individual

circumstances.230 As pregnancy progresses, both the incidence

and the degree of fetomaternal hemorrhage increase. Administrating Rho(D) immune globulin to G.G. before or shortly

after exposure to fetal Rh D-positive RBCs will prevent her

from becoming alloimmunized. Giving Rho(D) immune globulin at 28 weeks’ gestation has been shown to decrease the

antepartum sensitization rate from approximately 2% to 0.1%.230

One mechanism by which Rho(D) immune globulin might prevent sensitization is by suppression of the primary immune

response to the D antigen.229 The anti-D immune globulin binds

the D antigen, and this complex is filtered by the spleen and

lymph nodes whereby it inhibits D antigen–specific B cells from

proliferating.

POSTPARTUM PROPHYLAXIS

A second dose of Rho(D) immune globulin should be repeated

within 72 hours of delivery. A larger dose is needed if a large

transplacental bleed occurs at the time of delivery (0.4% of cases).

Therefore, all Rho(D)-negative women who deliver an Rho(D)-

positive newborn should be tested to detect fetal RBCs in maternal blood (e.g., Kleihauer-Betke test) to calculate the correct dose

of Rho(D) immune globulin. If a woman at risk for sensitization

has not been given Rho(D) immune globulin within 72 hours,

she should still be treated as soon as possible because it has been

demonstrated that protection can be seen in some individuals up

to 13 days after exposure to Rh-positive RBCs.230

ADVERSE EFFECTS OF RHo(D) IMMUNE GLOBULIN

The plasma from which immune globulin is obtained is tested

for viral infections, and the manufacturing process used to produce Rho(D) immune globulin inactivates viruses such as HIV,

hepatitis B virus, and hepatitis C virus.231 Adverse reactions associated with the use of anti-D immune globulin are rare. Pain

and swelling at the injection site and rash are the most common

adverse reactions. Hypersensitivity reactions such as anaphylaxis,

although rare, can occur owing to a small amount of IgA in the

product. Rho(D) immune globulin (RhoGAM) is latexfree and

thimerosalfree (contains no mercury).231

1144 Section 10 Women’s Health

Prophylaxis for First- and

Second-Trimester Events and

Procedures

CASE 49-9, QUESTION 3: G.G. will undergo amniocentesis

at 16 weeks’ gestation. Will she need a dose of Rho(D) at

that time?

Rho(D) immune globulin should be given after all clinical

events (e.g., spontaneous abortion) or procedures (e.g., abortion,

amniocentesis, fetal blood sampling, or chorionic villus sampling)

in which fetomaternal hemorrhage is a risk in an Rh-incompatible

pregnancy.231 Although little evidence supports the need for prophylaxis in the early first trimester, adverse effects are rare and

potential benefits are thought by most experts to outweigh the

risks.230,231 Although a 50-mcg dose (MICRhoGAM) is available

for first-trimester use (e.g., chorionic villus sampling or abortion), many hospitals do not stock this dose and so a 300-mcg

standard dose is often given.

LENGTH OF PROTECTION

CASE 49-9, QUESTION 4: G.G. had an amniocentesis at

16 weeks for which she received Rho(D) immune globulin

300 mcg IM. Will she need another dose at 28 weeks’ gestation? How long will this dose protect G.G. against alloimmunization?

G.G. will still need a dose of 300 mcg repeated at 28 weeks’

gestation and within 72 hours postpartum if her infant is Rho(D)-

positive. The half-life of Rho(D) immune globulin is approximately 23 to 26 days.231 Without a large fetomaternal hemorrhage, a standard dose of 300 mcg will protect against alloimmunization for up to 12 weeks. If more than 12 weeks have

lapsed between receipt of anti-D immune globulin and delivery,

many practitioners recommend administering another antepartum dose.230,231

Failure of Immunoprophylaxis

CASE 49-9, QUESTION 5: What are the most common reasons for Rh D alloimmunization during pregnancy?

The most common reasons for Rh D alloimmunization are

(a) failure to give a dose of anti-D immune globulin at 28 weeks’

gestation, (b) failure to give Rho(D) immune globulin in a timely

manner postpartum to women who have delivered an Rho(D)-

positive or untyped fetus, and (c) failure to recognize clinical

procedures and situations that increase maternal risk for alloimmunization (i.e., amniocentesis, abortions).229,230

Thus, G.G. should be told that with proper prophylaxis with

anti-D immune globulin, there is little chance for her to become

alloimmunized. She need not worry about her present pregnancy

or future pregnancies.

LACTATION

Lactation is controlled primarily by prolactin (PRL), but the

entire process is under the intricate control of several hormones.

Breast tissue maturation during pregnancy is influenced by many

factors, including estrogen, progesterone, PRL, insulin, growth

hormone, cortisol, thyroxine, and human placental lactogen.232

PRL concentrations gradually increase during pregnancy, but

high estrogen and progesterone concentrations inhibit milk

secretion by blocking PRL’s effect on the breast epithelium.232,233

It is the dramatic decrease in progesterone that triggers lactogenesis or milk secretion for the first 3 days after delivery. Infant

suckling at the breast is necessary to maintain an adequate milk

supply beyond postpartum day 3 or 4. Nipple stimulation transmits sensory impulses to the hypothalamus to initiate PRL release

from the anterior pituitary and oxytocin from the posterior pituitary. PRL stimulates the production and secretion of breast milk,

and oxytocin stimulates the contraction of the myoepithelial cells

in the breast alveoli and ducts so that milk can be ejected from

the breast (milk letdown). Oxytocin also can be secreted through

other sensory pathways, which is why women can release milk

on hearing, smelling, or even thinking about their infants. PRL,

however, is released only in response to nipple stimulation.

PRL synthesis and release depend on the inhibition of

hypothalamic prolactin inhibitory factor (PIF) secretion. PRL

secretion is regulated primarily by dopamine-releasing neurons.

Activating the dopamine receptors on the PRL-secreting cells of

the anterior pituitary inhibits the release of PRL. PIF is believed

to be closely associated with dopamine.232,233

Although PRL controls the volume of milk produced, once

lactation is established, milk production is regulated by infant

demand. Lactation eventually ceases if milk is not removed from

the breast. Absence of suckling stops milk letdown and restores

the normal production of PIF. Decreased blood flow to the breast

reduces oxytocin delivery to the myoepithelium. Consequently,

milk secretion stops within a few days.232,233

Stimulation

NONPHARMACOLOGIC MEASURES

CASE 49-10

QUESTION 1: C.C., a 22-year-old woman, vaginally delivered her first child, a healthy term infant. C.C. plans to

breast-feed and was educated about breast-feeding during obstetric visits and prenatal classes. After giving birth,

C.C. tried to breast-feed in the delivery room with great

difficulty. Afterward, she became extremely apprehensive

and continued to have trouble breast-feeding. What can be

done to encourage C.C. and help her with lactation?

The most effective stimulus for lactation is suckling. Many

women nurse in the delivery room after uncomplicated vaginal deliveries because nursing increases maternal–infant bonding

and helps establish good milk production. If a mother does not

nurse immediately after delivery, she should be encouraged to do

so as soon as she is physically able. C.C. did try to nurse after delivery, but experienced problems that may have been related to her

emotional or physical state, or to the physical state of her infant.

The nursing staff should encourage and support C.C. emotionally to help her relax, be comfortable, and relieve her anxiety

about breast-feeding. Health care personnel also should emphasize appropriate feeding techniques and proper positioning for

breast-feeding. Allowing C.C.’s infant to sleep in her room, rather

than the nursery, may help C.C. develop a breast-feeding routine.

Most new mothers who have difficulty breast-feeding initially

respond to the emotional and educational support of a good

obstetric nursing staff. Few require pharmaceutical intervention.

ENHANCEMENT OF MILK PRODUCTION

CASE 49-10, QUESTION 2: C.C. was successful in establishing breast-feeding. Despite good technique and adequate

nutrition, however, she had trouble maintaining adequate

milk production after about 2 to 3 weeks and was forced

to supplement her infant with formula. How can C.C.’s milk

production be enhanced?

1145Obstetric Drug Therapy Chapter 49

Although not an FDA-approved indication, metoclopramide

can be used to stimulate lactation in women with decreased

or inadequate milk production.43,234–237 Metoclopramide, a

dopamine-antagonist, increases PRL secretion. This is particularly useful in women whose infants do not breast-feed effectively (e.g., preterm infants).234 Metoclopramide 10 mg PO three

times daily for 1 to 2 weeks has been shown to help restore milk

production.43,234–236 Improvement in lactation occurs within 2 to

5 days of starting therapy and persists after discontinuing metoclopramide.

The estimated total daily dose of metoclopramide ingested

by the nursing infant of a woman on 30 mg/day is 1 to 45

mcg/kg/day.43 This is below the maximal recommended infant

daily dose of 0.5 mg/kg/day. Maternal doses of 30 mg/day do

not alter PRL, thyroid-stimulating hormone, or free thyroxin

serum concentrations in breast-fed infants.237 The only adverse

effect reported in nursing infants has been intestinal gas.43,236 The

short-term use of metoclopramide for re-establishing lactation

appears to be safe, even in preterm infants.43,234

Recent randomized control trials have examined the effects of

metoclopramide on breast milk volume and duration in women

with recent preterm deliveries and found that breast-feeding outcomes were poor despite medication treatment and lactation

support.238,239 In this special population, women likely need lactation support through various resources addressing nutritional,

medical, and psychosocial interventions.

Suppression

CASE 49-11

QUESTION 1: After delivery of a nonviable fetus at 24

weeks’ gestation, J.G., a 26-year-old G2, P2, informs her

obstetrician that she wishes to suppress her lactation. What

methods are available to suppress lactation?

Suppression of lactation is indicated for women who do not

want to breast-feed, women who have delivered a stillborn infant,

and those who have had an abortion. Both drugs and nonpharmacologic methods have been used. In 1988, the FDA, however,

recommended against drug-induced suppression of lactation.240

The only drug therapy that the FDA recommends in women

who are not breast-feeding are analgesics for the relief of breast

pain. Bromocriptine was approved for the postpartum suppression of lactation; however, the FDA rescinded its approval for that

indication because of cardiovascular complications (e.g., stroke,

myocardial infarction) associated with its use.233

If breast stimulation is avoided (with or without the use of

a breast binder), breast milk production will continue, leading

to engorgement and distension of breast alveoli. This leads to

the termination of lactation after several days. Approximately

40% of women using this method experience breast discomfort

and pain; 30% experience milk leakage from their nipples.240,241

Ice packs may be applied to the breasts for comfort, and a mild

analgesic may be used if necessary.

DRUG EXCRETION IN HUMAN MILK

Breast milk is recognized as the optimal source of nutrition for

infants, with documented benefits not only to infants, but also to

mothers, families, and societies.242 Evidence indicates that breastfeeding decreases the incidence or severity of many infectious

processes (e.g., otitis media, respiratory infections, urinary tract

infections) in infants. In children and adults who were breast-fed,

the risk of developing certain medical illnesses also may decrease

(e.g., obesity, inflammatory bowel disease, celiac disease, childhood leukemia).243 Breast-feeding may also positively influence

cognitive and intellectual development in children and young

adults.244 Numerous benefits to the mother also have been identified, such as decreased postpartum blood loss, more rapid uterine

involution, earlier return to prepregnancy weight, and decreased

risks of breast cancer, ovarian cancer, and osteoporosis.242

The perception that nursing should be discontinued while the

mother is medicated persists, although only a finite number of

drugs are absolutely contraindicated during lactation.104 Unlike

the use of drugs during pregnancy, drug excretion in breast milk

can be approximated to a certain extent. Actual measurements of

drug concentrations in milk and clinical observations in breastfed infants have been published for selected drugs.

Pharmacokinetics

Different pharmacokinetic models of drug excretion in milk have

been described.245 A two-compartment open model presents the

maternal fluids as one compartment and breast milk as the other.

After ingestion, the drug gets absorbed into the maternal compartment, with a proportion of drug passing into breast milk

and the remaining portion distributed in, and eliminated from,

the maternal system. Drugs reaching breast milk will ultimately

leave this compartment either by diffusing back into maternal fluids or through milk production and nursing.246 A more

popular model describes drug excretion in milk using a threecompartment model that incorporates the pharmacokinetics of

the mother, mammary tissues, and infant.245 The overall risk

to the infant depends on the amount of drug bioavailable to the

mother, the amount reaching breast milk, and the actual amount

of drug ingested and bioavailable to the nursing infant.

Transfer of Drugs From Plasma to Milk

Transfer of drugs from maternal plasma to milk is generally through passive diffusion.247 Low-molecular-weight,

water-soluble substances diffuse through small, water-filled

pores, whereas lipid-soluble compounds pass through lipid

membranes.246 Many factors affect the excretion of drugs in

breast milk, and they should be carefully assessed before making

a recommendation. The extent of drug passage into breast milk is

often expressed quantitatively as the milk to plasma (M/P) ratio.

This ratio should not be used as the sole determinant of whether

a drug is safe for use during breast-feeding (see Estimating Infant

Exposure section).

Several parameters affect drug excretion into breast milk

(Table 49-8). The pKa of a drug partially determines how much

drug can reach the milk, because only the nonionized portion

of free drug is transferred. Human milk, with an average pH of

7.1, is slightly more acidic than plasma. In general, drugs that are

weak acids (e.g., penicillin) tend to have a higher concentration

in plasma than milk (M/P <1). Conversely, the concentration of

weak bases (e.g., erythromycin) in milk are more likely to be

higher or to reach an equilibrium with that measured in plasma

(M/P ≥1).246 Once in the milk, the proportion of ionized weak

base rises in the relatively acidic solution, and thus drug trapping occurs. Drug reabsorption has been found for some agents,

and the prevention of passage back into the plasma by trapping

may be clinically important. Lipid solubility also is determined

to a large extent by the degree of ionization because drugs with

relatively high lipid solubility exist in the nonionized form. Diffusion through lipid membranes is probably the most important

pathway for drug transfer. Although pH, pKa, and lipid solubility

are important elements, other factors may significantly modify predictions based solely on these chemical characteristics.

Two of these other factors are protein binding and molecular

weight.246,247 Drugs with high molecular weights such as insulin

(MW >6,000) are less likely to transfer into breast milk, whereas

those less than 300 transfer more readily.43 Highly protein-bound

1146 Section 10 Women’s Health

TABLE 49-8

Factors Affecting the Fate of Drugs in Milk and the Nursing

Infant

Maternal Parameters  Drug dosage and duration of therapy

 Route and frequency of administration

 Metabolism

 Renal clearance

 Blood flow to the breasts

 Milk pH

 Milk composition

Drug Parameters  Oral bioavailability (to mother and infant)

 Molecular weight

 pKa  Lipid solubility

 Protein binding

Infant Parameters  Age of the infant

 Feeding pattern

 Amount of breast milk consumed

 Drug absorption, distribution, metabolism,

elimination

pKa, dissociation constant.

Source: Anderson PO. Drugs and breast milk [letter]. Pediatrics. 1995;95:957;

Dillon AE et al. Drug therapy in the nursing mother. Obstet Gynecol Clin North

Am. 1997;24:675; Begg EJ et al. Studying drugs in human milk: time to unify the

approach. J Hum Lact. 2002;18:323; Bennett PN, ed. Drugs and Human Lactation.

2nd ed. New York, NY: Elsevier; 1996; Hale TW. Medications and Mothers’ Milk.

13th ed. Amarillo, TX: Pharmasoft Medical Publishing; 2008.

drugs such as glyburide (99% protein bound) are less likely to be

transferred into breast milk, although infants should still be monitored for signs of hypoglycemia.

Drug transfer also is influenced by the yield of milk, which is

related to blood flow and PRL secretion.246 Lactation is associated

with a high blood flow to the breasts, but little is known about

this flow during or between feedings. The milk yield (volume)

differs slightly depending on the duration of lactation and the

time of day. A diurnal pattern has been observed, with highest

yields at 6 am and lowest yields at 6 pm or 10 pm. The mean composition of mature human milk is approximately 87% aqueous

solution, 3.5% lipids, 8% carbohydrate (83% of which is lactose),

0.9% protein, and 0.2% nitrogen.248 The proportions of these

components may vary widely from woman to woman and even

within the same woman. For example, hind milk (breast milk

that is expressed last and contains more fat) contains fourfold to

fivefold the fat content of foremilk (breast milk that is expressed

first and is high in water content, water-soluble vitamins, carbohydrates, and protein), whereas colostrum (first milk, secreted

late in pregnancy and in the first few days after delivery) contains

little fat. Fat content also has exhibited a diurnal variation.

After a drug reaches the milk, it equilibrates between the

aqueous and lipid phases. The nature of this equilibration can

modify how much drug actually reaches the infant. Infant

feeding patterns differ significantly from one baby to another.

The time spent suckling at each breast, and the volume of

milk taken in, also determine the amount of drug ingested,

especially if the drug has partitioned into one phase more so

than the other. Once the infant ingests the drug via breast milk,

the pharmacologic and adverse effects on the infant will be

determined by the extent of oral bioavailability, distribution,

metabolism, and rate of elimination. These pharmacokinetic

parameters differ, depending on the infant’s age and whether he

or she was born prematurely or at term.

CASE 49-12

QUESTION 1: H.P. is 25-year-old woman G3, P3 who

recently was diagnosed with a distal deep vein thrombosis (DVT) in her lower left extremity