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 preventively in the third stage of labor reduces
the risk of hemorrhage and need for medical therapy for uterine atony.
atony, the condition in which the uterus fails to contract after delivery of the placenta,
is the most common cause of postpartum hemorrhage.
include induction and augmentation of labor, prolonged labor, an overdistended
uterus such as with twins or polyhydramnios, and previous postpartum hemorrhage.
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 milliunits/minute until the uterus is firmly contracted reduces the
risk for postpartum hemorrhage secondary to uterine atony.
be administered undiluted as a bolus dose because it can cause severe hypotension
Misoprostol 400 to 600 mcg can be administered orally in the third stage of labor to
prevent postpartum hemorrhage.
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.
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.
210 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
hemorrhage in addition to the infusion of more oxytocin at this time?
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
207 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 2 to 4
times daily for 2 to 7 days to promote involution of the uterus (Table 49-5).
Bleeding caused by uterine atony that is unresponsive to oxytocin can be treated with
-tromethamine, also known as carboprost tromethamine
206 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
Uterotonic Medications Used for Postpartum Obstetric Hemorrhage
Oxytocin (Pitocin) 40 IU in 1 L NS or lactated Ringer
Do not give as undiluted IV bolus,
10 IU IM if no IV site available
0.2 mg IM every 2–4 hours Contraindicated in hypertensive
0.25 mg IM every 15–90 minutes,
Caution in use with patients with
Misoprostol 1,000 mcg rectally given once Can be also be given orally or
sublingually, but PR is preferred
IM, intramuscular; IV, intravenous; NS, normalsaline; PR, per rectum.
ed. New York, NY: McGraw-Hill; 2014
Carboprost tromethamine is approved for IM use, but also has been also
administered through direct myometrial injection.
administration has been associated with severe hypotension and pulmonary edema.
An initial dose of 0.25 mg IM is given followed by 0.25 mg every 15 to 90
207,211 The total cumulative dose should not exceed 2 mg (eight doses
211 Carboprost tromethamine is effective in treating 60% to 85% of women
with uterine atony who have failed standard treatment.
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.
Hypertension, although rare, typically occurs in women with preexisting hypertension
or preeclampsia. 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.
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.
213 A recent double-blind, randomized,
placebo-controlled clinical trial was performed to clarify the role of misoprostol for
the treatment of postpartum hemorrhage.
214 Treatment was either 800 mcg of
sublingual misoprostol or 40 IU 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, and oral
formulation), but the role for misoprostol as an adjunctive therapy when oxytocin is
already available remains uncertain.
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 IU 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
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.
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
216 These antibodies can cross the placenta during subsequent
pregnancies and destroy fetal Rh D-positive RBCs. Of Rh D-negative women who do
(D) immune globulin during pregnancy, 17% will become
alloimmunized during a term pregnancy, with most cases occurring at the time of
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.
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.
CASE 49-9, QUESTION 2: What interventions should be undertaken to prevent G.G. from becoming
G.G. should have antibody screens at the beginning of each pregnancy and
postpartum. Although the American Association of Blood Banks recommends that an
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.
217 As pregnancy progresses, both the
incidence and the degree of fetomaternal hemorrhage increase.
(D) immune globulin to G.G. before or shortly after exposure to
fetal Rh D-positive RBCs will prevent her from becoming alloimmunized. Giving
(D) immune globulin at 28 weeks’ gestation has been shown to decrease the
antepartum sensitization rate from approximately 2% to 0.1%.
(D) immune globulin might prevent sensitization is by suppression of the
primary immune response to the D antigen.
216 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.
(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
(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
If a woman at risk for sensitization has not been given Rho
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
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.
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
(D) immune globulin (RhoGAM) is latex-free and thimerosalfree (contains no mercury).
Prophylaxis for First- and Second-Trimester Events and
(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
218Although 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.
217,218 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
CASE 49-9, QUESTION 4: G.G. had an amniocentesis at 16 weeks for which she received Rho
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
globulin is approximately 23 to 26 days.
218 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.
CASE 49-9, QUESTION 5: What are the most common reasons for Rh D alloimmunization during
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
globulin in a timely manner postpartum to women who have delivered an Rho
positive or untyped fetus, and (c) failure to recognize clinical procedures and
situations that increase maternal risk for alloimmunization (i.e., amniocentesis,
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 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.
gradually increase during pregnancy, but high estrogen and progesterone
concentrations inhibit milk secretion by blocking PRL’s effect on the breast
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
PRL synthesis and release depend on the inhibition of hypothalamic prolactin
the anterior pituitary inhibits the release of PRL. PIF is believed to be closely
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
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. Healthcare
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
ENHANCEMENT OF MILK PRODUCTION
was forced to supplement her infant with formula. How can C.C.’s milk production be enhanced?
Although not an FDA-approved indication, metoclopramide can be used to
stimulate lactation in women with decreased or inadequate milk production.
Metoclopramide, a dopamine antagonist, increases PRL secretion. This is
particularly useful in women whose infants do not breast-feed effectively (e.g.,
224 Metoclopramide 10 mg PO 3 times daily for 1 to 2 weeks has
been shown to help restore milk production.
Improvement in lactation occurs
within 2 to 5 days of starting therapy and persists after discontinuing
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.
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
224 The only adverse effect reported in nursing infants has been
38,225 The short-term use of metoclopramide for re-establishing lactation
appears to be safe, even in preterm infants.
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
In this special population, women likely need lactation support through
various resources addressing nutritional, medical, and psychosocial interventions.
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.
drug therapy that the FDA recommends in women who are not breast-feeding is
analgesic 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.
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.
Ice packs may be applied to the
breasts for comfort, and a mild analgesic may be used if necessary.
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
229 Evidence indicates that breast-feeding 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).
may also positively influence cognitive and intellectual development in children and
231 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
The perception that nursing should be discontinued while the mother is medicated
persists, although only a finite number of drugs are absolutely contraindicated during
95 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 breast-fed infants have been published for
Different pharmacokinetic models of drug excretion in milk have been described.
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
fluids or through milk production and nursing.
232 A more popular model describes
drug excretion in milk using a three-compartment model that incorporates the
pharmacokinetics of the mother, mammary tissues, and infant.
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
Transfer of Drugs From Plasma to Milk
Transfer of drugs from maternal plasma to milk is generally through passive
233 Low-molecular-weight, water-soluble substances diffuse through small,
water-filled pores, whereas lipid-soluble compounds pass through lipid
232 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 49-6). The pKα 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
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