ISSUES IN HIGH-RISK OBSTETRICS
Educational Objectives
| The goal of this program is to improve the care of pregnant women at risk for preterm birth. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Identify pregnant women at risk for preterm birth.
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| 2. Discuss complications associated with various tocolytic agents.
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| 3. Manage women having preterm contractions.
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| 4. Discuss evidence supporting cerclage for prevention of preterm birth.
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| 5. Discuss contrary evidence showing cerclage is not beneficial for prevention of preterm birth.
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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 following has been
disclosed: Dr. Brown is on the Speakers’ Bureau of Matria Healthcare and is a consultant for Bayer and GlaxoSmithKline.
Drs. Porto and Resnick and the planning committee reported nothing to disclose.
Acknowledgments
Dr. Brown was recorded at New Concepts in Obstetrics and Gynecology, sponsored by the University of Miami Miller
School of Medicine, and held February 21-23, 2008, in Miami, FL. Drs. Porto and Resnick were recorded at the 63rd
Annual Obstetrical and Gynecological Assembly of Southern California, sponsored by the Obstetrical and Gynecological
Assembly of Southern California, and held March 21-22, 2008, in Los Angeles, CA. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
| PRETERM LABOR: EXPLORING THE CONTROVERSY —Haywood L. Brown, MD, Professor and Chair, Department
of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC
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| General considerations: preterm birth major cause of neonatal morbidity and mortality; 10% to 15% of pregnancies
at risk for preterm labor; antenatal steroid therapy significantly decreases respiratory distress syndrome; preterm
birth expensive and challenging problem in obstetrics; preterm infant in neonatal intensive care unit (NICU)
has significant effect on mothers and families; incidence in United States—≈500,000 babies born prematurely each
year (≈1300 preterm births every day); 1 in 8 babies born prematurely; 27% increase in premature births since
1981; by year 2010, objective to reduce incidence to 7.6 per 1000 live births; significant disparities among ethnic
groups; greater risk among black women in United States than among American Indian, Hispanic, or white women;
increased risk among women of low socioeconomic status; cost—$12 billion total national hospital cost for premature
babies in 2000; $1.2 billion total hospital stay charges; ≈$23,000 per preterm infant in 2000; $58,000 average
hospital charge per premature neonate, compared to $4300 for typical newborn stay
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| Risk factors: early prenatal assessment for risk important; history of preterm delivery; multifetal gestation; history of
preterm labor and term delivery; incompetent cervix; history of abdominal surgery at >20-wk gestation; uterine anomaly
or septum; cervical shortening (universal ultrasonography [US] screening not recommended); cervical dilation
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| Diagnosis: compromised by differences in cervical dilation and effacement measurements; causes study flaws leading
to controversies about treatment; examination of cervix warranted with symptoms (eg, pelvic pressure, change
in vaginal discharge, menstrual cramps, constant backache)
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| Interventions: bed rest and hydration stop contractions, but no convincing evidence of reduction in preterm labor
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| Tocolytic therapy: interrupts uterine contractions; trial data suggest prolongation of pregnancy for 48 hr; therapy
must be individualized; pharmacologic agents—terbutaline (beta-adrenergic agonist); magnesium sulfate; nifedipine
(calcium channel blocker); indomethacin (prostaglandin synthesis inhibitor); atosiban (oxytocin receptor
antagonist; not approved for use in United States); maternal complications associated with beta-adrenergic agonists
(ritodrine and terbutaline)—hypotension, cardiac arrhythmias, myocardial ischemia, and pulmonary edema; metabolic
side effects associated with beta-adrenergic agonists—hyperglycemia; glucose intolerance; ketoacidosis;
changes in calcium and potassium; lactic acidosis; predisposing factors for pulmonary edema—multifetal gestation,
increased heart rate; iatrogenic fluid overload; decreased urine output; decreased colloid osmotic pressure;
edema responds to cessation of infusion and initiation of appropriate treatment, although preterm condition still
present
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| Magnesium sulfate: off-label use; few randomized trials until recently; central depressant effects on myometrial contractions;
direct cellular effect on calcium; adverse events— toxic medication; hypermagnesemia with impaired
maternal renal function; hyponatremia; inappropriate antidiuretic hormone syndrome; pulmonary edema; depression
of central nervous system (CNS); dosage—loading dose, 4 to 6 g intravenously (IV) over 20 min; maintenance
dose, 1 to 3 g/hr (bedside surveillance recommended with 4 g/hr); neonatal effects—affects tone; low Apgar scores;
half-life ≈40 hr; turn pump off and allow magnesium to wash out if delivery planned
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| Indomethacin: in speaker’s opinion, probably best tocolytic available; true prostaglandin inhibitor; pharmacokinetics—
absorbed orally and rectally; plasma concentration peaks in 1 to 2 hr; protein-bound and eliminated unchanged
in pregnant women; readily crosses placenta; contraindications—women with asthma, coagulation disorders, hepatic
or renal insufficiency, or peptic ulcer disease; decreases maternal urine output; recommended treatment—
limit use to 32-wk gestation; use for no longer than 24 to 72 hr; dosing—loading dose, 100 mg; 25 to 50 mg q6h
for ≈48 hr; discontinue promptly if delivery imminent (crosses placenta); fetal-neonatal effects—oliguria; intestinal
infarction; constriction of ductus arteriosus; pulmonary hypertension; more preterm the infant, greater the
risk; concentrations remain for ≈15 hr; 90% protein-bound in neonate
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| Calcium channel blockers: pharmacokinetics—duration of action ≈6 hr; nifedipine initial dose, 10 to 20 mg; 20 mg
every 6 to 8 hr; profound hypotension if used in conjunction with other drugs; lower maternal side effects than
with betamimetics; should not be combined with betamimetics or magnesium sulfate; maintenance oral tocolysis—
data show no benefit to prophylactic oral tocolysis for prematurity reduction with maintenance therapy; fails due
to lack of bioavailability and receptor desensitization (similar to effect of oxytocin)
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| Tocolytic therapy: contraindications—chorioamnionitis and preeclampsia (absolute contraindications); stable placenta
previa (relative contraindication); successful tocolysis—does not require elimination of contractions, only that
frequency of contractions does not define labor; most patients have contractions regardless of tocolytic therapy;
goal is decreased frequency of contractions, so that labor does not occur; second agent or combination agents may
improve efficacy, but increase side effects and maternal risk; progesterone therapy—data show 120 mg of 17 alpha-
hydroxyprogesterone caproate (17P) significantly reduced risk for delivery at <37 wk (incidence, 36% vs 54%);
O’Brien showed reduced rate of cervical shortening in women receiving intravaginal progesterone
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| Cervical length and prematurity: data show significantly increased risk for premature delivery when cervical
length <2.5 cm; numerous studies show shorter the cervix, greater the risk for preterm delivery; historically, studies
focused on dilation and treatment, failing to take into account cervical length as possible reason why some women
went into labor and others did not
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| Fetal fibronectin: positive predictive value ≈30% to 35%; data show 93% of patients with positive fibronectin and
shortened cervical length delivered at <35 wk, compared to 5% of patients with longer cervical length and negative
fibronectin
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| Folate: data show 70% decrease in incidence of spontaneous preterm delivery (between 28 and 32 wk) in women
taking 1 mg of folate for >1 yr; effect not significant beyond 32 wk if supplementation <1 yr; equally effective in
women with and without previous preterm birth
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| Management of progressive preterm labor: rule out infection (eg, pyelonephritis, appendicitis, abruption) if
contractions persist despite 12 to 24 hr of tocolysis; amniotic fluid assessment for chorioamnionitis—infection diagnosed
based on low glucose; interleukin-6 (IL-6) levels only done experimentally; Gram stain; culture (results delayed
24-48 hr, so base conclusion on evidence at hand); white blood cells (contradictory); weigh benefits vs risks before implementing
combination therapy; may be beneficial in low gestational age preterm situation, likely not after 31.5 wk;
tertiary referral hospital recommended for delivery of preterm infant
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| Conclusions: tocolytic treatment should be reserved for patients with documented cervical changes; oral maintenance
therapy for preterm labor has no effect on total days gained in utero after IV therapy; amniocentesis to rule out chorioamnionitis
should be considered in women who continue to progress despite high-dose tocolytic treatment; magnesium
sulfate or terbutaline associated with maternal and neonatal side effects; indomethacin (eg, Indocin) should be
reserved for patients refractory to IV therapy and should be used in short window; future research should focus on understanding
genetics, epidemiologic factors, and prevention
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| DEBATE: CERCLAGE IMPROVES PREGNANCY OUTCOME WITH A FUNNELING CERVIX IN MIDTRIMESTER
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| PRO—Manuel Porto, MD, Professor and EJ Quilligan Endowed Chair, Department of Obstetrics and Gynecology,
University of California, Irvine, School of Medicine
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| US evaluation: no evidence to support routine screening or cerclage in low-risk patients or those with history of
first-trimester pregnancy loss; significant false-positive rate; abnormal results can lead to iatrogenic problems; patient
with 1 second-trimester or early third-trimester loss—US evaluation warranted; large group of asymptomatic
patients, of whom 40% had cervical shortening to 2.5 cm (transvaginal US measurement normally ≈4.0 cm); ≈50%
had significant preterm delivery; funneling associated with cervical shortening; data involving high-risk patients
with history of mid-trimester pregnancy loss showed 80% of patients who underwent US surveillance rather than
elective cerclage never developed shortened cervix; preterm delivery rate and pregnancy loss rate identical in patients
who underwent urgent cerclage after cervical shortening and those who had elective cerclage; meta-analysis
of trial data shows 56% reduction in preterm delivery <35 wk; in contrast, cerclage associated with significantly
higher incidence of preterm delivery in multiple-gestation pregnancies; American College of Obstetricians and Gynecologists
(ACOG) suggests serial transvaginal US examinations should be considered in women with history of
second- or early-trimester pregnancy loss; US examinations should not begin before ≈16 wk, since upper portion of
cervix not easily distinguished from lower segment in early pregnancy (most cases of incompetent cervix occur significantly
later than 16 wk)
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| Elective cerclage: data show only subgroup of patients with 3 second-trimester losses experienced significant benefit
from elective cerclage; speaker believes only small subgroup of patients with second-trimester cervical shortening
benefit from urgent cerclage; perform transvaginal US to rule out fetal malformations; maternal risk for chorioamnionitis
important component; cervical change documented before fetal viability better predictor of need for cerclage
than change identified after viability (ACOG statement); elective cerclage and increased morbidity—no evidence that
elective cerclage not associated with morbidity
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| Summary: no evidence supporting transvaginal US in low-risk patients; elective cerclage should be considered in
patients with 3 unexplained mid-trimester losses; surveillance with serial transvaginal US from 16 to 24 wk recommended
for high-risk patients not meeting criteria of 3 pregnancy losses; cerclage not recommended beyond 24 wk;
more data needed on use of progesterone
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| DEBATE: CON —Robert Resnick, MD, Professor Emeritus of Reproductive Medicine, Department of Obstetrics
and Gynecology, University of California, San Diego, School of Medicine
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| Pathways to preterm birth: J. Iams—first to describe monitoring of cervical length; stated no value in looking at
cervix at <16-wk gestation, and labor starts at level of internal os; believed that funneling simply expression of
early parturitional event occurring at wrong time; can be difficult to establish if patient with history of preterm birth
actually had preterm labor, cervical incompetence, or preterm premature rupture of membranes (PPROM)
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| Cervical cerclage for patient with short cervix: retrospective cohort study of 70 women between 14 and 24 wk
gestation with cervical length <15 mm; showed cerclage in patients with short cervix did not reduce rate of spontaneous
preterm delivery and increased risk for PPROM; Cochrane Database meta-analysis of 6 trials (2175 women)
showed no difference in preterm birth (<33 wk) in women who had cerclage (2 trials among patients with short cervices);
trial involved cerclage in 67 low-risk women whose cervices were 25 mm at 16 to 24 wk gestation, and who
had no history of preterm birth or mid-trimester loss; 31 patients who had cerclage plus bed rest compared to 36
women treated with bed rest alone; primary outcome preterm birth at <35 wk; no difference in gestational age at
delivery; meta-analysis by Berghella et al involved 4 randomized trials of 607 women with cerclage for short cervix;
preterm birth (<35-wk gestation) occurred in 29% of cerclage group, compared to 35% of controls (relative
risk 0.84, barely significant); cerclage associated with significantly higher incidence of preterm birth in twin gestations;
each of 4 studies in meta-analysis had different criterion for cervical length at time of cerclage (meta-analysis
adding additional patients not peer-reviewed)
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| Preterm birth and intrauterine infection: 3 components to parturition (myometrial contractility, cervical ripening,
and molecular-biochemical interaction between decidua and fetal membranes); inflammatory mediators
present in amniotic fluid in 50% of women with preterm birth (incidence higher among women delivering in “window”
of incompetent cervix); elevated IL-1 (IL-1α and IL-1 β), IL-6, IL-8, tumor necrosis factor alpha (TNF-α),
monocyte chemotactic protein 1, and other inflammatory mediators found in amniotic fluid in women delivering
preterm (with intact membranes); subclinical infection plays significant role in early preterm birth; data concluded
that level of IL-6 in ammiotic fluid increased in presence of cervical incompetence; speaker does not believe evidence
supports cerclage as treatment for cervical incompetence; data show shorter cervical length in women with
intra-amniotic infection; receiver operating characteristic (ROC) curve analysis showed cervical length cutoff of 15
mm predicted intra-amniotic infection; data evaluating effectiveness of prophylactic cerclage of short cervix based on
IL-8 in cervical mucus—women with short cervix and normal IL-8 less likely to deliver if cerclage done; when cervical
mucus IL-8 elevated, delivery at <37 wk more likely with cerclage (again suggesting that presence of inflammatory
mediators may be cause of cervical incompetence in second trimester, but results of cerclage may be
affected by presence or absence of mediators)
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| Progesterone to prevent preterm birth in women with short cervix: progesterone likely to have biochemical
molecular impact at level of uterine myometrial contractility, cervical ripening, and interaction between decidua
and fetal membranes; data show progesterone decreases rate of preterm birth in women with short cervices; secondary
analysis of previous trial data looking at progesterone compared to placebo show preterm birth lower for
women receiving progesterone (0% vs 30%) and admissions to NICU decreased; speaker believes cervical shortening
and funneling result of biologic and molecular mechanism, and not something that can be cured by suturing
cervix
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Suggested Reading
Berghella V et al: Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level
data. Obstet Gynecol 106:181, 2005; Brown HL et al: Tocolytic treatment for preterm contractions with and without
cervical changes. Am J Perinatol 14:405, 1997; Cox SM et al: Randomized investigation of magnesium sulfate for
prevention of preterm birth. Am J Obstet Gynecol 163:767, 1990; Drakeley AJ et al: Cervical stitch (cerclage) for
preventing pregnancy loss in women. Cochrane Database Syst Rev (1):CDOO3253, 2003; Goldenberg RL et al: Intrauterine
infection and preterm delivery. N Engl J Med 342:1500, 2000; Hassan SS et al: Does cervical cerclage prevent
preterm delivery in patients with a short cervix? Am J Obstet Gynecol 184:1325, 2001; Holst RM et al: Cervical
length in women in preterm labor with intact membranes: relationship to intra-amniotic inflammation/microbial invasion,
cervical inflammation and preterm delivery. Ultrasound Obstet Gynecol 28:768, 2006; Macones GA et al: Efficacy
of oral beta-agonist maintenance therapy in preterm labor: a meta-analysis. Obstet Gynecol 85:313, 1995; Meis
PJ et al: Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 348:2379,
2003; O’Brien JM et al: Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from
a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 30:687, 2007.
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