Obstetrics and Gynecology - 2009

Editor-in-Chief Rogerio A. Lobo, M.D.
Professor of Obstetrics & Gynecology, College of Physicians and Surgeons of Columbia University, New York, NY

Chapter 9: Obstetric Complications
Errol R. Norwitz, MD, PhD Men-Jean Lee, MD

Contents

1. Cervical Insufficiency 2. Preterm Labor 3. Post-term Pregnancy 4. Hypertensive Disorders of Pregnancy 5. Intrauterine Fetal Demise 6. Intrauterine Growth Restriction 7. Multiple Pregnancy 8. Premature Rupture of Membranes 9. Antepartum Hemorrhage 10. References 11. Questions

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1. Cervical Insufficiency
Cervical insufficiency (also known as cervical incompetence) is defined as a functional weakness of the cervix resulting in a failure to carry a pregnancy to term.1, 2 It complicates 0.1%-2% of all pregnancies, and is estimated to be responsible for 15% of deliveries between 16 and 28 weeks of gestation.3-5 The classic presentation is that of painless cervical dilatation and shortening without evidence of uterine contractions.6
Etiology

Management

Some risk factors for cervical insufficiency are described (Table 1), but most patients have no risk factors.1, 2

The exact etiology of cervical insufficiency has not been elucidated.6
Diagnosis

Cervical insufficiency is a clinical diagnosis characterized by acute, painless dilatation of the cervix, usually in the mid-trimester (generally between 16-24 weeks), culminating in fetal membrane prolapse and/or premature rupture of the membranes (PROM) with resultant preterm and often previable delivery.

Types of Cerclage Prophylactic (elective) cervical cerclage is indicated in women with a history of prior pregnancy loss and/or preterm delivery with a history consistent with cervical insufficiency, because the probability of recurrence of cervical insufficiency in a subsequent pregnancy is 15%-30%.1, 7, 8 Prophylactic cervical cerclage is placed most commonly at 13-16 weeks of gestation, at which time the complication rate is low (<1%).2 Prophylactic cerclage for diethylstilbestrol (DES) exposure (when the patient was exposed in utero to DES taken by her mother) alone remains controversial. Most clinicians believe that a history of in utero DES exposure per se (without a history of prior pregnancy loss) is not an indication for prophylactic cerclage placement. Similarly, elective cerclage has not been shown to be beneficial in women with multiple pregnancies without a prior history of cervical insufficiency.9-12 The primary indication for emergent (salvage, rescue) cervical cerclage is premature effacement and/or dilatation of the cervix in the absence of labor prior to 28 weeks gestation. It is associated with a less than 50% success rate. Poor prognostic features include cervical dilatation >4 cm and prolapsed membranes. In

Cervical cerclage has become the mainstay for the management of cervical insufficiency. If the prior preterm delivery was the result of preterm labor (documented active contractions) and not cervical insufficiency, cerclage placement is not indicated.2

Table 1 Risk Factors for Cervical Insufficiency

Congenital

Acquired

Müllerian abnormalities (congenital cervical hypoplasia or aplasia) In utero diethylstilbestrol (DES) exposure

Cervical trauma (prior surgical or obstetric trauma) Connective tissue abnormalities (Ehlers-Danlos syndrome)

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general, most practitioners do not place an emergent cerclage after fetal viability is reached (after 24 weeks), due to the inherent high risk of causing an iatrogenic rupture of fetal membranes and accelerating the preterm delivery. An alternative plan of management in these pregnancies is bed rest for the duration of the pregnancy without cerclage placement.8

The benefit of cervical cerclage for asymptomatic cervical shortening diagnosed either by digital examination or transvaginal ultrasound in women without a prior history suggestive of cervical insufficiency remains controversial.8 Although earlier studies suggested that cerclage placement in women with an incidental finding of a shortened cervix on ultrasound examination may improve perinatal outcome, subseTable 2 Contraindications to Cervical Cerclage

quent studies were unable to confirm these observations. In a recent multicenter randomized clinical trial, 47,123 women with singleton pregnancies were screened by transvaginal cervical length measurements at 22-24 weeks gestation. Cervical length was shortened (≤15 mm) in 470 women. Of these, 253 (54%) participated in the study: 127 were randomized to Shirodkar cerclage and 126 to expectant management. Although cervical shortening was associated with a high risk for preterm birth prior to 33 weeks, placement of a cerclage did not reduce the risk of early preterm birth (22% [28/127] in cerclage group vs. 26% [33/126] in control group; P=0.44).13

Maternal Factors Absolute contraindications

Uteroplacental Factors

Fetal Factors

Uterine contractions / labor Life-threatening maternal conditions that preclude anesthesia

Rupture of fetal membranes Unexplained vaginal bleeding (abruption)

Intrauterine fetal demise Major fetal anomaly not compatible with life

Intrauterine infection
Relative contraindications

Gestational age >28 weeks

A mucopurulent cervical discharge with membrane opacification

Placental previa

Intrauterine fetal growth restriction

Positive Gram stain or culture on amniotic fluid (because of a failure rate ≥90%) Fetal membranes prolapsing through the cervical os (because of the high incidence of preterm PROM) Vaginal infection

After the limit of fetal viability has been reached (≥24 weeks gestation)

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Contraindications. Contraindications to cerclage are listed in Table 2. Intra-amniotic infection is an absolute contraindication to cerclage placement,14, 15 and the presence of bacteria on Gram stain or a positive culture from preoperative amniocentesis is associated with a failure rate of >90%. Preoperative amniocentesis in asymptomatic patients with cervical insufficiency may be considered prior to emergent cerclage placement. Although ACOG supports cervical cerclage placement up to 28 weeks gestation, many practitioners would not recommend cerclage placement beyond the limit of fetal viability (≥24 weeks), because the risk of complications outweighs the potential benefit.7, 16 Furthermore, placement of a cerclage in a patient that is in preterm labor (actively contracting) is contraindicated due to the risks of cervical trauma and/or uterine rupture caused by maternal contractions against a surgically sutured cervix.

Technical considerations. Once the decision has been made to proceed with cerclage placement, a preoperative ultrasound examination should be performed to confirm fetal viability and exclude major structural anomalies. Regional anesthesia is preferred to general endotracheal anesthesia because of the decreased maternal morbidity. Prophylactic tocolysis may be used to inhibit transient uterine contractions associated with emergent cerclage placement, but there is no objective evidence that tocolysis improves outcome. Prophylactic broad-spectrum antibiotics are recommended for emergent cerclage placement. However, there are insufficient data to recommend routine use of prophylactic antibiotics for elective cerclage placement. If the fetal membranes are found to be prolapsing through the external os, the risk of iatrogenic rupture of the fetal membranes may be as high as 50%. Trendelenburg position,17 retrograde filling of the bladder,18 placement of a 30 mL Foley catheter trancervically past the internal os and filling the balloon,19 placement of a moistened sponge forceps into the cervical os,20 and/or therapeutic amniocentesis21-23 can be used to reduce the fetal membranes prior to cerclage placement. In addition, the edges of the cervix can be grasped by sponge forceps to build length to the cervix for cerclage placement.24 Transvaginal cervical cerclage has been the mainstay for the management of cervical insufficiency. There are 2 basic types of transvaginal cerclage placement techniques: Shirodkar and McDonald.25 The choice of
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cervical cerclage is best left to the discretion of the obstetric care provider, especially in the setting of a prophylactic cerclage. The selection of the type of cerclage placement for emergent cases may be limited by the thickness and length of cervical tissue available for suture placement. The choice of suture material has evolved over the decades from fascia lata or silk to currently a wide selection of non-absorbable sutures, including Mersilene® tape (Dacron® tape), Prolene® (monofilament), and Ethibond® (braided, coated polyester).26 The choice of suture is based on practitioner preference and choice of technique. Shirodkar cerclage is a single suture placed submucosally around the cervix at the level of the internal os after surgically reflecting the bladder anteriorly and the rectum posteriorly.27 The suture can be secured anteriorly or posteriorly, and the mucosal incisions closed. McDonald cerclage is 1 or more purse-string sutures around the cervix placed without dissection of the bladder or rectum.20 These 2 types of cerclage are likely equally efficacious, but have never been tested “head-to-head” in a well-designed clinical trial. Transabdominal cerclage has not been compared directly with transvaginal cerclage, and is a far more invasive procedure requiring a laparotomy and subsequent cesarean delivery. Transabdominal cerclage should therefore be reserved for women in whom a prophylactic cerclage is indicated but technically impossible to place transvaginally or that have failed previous prophylactic transvaginal cerclage placement.28, 29 Once a cerclage is in place, weekly or biweekly follow-up visits for cervical examinations are probably sufficient in the absence of clinical symptoms. Cervical assessment may be by simple bimanual examination or by ultrasound to assess the length of cervix, any loosening of the suture or prolapse of membranes through the suture, tearing of the cervix, loss of the surgical knot, or loss of the suture. Modified bed rest and “pelvic rest” (no coitus, tampons, or douching) are usually recommended until a favorable gestational age is reached, but without proven benefit. The cerclage is usually removed electively at 37 weeks gestation, but earlier removal may be necessary in the event of premature uterine contractions. In the setting of preterm PROM, evidence of amnionitis should prompt immediate removal of the cerclage. In preterm PROM without evidence of infection, the risk of premature delivery with removal must be weighed

2. Preterm Labor
against the risk of ascending infection with a foreign body in place.30, 31 Preterm (premature) labor refers to labor occurring prior to 37 completed weeks of gestation. This should be differentiated from preterm contractions without documentation of cervical change (effacement and dilatation). Preterm birth occurs in 7%-12% of all deliveries, but accounts for over 85% of all perinatal morbidity and mortality.33, 34 Preterm labor represents a syndrome rather than a diagnosis since the etiologies are varied. Preterm labor may reflect a breakdown in the normal mechanisms responsible for maintaining uterine quiescence, or a short-circuiting or overwhelming of the normal parturition cascade.5, 35 Up to 30% of preterm labor is thought to result from intra-amniotic infection, and is likely mediated through the interaction of cytokines and eicosanoids.36, 37 Definitive diagnosis requires a positive amniotic fluid culture, but amniotic fluid markers of infection (such as interleukin-6, glucose, and white blood cell count) may suggest the diagnosis. Recently, thrombin has been shown to be a powerful uterotonic agent providing a mechanism for preterm labor resulting from placental abruption.
Diagnosis Etiology

Complications. Complications of cervical cerclage increase with increasing gestational age and cervical dilatation (Table 3). Cervical cerclage is also associated with increased obstetric interventions, including higher rates of admission to hospital, administration of tocolytics, induction of labor, and cesarean delivery.5 Puerperal infection occurs in approximately 6% of patients with cerclage, which is twice as common as the incidence in gestational age-matched controls without cerclage.5, 32 There is no demonstrable association between the presence of a cerclage and preterm PROM remote from placement.

Preterm labor is a clinical diagnosis characterized by increasing intensity and frequency of uterine contracTable 3 Complications of Cervical Cerclage

≤ Short-term (≤48 hours)

Long-term (>48 hours)

Premature rupture of fetal membranes Excessive blood loss (may require blood transfusion) Pregnancy loss (abortion) Complications from anesthesia

Cervical laceration (3%-4%) Chorioamnionitis (4%) Cervical stenosis (1%) Other rare complications (including fetal growth restriction, fetal demise, thrombophlebitis, placental abruption, bladder pain, migration of suture)

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tions leading to effacement and dilatation of the cervix, and culminating in expulsion of the products of conception prior to 37 weeks of gestation. Screening Several risk factors for preterm labor have been described (Table 4). However, risk factor screening alone will fail to identify over 50% of pregnancies that deliver preterm.38, 39 As such, a number of modalities have been developed in an attempt to identify women at high-risk of preterm birth (Table 5).40-50 Currently, the most reliable screening tests include serial sonographic measurement of cervical length42, 43 and/or measurement of fetal fibronectin (fFN) in cervicovaginal secretions.46-48
Management

Clinical Management In the setting of preterm labor, bed rest and hydration are commonly recommended but without proven efficacy.51 Pharmacologic tocolytic therapy remains the cornerstone of modern management. Although a number of alternative agents are now available (Table 6), only ritodrine hydrochloride has received approval from the Food and Drug Administration (FDA) of the United States (FDA) for the treatment of preterm labor. The risks and benefits of the individual drugs have been reviewed in detail elsewhere.35, 52-54 All of the recommended agents appear equally effective in delaying delivery for 24-48 hours, thereby creating a window of opportunity for antenatal corticosteroid administration. There is no good clinical evidence that any of these agents can prolong pregnancy beyond 48 hours and prevent preterm delivery.55 Since no single agent has a clear therapeutic advantage, the side-effect profile of each of the drugs will often determine which to use in a given clinical setting. Intravenous magnesium sulfate as a continuous infusion has a wide margin of safety and has traditionally been regarded as the first-line agent for use in preterm labor in North America. More recently, however, this agent has fallen out of favor because of its potential risk of maternal cardiopulmonary failure from overdose or neonatal rickets and neurologic injury from prolonged or excessive use.56, 57 Adrenergic agonists are commonly used (eg, subcutaneous terbutaline in an injection, continuous infusion or oral administra-

Tocolysis should be continued until preterm labor has been effectively halted, or empirically until 48 hours after the first dose of corticosteroid. Maintenance tocolytic (including terbutaline pump or chronic oral tocolysis) therapy has not been shown to confer any therapeutic benefit73, 74 and poses a risk of adverse side effects. Similarly, concurrent use of 2 or more tocolytic agents has not consistently been shown to be more effective than a single agent and exposes the parturient to cumulative risk of side effects, including pulmonary edema.75, 76 The use of sequential therapy, however, may be beneficial if initial therapy is unsuccessful.77 Although effective in the setting of preterm PROM, there is no role for broad-spectrum antibiotic therapy to prolong latency in preterm labor with intact membranes.78

A single course of antenatal glucocorticoids decreases the incidence of respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC) by 50%, and is recommended for all pregnancies at high risk of delivering before 34 weeks gestation with intact membranes and before 32 weeks gestation with preterm PROM.68-70 Maximal benefit is achieved 2448 hours after the initial dose. This effect lasts for 7 days, but it is unclear what happens thereafter. Repeated courses of steroids are not generally recommended, although a single rescue dose (or rescue course) may be appropriate if the initial course was administered prior to 28-30 weeks gestation.71, 72

tion), but have a higher incidence of adverse effects, including maternal tachycardia, EKG changes, and hyperglycemia.55, 58, 59 Indomethacin, although effective, may be associated with fetal complications such as oligohydramnios and premature closure of the ductus arteriosus, as well as serious neonatal complications, such as patent ductus arteriosus that is refractory to pharmacological therapy, especially if given shortly prior to delivery.60-63 Calcium channel blockers (nifedipine and amlodipine) are becoming increasing popular agents for tocolysis, since they can be orally administered, but maternal hypotension and cardiac arrhythmias are a concern.64, 65 Promising newer agents include oxytocin receptor antagonists (used commonly in Europe) and selective cyclooxygenase-2 inhibitors.66, 67

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Table 4 Risk Factors for Preterm Birth

Nonmodifiable

Possibly Modifiable

Prior preterm birth African American Age <18 or >40 years Low socioeconomic status Cervical injury or anomaly Uterine anomaly or fibroids Excessive uterine activity Premature cervical dilation (>2 cm) or effacement (>80%) Overdistended uterus (twins, polyhydramnios) Vaginal bleeding

Cigarette smoking Illicit substance use (cocaine) Absent prenatal care Poor nutrition Anemia Low prepregnancy weight Bacteriuria / urinary tract infection Genital infection and/or gingival infection

Strenuous work High personal stress

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Table 5 Screening for Preterm Birth

Screening Modality

Comment

Home uterine activity monitoring (HUAM)

Although an increase in uterine activity is a prerequisite for preterm labor, HUAM of women at low risk and high risk has not been shown to reduce the incidence of preterm delivery.

Cervical evaluation

Serial digital examination

Serial digital evaluation of the cervix has not been shown to be useful in predicting preterm delivery. An abnormal cervical finding (shortening and/or dilatation) is associated with preterm delivery in only 4% of low-risk women and 12%-20% of high-risk women. Real-time sonographic evaluation of the cervix has demonstrated an inverse correlation between cervical length and risk of preterm delivery. If the cervical length is below the 10th percentile for gestational age, there is a 6-fold increased risk of delivery prior to 35 weeks gestation. Vaginal infections (specifically bacterial vaginosis, Neisseria gonorrhoea, Chlamydia trachomatis, Group B Streptococcus, Ureaplasma urealyticum and Trichomonas vaginalis) have been associated with preterm labor. However, screening and treating for such organisms has not been demonstrated to impact preterm birth.

Serial sonographic evaluation

Vaginal infection

Biochemical markers

Fetal fibronectin (fFN)

Elevated levels of fFN in cervicovaginal secretions are associated with premature delivery and may reflect separation of the fetal membranes from the maternal decidua. The real value of this test appears to lie in its negative predictive value (99% of patients with a negative fFN test will not deliver within 7 days), which may prevent unnecessary hospitalization. In a low-risk population, the predictive value of a positive fFN test at 22-24 weeks gestation for spontaneous preterm delivery prior to 28 weeks and 37 weeks is only 13% and 36%, respectively.

Endocrine markers

Salivary estriol

Progesterone withdrawal is not a prerequisite for labor in the human and serum progesterone levels, andprogesterone/ 17 -estradiol ratios are not predictive of preterm labor. However, maternal salivary estriol can accurately identify activation of the fetal hypothalamic-pituitary-adrenal axis that occurs prior to the onset of labor, both at term and preterm. The detection of elevated levels of estriol in maternal saliva (≥2.1 ng/mL) is predictive of delivery prior to 37 weeks gestation in a high-risk population with a sensitivity of 68%-87% and specificity of 77% (and a false positive rate of 23%).

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Table 6

Tocolytic Agents Commonly Used for the Management of Preterm Labor

Agent Side Effects Side Effects

Administration

Efficacy

Major Maternal

Major Fetal

(Dosage)

Magnesium sulfate Not effective

IV (4-6 g bolus, then 2-3 g/h infusion) Oral maintenance (100-120 mcg Q4h) Effective Effective

Effective

Nausea, ileus, headache, weakness Hypotension Pulmonary edema Cardiorespiratory arrest

Decreased beat-to-beat variability Neonatal drowsiness, hypotonia Ileus Congenital ricketic syndrome (with treatment >3 weeks) Fetal tachycardia Hypotension Ileus Hyperinsulinemia, hypoglycemia, hyperbilirubinemia Hypocalcemia

-adrenergic agonists IV (2 mcg/min infusion, Terbutaline sulfate maximum 80 mcg/min) SC (0.25 mcg Q20 min)

Oral maintenance (2.5-5 mcg Q4-6h) Effective IV pump (0.05 mL/h) Not effective

Jitteriness, anxiety, restlessness, nausea, vomiting, rash Cardiac dysrhythmias, myocardial hypotension, tachycardia Pulmonary edema Paralytic ileus

Prostaglandin inhibitors Indomethacin Oral (25-50 mcg Q4-6h) Effective Effective

Rectal (100 mcg BID)

Gastrointestinal effects (nausea, heartburn), headache, rash Interstitial nephritis Increased bleeding time (most common with aspirin)

Transient oliguria, oligo-hydramnios Premature closure of neonatal ductus arteriosus and persistent pulmonary hypertension Necrotizing enterocolitis, intraventricular hemorrhage

Calcium channel blockers Nifedipine Oral (20-30 mcg Q4-8h) Effective

Hypotension, reflex tachycardia, headache, nausea, flushing

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Oxytocin antagonists Atosiban

IV (1 mM/min infusion)

Effective

Nausea, vomiting, headache, chest pain, arthralgias

Inhibit lactation

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The only tocolytic agent approved by the Food and Drug Administration of the U.S. Efficacy is defined as proven benefit in delaying delivery by 24-48 hours as compared with placebo or standard control. IM, intramuscular; IV, intravenous; SC, subcutaneous; TD, transdermal. Modified from Norwitz ER, Robinson JN, Challis JRG. The control of labor. N Engl J Med. 1999;341:660-666.

3. Post-term Pregnancy
Post-term (prolonged) pregnancy refers to a pregnancy that has extended to or beyond a gestational age of 42.0 weeks (294 days) from the first day of the last menstrual period.79, 80 In the United States, around 10% of all singleton pregnancies continue beyond 42 weeks of gestation and 4% continue beyond 43 completed weeks in the absence of obstetric intervention.79, 80 Post-term pregnancy should be differentiated from a post-mature pregnancy, which is a distinct clinical fetal syndrome consisting of a fetus that has wrinkled, peeling skin with a thin body, and meconiumstained skin and nails that is diagnosed postnatally.81, 82
Etiology

fetal weight > 4500 g84 ) (2.5%-10% vs. 0.8%1%).85, 86 Complications associated with fetal macrosomia include prolonged labor, cephalopelvic disproportion and shoulder dystocia, with resultant risks of orthopedic or neurologic injury.84 Post-term pregnancies are also at increased risk of umbilical cord compression from oligohydramnios, nonreassuring fetal antepartum or intrapartum assessment, meconium aspiration, short-term neonatal complications (hypoglycemia, seizures) and long-term neurologic sequelae. Maternal risks of prolonged pregnancy include an increase in labor dystocia (9%-12% vs. 2%-7% at term), an increase in severe perineal injury (3.3% vs. 2.6% at term) and a doubling in the rate of cesarean delivery.87-89 The latter is associated with higher risks of complications such as endometritis, hemorrhage, and thromboembolic disease.
Management

Primiparity and prior post-term pregnancy are the most common identifiable risk factors for a post-term pregnancy. Rarely, post-term pregnancy may be associated with placental sulfatase deficiency or fetal anencephaly (in the absence of polyhydramnios). Genetic predisposition may also play a role. However, in the vast majority of cases, the cause of post-term pregnancy is unknown.79
Diagnosis

Accurate pregnancy dating is critical to the diagnosis. The incidence of post-term pregnancy depends upon the patient population, including such factors as the percentage of primigravid women, women with pregnancy complications, the prevalence of ultrasound assessment of gestational age and the frequency of spontaneous preterm birth. Local practice patterns, such as the rates of scheduled cesarean delivery and routine labor induction, will also affect the overall incidence of post-term birth. Post-term pregnancy is associated with both fetal and maternal risks. Perinatal mortality (stillbirths plus early neonatal deaths) at ≥42 weeks of gestation is twice that at term (4-7 vs. 2-3 per 1000 deliveries) and increases 4-fold at 43 weeks and 5- to 7-fold at 44 weeks.79, 80, 83 Chronic uteroplacental insufficiency, asphyxia and intrauterine infection all contribute to the excess perinatal deaths. Post-term infants are larger than term infants, with a higher incidence of macrosomia (defined as an estimated
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Complications

Post-term pregnancy is an accepted indication for antenatal fetal monitoring. ACOG has recommended that antepartum fetal surveillance be initiated after 42 weeks of gestation, without a specific recommendation regarding type of test or frequency.79, 80 Options for evaluating fetal well-being include weekly or twice weekly nonstress testing with amniotic fluid volume assessment, the biophysical profile (BPP) or modified BPP, the oxytocin challenge test or a combination of these modalities; no single method has been shown to be superior. Umbilical artery Doppler velocimetry testing alone has not been shown to be beneficial in monitoring the post-term fetus.79 It should be noted that there is insufficient evidence to show that initiating antenatal surveillance between 40 and 42 weeks of gestation improves pregnancy outcome or confers any benefit to the fetus.79

An accurately estimated date of delivery should be calculated early in pregnancy. This may be based upon a known last menstrual period in women with regular, normal menstrual cycles and confirmatory uterine sizing. Uncertainty in historical or physical dating parameters should prompt ultrasound assessment of gestational age.90

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4. Hypertensive Disorders of Pregnancy
Delivery is recommended when the risks to the fetus by continuing the pregnancy are greater than those faced by the neonate after birth. Both expectant management and labor induction are associated with low complication rates in low-risk post-term gravida.91-93 Factors that need to be considered include gestational age, results of antepartum fetal assessment, favorability of the cervix, and maternal preference. Delivery should be initiated immediately if there is evidence of fetal compromise or oligohydramnios. There does appear to be a small advantage to routine induction of labor at 41 weeks gestation, regardless of parity or method of induction.87, 88 In women with unfavorable cervical exams, the routine use of preinduction cervical ripening has resulted in fewer failed and serial inductions, lower fetal and maternal morbidity, a shorter hospital stay, lower medical cost and possibly a lower rate of cesarean delivery in the general obstetric population. The post-term fetus is at increased risk of intrapartum fetal heart rate abnormalities and passage of meconium. For this reason, continuous electronic fetal monitoring in labor is recommended for such pregnancies. Hypertensive disorders of pregnancy are the second most common cause of maternal death in the United States (behind venous thromboembolic disease), accounting for 15%-20% of all maternal deaths.94, 95 Hypertension is also associated with high perinatal mortality and morbidity rates, primarily due to iatrogenic prematurity.96 Hypertensive disorders of pregnancy can be classified into 4 categories:

1.) Chronic hypertension is defined as hypertension prior to pregnancy and should also be considered in parturients with a sustained BP ≥140/90 prior to 20 weeks gestation. Such pregnancies are at increased risk of superimposed preeclampsia, uteroplacental insufficiency and IUGR, placental abruption and stillbirth. Angiotensin converting enzyme (ACE) inhibitors should be discontinued in pregnancy. These drugs have not consistently been associated with an increased risk of structural anomalies in the first trimester over baseline, but exposure in the latter half of pregnancy has been associated with progressive and irreversible renal injury in the fetus, including renal dysplasia and hypocalcified calvaria resulting from the blockade of the conversion of angiotensin 1 to angiogensin 2 in the developing kidneys and low fetal blood pressure on the fetal skull, respectively.97, 98 Because the perinatal mortality associated with maternal chronic hypertension is increased above baseline (6-25/1000 vs. 6.4/1000 in normotensive pregnancies),99 antepartum fetal testing (weekly non-stress tests, serial ultrasound examinations for fetal growth) should be initiated after 32 weeks gestation. Delivery should ideally be achieved by 40 weeks with a favorable cervix. 2.) Chronic hypertension with superimposed preeclampsia is defined as pre-existing chronic hypertension with worsening features during pregnancy, and may be difficult to differentiate from preeclampsia.

3.) Pregnancy-induced hypertension (PIH), also known as transient hypertension or gestational nonproteinuric hypertension, refers to persistent elevation of BP ≥140/90 in the third trimester without evidence of preeclampsia in a previously normotensive woman. It is a diagnosis of exclusion. PIH likely represents an exaggerated physiologic response of maternal cardiovascular system to pregnancy. It is rarely associated with adverse maternal or fetal outcome, but may be
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4.) Preeclampsia, also known as gestational proteinuric hypertension, complicates 6%-8% of all pregnancies.94, 100, 101 It is an idiopathic multisystem disorder specific to human pregnancy and the puerperium. More precisely, it is a disease of the placenta since it occurs also in pregnancies where there is trophoblast but no fetal tissue (complete molar pregnancies). Preeclampsia is discussed in more detail below.
Etiology

difficult to distinguish from preeclampsia. PIH (but not preeclampsia) is associated with an increased risk of chronic hypertension in later life.

The pathogenesis of preeclampsia remains poorly understood. At present, 5 hypotheses are the subject of intense investigation:100-103 (1.) genetic imprinting; (2.) immune maladaption; (3.) placental ischemia; (4.) generalized endothelial dysfunction; and (5.) defective-free fatty acid, lipoprotein and/or lipid peroxidase metabolism. However, there is as yet no single unifying theory that can account for all of the findings in preeclampsia. Although the pathophysiology of preeclampsia is not well understood, it is clear that the blueprint for its development is laid down early in pregnancy. It has been suggested that the pathologic hallmark is a complete or partial failure of the second wave of trophoblast invasion from 16-20 weeks of gestation that, in normal pregnancies, causes destruction of the muscularis layer of the spiral arterioles.104-106 As pregnancy progresses, the metabolic demands of the fetoplacental unit increase. Because of the abnormally shallow invasion of the placenta in preeclampsia and the lack of vascular remodeling, the spiral arterioles are unable to dilate to accommodate the required increase in blood flow, resulting in “placental dysfunction” that manifests clinically as preeclampsia. Recent data suggest that excessive placental production of the fms-like tyrosine kinase receptor (also known as soluble Flt-1 [sFlt-1]), the soluble form of the vascular endothelial growth factor (VEGF) receptor type I that binds both circulating VEGF and placental growth factor, may be responsible for the widespread endothelial injury that characterizes preeclampsia.107, 108 In this way, sFlt-1 may be the elusive “toxemia factor” of preeclampsia. Although attractive, this hypothesis remains to be validated.

Preeclampsia is a clinical diagnosis encompassing 3 elements: (1.) new-onset hypertension (defined as a sustained sitting BP ≥140/90 in a previously normotensive woman); (2.) new-onset proteinuria (>300 mg/24 h or ≥1+ on a clean-catch urinalysis in the absence of urinary infection); and (3.) nondependent edema.100, 101 However, more recent consensus reports have suggested eliminating edema as a criterion for the diagnosis.109 A definitive diagnosis of preeclampsia should only be made after 20 weeks gestation. Evidence of gestational proteinuric hypertension prior to 20 weeks should raise the possibility of an underlying molar pregnancy, collagen vascular disease, antiphospholipid antibody syndrome, drug withdrawal, multiple pregnancy, or chromosomal abnormality (trisomy) in the fetus.

Diagnosis

Preeclampsia is classified as either “mild” or “severe” (there is no category of “moderate” preeclampsia). A diagnosis of severe preeclampsia should be entertained in women with new-onset proteinuric hypertension along with 1 or more of a series of complications (Table 7). IUGR was excluded from the criteria in 2000 by the National High Blood Pressure in Pregnancy Working Group because of inconsistencies in its definition, but was still included as a criterion for the diagnosis of severe preeclampsia by ACOG in 2002.101 Mild preeclampsia includes all women with preeclampsia, but without any features of severe disease.
Management

Timing of Delivery Delivery is the only effective treatment for preeclampsia. Delivery is recommended in women with mild preeclampsia once a favorable gestational age has been reached (>36-37 weeks) and in all women with severe preeclampsia regardless of gestational age (with the exception of severe preeclampsia due to proteinuria alone or IUGR remote from term with good fetal testing). There has also been a recent trend towards expectant management of severe preeclampsia by BP criteria alone <32 weeks gestation.110, 111 Every effort should be made to delay delivery for 24-48 hours to administer antenatal corticosteroids, if indicated.

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Table 7 Diagnostic Features of Severe Preeclampsia
Symptoms

Symptoms of central nervous system dysfunction (blurred vision, scotomata, altered mental status, and/or severe headache) Symptoms of liver capsule distention or rupture (right upper quadrant and/or epigastric pain)
Signs

Severe elevations in BP (defined as BP ≥160/110 on 2 separate occasions at least 6 hours apart) Pulmonary edema Eclampsia (generalized seizures and/or unexplained coma in the setting of preeclampsia and in the absence of other neurologic conditions) Cerebrovascular accident Cortical blindness Fetal intrauterine growth restriction
Laboratory Findings

Proteinuria (>5 g/24 hours) Renal failure or oliguria (<500 mL/24 hours) Hepatocellular injury (serum transaminase levels ≥2 x normal) Thrombocytopenia (<100,000 platelets/mm3) Coagulopathy HELLP (Hemolysis, elevated liver enzymes, low platelets) syndrome

Route of Delivery Severe preeclampsia does not mandate immediate cesarean delivery. The decision of whether to proceed with cesarean or induction of labor and attempted vaginal delivery should be individualized based on such factors as parity, gestational age, cervical examination (Bishop score), maternal desire for vaginal

delivery, and fetal status and presentation. In general, less than one-quarter of women with severe preeclampsia remote from term with an unfavorable cervix will have a successful vaginal delivery.112, 113 Cervical ripening agents may be used if the cervix is not favorable prior to induction, but prolonged inductions should be avoided.
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Treatment of Hypertension The use of antihypertensive agents to control mildly elevated BP in the setting of preeclampsia has not been shown to alter the course of the disease, nor to diminish perinatal morbidity or mortality, and may even reduce birth weight. However, antihypertensive agents should be administered to prevent a maternal cerebrovascular accident (stroke) with severe hypertension while effecting delivery. Most clinicians would recommend initiation of antihypertensive therapy for a systolic BP ≥160 mm Hg and/or diastolic BP ≥110 mm Hg, although these cut-offs have not been tested prospectively.114, 115 Treatment options are summarized in Table 8. Sodium restriction and diuretics have no role in therapy. Restricted physical activity (bed rest) can lower BP, although its efficacy for improving perinatal outcome has not been proven. Intrapartum Anesthesia Neuraxial techniques (epidural, spinal) can be safely administered in the setting of preeclampsia (in the absence of thrombocytopenia) with close attention to volume expansion and anesthetic technique. Hypotension is a major concern, because preeclampsia causes total body fluid overload but depleted intravascular volume. Airway edema and exacerbation of hypertension with intubation can complicate induction of general anesthesia.

Seizure Prophylaxis Seizure prophylaxis is generally initiated during labor or while administering corticosteroids or prostaglandins prior to planned delivery and continued until 24-48 hours postpartum, when the risk of seizures is decreased.116 Magnesium sulfate is the drug of choice to prevent seizures (eclampsia) in the setting of mild or severe preeclampsia (Table 9).117, 118 The incidence of seizures is much lower in women with nonproteinuric mild hypertension (0.1% as compared with 1%-2% for severe preeclampsia119), and it is safe to withhold seizure prophylaxis in this setting. Magnesium sulfate must be given intravenously or by intramuscular injection, as it is not absorbed orally. Because magnesium is renally excreted, infusion rates should be decreased for maternal serum creatinine levels of 1.0 mg/dL or higher.120 Postpartum Care Preeclampsia and its complications resolve following delivery, often within a few days. Permanent neuroOBSTETRICS AND GYNECOLOGY—2009

Recurrence Risk and Prevention The risk of recurrence of preeclampsia in a subsequent pregnancy is related to the severity and nature of the presentation and to the gestational age at presentation.123 Preeclampsia is a disorder of placental implantation and therefore not entirely preventable. Despite promising early studies, low-dose aspirin (acetylsalicylic acid [ASA]) and/or supplemental calcium does not appear to prevent preeclampsia recurrence in either high- or low-risk parturients.124, 125 A recent meta-analysis suggests that low-dose aspirin (80 mg per day) may be useful in preventing preeclampsia, but only in women with prior early, severe preeclampsia.126 Moreover, low-dose aspirin in low-risk women may increase their risk of placental abruption. Women at high-risk for preeclampsia should be seen early in pregnancy to establish accurate pregnancy dating, and to perform baseline BP and laboratory tests. Measurement of BP and urine protein at regular intervals in the late second and third trimesters is critical for timely diagnosis of preeclampsia.

logic sequelae or renal failure are rare. Diuresis (>4 liters/day) often heralds clinical resolution. BP that remains elevated more than 12 weeks postpartum are unlikely to be related to preeclampsia. Patients with severe hypertension (160/100 mmHg) can be treated with oral antihypertensive medications until their 6week postpartum check, and then weaned off. If they continue to require antihypertensive medication, they should be referred to an internist for further investigation.121, 122

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Table 8 Pharmacologic Management of Acute Hypertensive Crisisa

Drug

Dosing

Comment

Recommended first-line therapy

Hydralazine

5 mg IV push Q 10 min x 2 doses; then 10 mg IV push Q 20 min as needed until blood pressure has stabilized at 140-150/90-100 10-20 mg IV push; repeat Q 10-20 min with doubling doses (not to exceed 80 mg in any single dose) to a maximum of 300 mg total 10 mg orally Q 30 min x 2 doses; then 10-20 mg orally Q 4-6 hourly

Be aware of hypotension and potential to adversely affect uteroplacental perfusion Be aware of hypotension and potential to adversely affect uteroplacental perfusion Sublingual nifedipine is best avoidedb

Labetalol

Nifedipine

Recommended therapy in women refractory to first-line agents

Sodium nitroprusside 0.5–3.0 mcg/kg/min IV infusion (not to exceed 800 mcg/min) Nitroglycerin 5 mg/min IV infusion, increase as required every 5 min to maximum dose of 100 mg/min

Should be used only by someone with critical care experience Relatively contraindicated in the setting of hypertensive encephalopathy as it may increase cerebral blood flow and intracranial pressure

a Adapted from Repke JT. Preeclampsia and hypertension. In: Repke JT, ed. Intrapartum Obstetrics. New York, NY: Churchill

Livingstone; 1996:271.
b Grossman E, Messerli FH, Grodzicki T, Kowey P. Should a moratorium be placed on sublingual nifedipine capsules

given for hypertensive emergencies and pseudoemergencies? JAMA. 1996;276:1328-1331.

Table 9 Prevention of Seizures in Parturients with Preeclampsia

Drug

Loading Dose

Maintenance Dose

Therapeutic Level

Recommended first-line therapy

Magnesium sulfate

4-6 g IV over 10-20 min 10 g IM (5 g IM into each buttock)

2-3 g/h IV infusionb 5 g IM every 4 h

4-8 mEq/La as above

Recommended therapy in women refractory to magnesium sulfate

Phenytoin

1-1.5 g over 1 h (depending on body weight)

250-500 mg Q 10-12 h orally or IV

10-20 mcg/mL

a Adapted from Repke JT. Preeclampsia and hypertension. In: Repke JT, ed. Intrapartum Obstetrics. New York, NY:

Churchill Livingstone;1996: 271. b Grossman E, Messerli FH, Grodzicki T, Kowey P. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA. 1996;276:1328-1331.

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5. Intrauterine Fetal Demise
Intrauterine fetal demise (IUFD)—also known as stillbirth—is defined in the United States as fetal demise after 20 weeks gestation and prior to delivery.127 In the United States, the stillbirth rate decreased from 15.8 per 1000 total births in 1960 to 7.5 per 1000 births in 1990.99, 128 Risk factors for IUFD include extremes of maternal age, multiple pregnancy, postterm pregnancy, male fetus, fetal macrosomia and maternal disease, such as pregestational diabetes, systemic lupus erythematosus (SLE) and preeclampsia.129, 130 Causes of IUFD can be identified in only around 50% of cases (Table 10). Pathologic examination of the fetus and placenta/fetal membranes is the single most useful test to identify a cause for the IUFD. Early detection and appropriate management of underlying maternal disorders (diabetes, preeclampsia) may reduce the risk of IUFD.131, 132 Fetal karyotyping should be considered in all cases of fetal death to identify chromosomal abnormalities, particularly in cases with documented fetal structural abnormalities. Approximately 6%-10% of stillborn fetuses have abnormal karyotypes.133 Amniocentesis may be recommended to salvage viable amniocytes for cytogenetic analysis prior to delivery. Fetal-maternal hemorrhage (fetal cells spilling into maternal circulation) occurs in all pregnancies, but is usually minimal (<0.1 mL total volume). In rare instances, fetal-maternal hemorrhage may be massive, leading to fetal demise. The Kleihauer-Betke (acid elution) test allows an estimate of the volume of fetal blood in the maternal circulation, and should be drawn within 6 - 8 hours of the purported time of bleeding episode due to rapid clearance of fetal cells from maternal circulation.134 Intra-amniotic infection resulting in fetal death is usually evident on clinical exam. Placental membrane culture and autopsy examination of the fetus, placenta/fetal membranes and umbilical cord may be useful. Fetal x-rays or MRI may sometimes be valuable if autopsy is declined.135, 136
Diagnosis Etiology

IUFD by documenting the absence of fetal cardiac activity. Other sonographic findings in later pregnancy may include scalp edema, overlapping sutures and fetal maceration. Every effort should be made to avoid cesarean delivery in the setting of IUFD. As such, expectant management is often recommended. Latency (the period from fetal demise to delivery) varies depending on the underlying cause and gestational age. In general, the earlier the gestational age, the longer the latency period. Overall, >90% of women will go into spontaneous labor within 2 weeks of fetal death. However, many women find the prospect of carrying a dead fetus distressing and want the pregnancy terminated as soon as possible. Management options include surgical dilatation and evacuation or induction of labor with cervical ripening, if indicated. Around 20%-25% of women who retain a dead singleton fetus for longer than 3 weeks will develop disseminated intravascular coagulopathy (DIC) due to excessive consumption of clotting factors.137, 138 Therefore, delivery should be effected within this time period.
Management

The inability to identify fetal heart tones or the absence of uterine growth may suggest the diagnosis. Ultrasound is the gold standard to confirm an

Death of a Co-twin The death of 1 twin confers an increased risk of major morbidity to the surviving twin, including IUFD, neurologic injury, multiorgan system failure, thrombosis, distal limb necrosis, placental abruption and premature labor.99-101 The prognosis for the surviving twin is dependent on the cause of death, gestational age, chorionicity and time interval between death of the first twin and delivery of the second. Dizygous twin pregnancies do not share circulation, and the death of 1 twin may have little impact on the surviving twin. The dead twin may be resorbed completely or become compressed and incorporated into the membranes (fetus papyraceus). DIC in the surviving fetus and/or mother is rare.102 On the other hand, some degree of shared circulation can be demonstrated in almost all monozygous twin pregnancies, and death of 1 fetus in this setting carries an increased risk of death of its cotwin due to profound hypotension and/or purported transfer of thromboplastic proteins from the dead fetus to the live fetus.143 If it survives, the co-twin, has a 40% risk of developing neurologic injury (multicystic

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6. Intrauterine Growth Restriction
encephalomalacia), which may not be prevented by immediate delivery.144, 145 Therefore, management of a surviving co-twin depends on chorionicity and gestational age. Fetal surveillance (kickcharts, nonstress testing, biophysical profile) should be instituted on a regular basis, and delivery considered in the setting of nonreassuring fetal testing or at a favorable gestational age. Birth weight is a function of both gestational age and rate of fetal growth. Intrauterine growth restriction (IUGR) refers to any fetus that fails to reach its full growth potential. In the United States, 4%-8% of fetuses are diagnosed with IUGR.146, 147 IUGR should be differentiated from the term SGA (small for gestational age), a term commonly used by the pediatricians to represent both constitutionally small neonates that are healthy and the growth restricted fetus that is at risk for poor perinatal outcomes.148
Etiology

IUGR likely represents the clinical end-point of many different fetal, uteroplacental, and maternal conditions (Table 11). Every attempt should be made to determine the cause prior to delivery.
Diagnosis

The clinical diagnosis of IUGR is difficult, and physical examination alone will fail to identify over 50% of IUGR fetuses. If the fundal height measurement is significantly less than expected (<3-4 cm for gestational age), an ultrasound examination should be performed. IUGR is a radiologic diagnosis that requires either: (1.) an estimated fetal weight (EFW) <3rd perTable 10 Causes of Intrauterine Fetal Demise (IUFD)

Maternal causes

Uteroplacental causes

Fetal causes

Underlying medical conditions (diabetes mellitus, thyroid disease, antiphospholipid antibody syndrome) Preeclampsia Isoimmunization Illicit drug use (cocaine)

Placental abruption

Fetal chromosomal / genetic anomalies

Placenta previa Vasa previa Fetal-maternal hemorrhage

Fetal structural abnormalities Intra-amniotic infection Complications of multiple pregnancies (including twin-to-twin transfusion syndrome)

Antepartum drug / toxin exposure

Cord accident

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centile (2 standard deviations from the mean) for gestational age, or (2.) an EFW <10th percentile for gestational age along with evidence of fetal compromise (usually oligohydramnios or abnormal umbilical artery Doppler velocimetry).146,147,149 Fetuses who are <10th percentile without evidence of compromise should be referred to as SGA and not IUGR. Accurate gestational age dating is clearly a prerequisite for the diagnosis. A small calcified (Grade 3) placenta detected on ultrasound examination in association with a small biparietal circumference may also be suggestive of an IUGR pregnancy.150 IUGR infants have higher rates of perinatal morbidity and mortality as compared with appropriate for gestational age (AGA) fetuses for any given gestational age. Neonatal morbidity (meconium aspiration syndrome, hypoglycemia, polycythemia, pulmonary hemorrhage) may be present in up to 50% of IUGR neonates.146,147,149,151 Premature IUGR infants also have difficulty with nutritional support, and many develop feeding intolerance and failure to thrive in the NICU.152 Long-term studies show a 2-fold increased incidence of cerebral dysfunction (ranging from minor learning disability to cerebral palsy) in IUGR infants delivered at term, and an even higher incidence if the infant was born preterm. Epidemiological studies also suggest that these infants may also be at higher risk for developing chronic disease in adulthood such as diabetes, hypertension, stroke and coronary heart disease (the Barker Hypothesis).153
Management Complications

pregnancies should be followed on a regular basis to exclude this complication.

IUGR fetuses can undergo vaginal delivery and cesarean delivery should be reserved for the usual obstetric indications. However, up to 50%-80% of IUGR fetuses will show evidence of nonreassuring fetal testing in labor requiring cesarean delivery.146 Timing of delivery also depends on the precise gestational age, any superimposed maternal conditions (eg, severe preeclampsia), the presence or absence of abnormal umbilical cord Dopplers (reversed enddiastolic flow), whether or not there has been any interval fetal growth over a 2- to 3-week period, and whether or not the IUGR fetus is a singleton vs. a multiple gestation in which the other fetus(es) are growing appropriately.154 If a premature delivery <34 weeks is anticipated, a course of antenatal corticosteroids may be warranted. Note that antepartum fetal testing (including the BPP and umbilical artery Doppler velocimetry) may temporarily worsen in the 24-48 hours following steroid administration in some fetuses.155

Bed rest and low-dose aspirin have not been shown to prevent IUGR in women at high risk; however, a recent meta-analysis suggests that women with prior history of an IUGR pregnancy with early severe preeclampsia may benefit from empiric low-dose aspirin therapy during subsequent pregnancies.126 Principles of management of IUGR pregnancies include identification of women at high risk, early antepartum diagnosis, attempts to identify etiology (karyotype, infection, antiphospholipid antibody syndrome), regular (usually twice-weekly) fetal surveillance and appropriate timing of delivery. IUGR may be the first manifestation of preeclampsia, and such

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Table 11 Risk Factors for Intrauterine Growth Restriction (IUGR)
Maternal Causes

Demographic factors

Drug / toxin exposure

Underlying medical conditions

Infections

Prior IUGR infant African American

Illicit drugs (cocaine) Cigarette smoking Chemotherapy

Hyperthyroidism Hemoglobinopathies Chronic pulmonary disease Cyanotic heart disease Diabetes mellitus with vascular disease Anemia Malnutrition

Malaria Rubella Cytomegalovirus HIV Varicella

Uteroplacental Causes Uteroplacental insufficiency Velamentous cord insertion

Chronic hypertension Preeclampsia Antiphospholipid antibody syndrome Unexplained chronic proteinuria Chronic placental abruption
Fetal Causes Genetic factors Fetal structural anomalies Multiple pregnancy

Fetal chromosomal anomalies (including trisomy 18>13>21 and sex chomosome abnormalities) Single gene defects (such as phenylketonuria and dwarfism) Confined placental mosaicism

Cardiovascular anomalies Bilateral renal agenesis Single umbilical artery

Polyhydramnios / oligohydramnios sequence (including twin-to-twin transfusion syndrome)

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7. Multiple Pregnancy
Multiple pregnancies complicate 1%-2% of all deliveries and are becoming increasingly common, primarily as a result of assisted reproductive technology (ART). This is especially true of higher-order multiple pregnancies (triplets and up) which now constitute 0.103% of all births.156 The vast majority (97%-98%) of multiple gestations are twin pregnancies.
Diagnosis

monochorionic (no peak, but a thin filmy membrane).162 Identification of separate sex fetuses or 2 separate placentae confirms dichorionic/diamniotic placentation. Overall, antepartum complications develop in 80% of multiple pregnancies, compared with around 30% of singleton gestations (Table 12).163 Preterm delivery is the most common complication, and the risk of preterm delivery increases as fetal number increases: the average length of gestation is 40 weeks in singletons, 37 weeks in twins, 33 weeks in triplets, and 29 weeks in quadruplets.164 Fetal growth discordance (defined as a ≥25% difference in EFW between fetuses of the same pregnancy) occurs in 5%-15% of twins and 30% of triplets, and is associated with a 6fold increase in perinatal mortality.165,166 Cord entanglement is rare (1 in 25,000 births), but may occur in up to 70% of monochorionic/monoamniotic pregnancies, and accounts for >50% of perinatal mortality in this subgroup.163,167,168 Maternal complications include an increased risk of gestational diabetes, preeclampsia, anemia, cholestasis of pregnancy,169 cesarean delivery (due primarily to malpresentation), and postpartum hemorrhage.
Complications

Multiple pregnancy should be suspected in women at high risk, women with excessive symptoms of pregnancy (such as nausea and vomiting), or uterine size larger than expected. The overall incidence of dizygous twinning in the U.S. is around 1 in 89 pregnancies, and is influenced by a number of epidemiologic factors, including a family or personal history of multiple pregnancy, advanced maternal age, multiparity, African American, and ART.157 Monozygous twinning, on the other hand, is a random event that occurs in around 1 in 300 pregnancies (although the risk may be increased 2- to 3-fold with in vitro fertilization).158 Ultrasound will confirm the diagnosis.

Zygosity and Chorionicity 80% of twin pregnancies are dizygous (derived from 2 separate embryos). Perinatal mortality is higher with monozygous (30%-50%) than with dizygous twins (10%-20%). Chorionicity refers to the arrangement of membranes in multiple pregnancies. In monozygous twinning, the timing of the cell division determines the chorionicity. If the zygote divides within 3 days of fertilization, the result is dichorionic/diamniotic placentation (30% of all monozygous pregnancies); if the division occurs between day 3 and day 8, the result is a monochorionic/diamniotic pregnancy (65%); between day 8 and day 13, a monochorionic/monoamniotic pregnancy ensues (<5%); and if the division occurs on or after day 13, incomplete separation (conjoined twins) is the rule (<0.5%). Chorionicity correlates directly with perinatal mortality, which is especially high with monochorionic/monoamniotic twins (65%-70%). Chorionicity is determined most accurately by examination of the membranes after delivery. Antenatal diagnosis is more difficult.159-161 Typically, ultrasound examination in the first half of the pregnancy can be performed to evaluate the point at which the amniotic/chorionic membranes arise from the placenta to determine if the fetuses are dichorionic (twin peak or lamda sign) or
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Twin polyhydramnios/oligohydramnios (“poly/oligo”) sequence results from an imbalance in blood flow from the “donor” twin to the “recipient.” Both twins are at risk for adverse events. Twin-to-twin transfusion syndrome is a subset of polyhydramnios/oligohydramnios sequence seen in 15% of monochorionic pregnancies,170, 171 and is due to unbalanced vascular communications between the fetal circulations. One twin is usually appropriate for gestational age (AGA) while the other twin is usually IUGR. The IUGR twin is typically in the oligohydramniotic sac and is compressed against one edge of the uterus, also known as the “stuck twin” syndrome.172 Following delivery, a difference in birth weight of ≥20% or a difference in hematocrit of ≥5 g/dL confirms the diagnosis. The larger twin is often polycythemic while the IUGR twin is anemic. Prognosis depends on gestational age, severity, and underlying etiology. Overall perinatal mortality is 40%80%.173, 174 Treatment options include expectant management, serial amniocentesis of the polyhydramniotic sac, indomethacin (to decrease fetal urine output),

laser obliteration of the placental vascular communications or selective fetal reduction.175-178 Gravidas with multiple gestations should be counseled about the increased risk of preeclampsia, preterm labor, postpartum hemorrhage, anemia, fetal loss, fetal anomalies, IUGR, and cesarean delivery. Principles of management include early diagnosis, screening for fetal anomalies, determination of chorionicity, and regular antepartum follow-up (serial ultrasound for growth at least every 3-4 weeks to screen for discordant growth).179 Maternal serum alpha-fetoprotein (MS-AFP) screening for multiple gestation is a reliable screen for neural tube defects; however, serum biochemical marker screening for aneuploidy in the presence of more than one fetus is not particularly reliable, due to the inherent structure of the test parameters.180 Maternal plasma volume is increased by 100%-200% with multiple gestation, placing the gravida at higher risk for anemia. Additional folate and iron supplementation should be considered in multiple gestation. Multifetal pregnancies are at higher risk for cesarean delivery. Patients should be counseled about labor analgesia and anesthesia, the possible need for emergent delivery, and the need for multiple pediatric teams in the delivery room. There
Table 12 Complications of Multiple Pregnancy Management

are several management considerations specific to multiple gestation, outlined below. Overall, 10%-15% of higher-order multiple pregnancies (triplets and up) will reduce spontaneously during the first trimester.164 If not, the option of multifetal pregnancy reduction to twins at 13-15 weeks should be discussed. The benefits of reduction include increased length of gestation, increased birth weight, and reduced prematurity and perinatal mortality and mortality.164, 181-183 The procedure-related loss rate prior to 20 weeks may be as high as 15% (range: 5%-35%), which is comparable to the background risk for higher-order multiple pregnancies.164, 182-185 However, the fetal loss rate increases with advancing gestation at the time of the reduction. Multifetal pregnancy reduction should be distinguished from selective fetal reduction, in which one fetus is selectively terminated because of a known structural or chromosomal abnormality.186, 187
Screening for Congenital Anomalies Multifetal Pregnancy Reduction

Using twin populations, maternal serum alpha-feto protein (MS-AFP) and “quadruple panel” screening (MS-AFP, estriol, hCG and activin A) has been stan-

Maternal complications

Uteroplacental complications

Fetal complications

Anemia Hyperemesis gravidarum Gestational diabetes Preterm labor Cesarean delivery

Placenta previa Preterm PROM Cord entanglement Postpartum hemorrhage

Fetal growth discordance IUGR IUFD of one or both twins Congenital anomalies Twin-to-twin transfusion syndrome

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8. Premature Rupture of Membranes
dardized for twins as it is for singletons at 15-20 weeks.188, 189 In dizygous pregnancies, the risk of aneuploidy (genetic abnormality) is independent for each fetus. As such, the chance that 1 or both fetuses have a karyotypic abnormality is greater than for a singleton. Amniocentesis is recommended when the probability of aneuploidy is equal to or greater than the procedure-related pregnancy loss rate (estimated at 1 in 270).190, 191 In singleton pregnancies, this balance is reached at a maternal age at delivery of 35 years. In twin pregnancies, amniocentesis should be offered to women at approximately 32 years of age.192, 193
Route of Delivery

The recommended route of delivery of twins depends on presentation, gestational age (or EFW), concordance, and maternal and fetal well-being. Prior cesarean is not an absolute contraindication to vaginal delivery of twins.194 Breech extraction of a nonvertex, concordant second twin is a safe procedure,195, 196 but should only be performed by an experienced obstetric care provider. Preparation for a possible breech extraction should include an ultrasound machine to assist in evaluation of fetal heart rate and presentation, specialized forceps to assist in delivery of the aftercoming head (Piper forceps), an experienced anesthesiologist and a uterine relaxant, such as intravenous nitroglycerin or halothane by mask. Cesarean delivery has traditionally been recommended for multiple pregnancies in which the presenting fetus is not vertex and for all higher-order multiple pregnancies, although vaginal delivery may be appropriate in selected patients.197

PROM refers to rupture of the fetal membranes prior to the onset of uterine contractions.198 It can be classified as term PROM (≥37 weeks) or preterm PROM (<37 weeks). Latency (the time interval between PROM and delivery) is dependent on several factors: (1.) gestational age (at term, 50% of women with PROM will go into spontaneous labor within 12 hours and 95% within 72 hours; latency is generally longer if PROM occurs preterm with 50% of women going into labor within 24-48 hours and 70%-90% within 7 days)199; (2.) severity of oligohydramnios (severe oligohydramnios is associated with shortened latency period );200 and (3.) number of fetuses (twins have a shorter latency period than singletons).201
Diagnosis

PROM is a clinical diagnosis with evidence of vaginal pooling of amniotic fluid on sterile speculum examination, which is alkaline (vaginal fluid turns yellow nitrazine paper blue) and demonstrates “ferning” (microscopic crystallization) on drying. Evidence of diminished amniotic fluid volume on ultrasound may help to confirm the diagnosis, but is not a prerequisite for the diagnosis. Sometimes a gush of fluid can be observed to emanate from the cervix when a patient coughs during a speculum exam. The fluid should also be categorized as clear, blood-tinged, or meconiumstained. Differential diagnosis includes leakage of urine and vaginal discharge. If equivocal, an amniocentesis can be performed with instillation of indigo carmine dye into the amniotic cavity (“amnio-dye test”). Leakage of the dye into the vagina as evidenced by staining of a tampon within 15-20 minutes will confirm the diagnosis. The patient should be advised that, after an hour or so, her urine may also stain blue. Rupture of the membranes is a normal physiologic event at term. Rupture of membranes at term prior to the onset of uterine contractions (term PROM) occurs in 8%-10% of term pregnancies.202 Contraindications to expectant management in the setting of term PROM include intra-amniotic infection, non-reassuring fetal testing, vaginal bleeding and active labor. In the absence of such contraindications, both expectant management and immediate augmentation of labor are acceptable options.203 Severe oligohydramnios may be associated with umbilical cord compression in
Term PROM

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labor leading to non-reassuring fetal testing and cesarean delivery. In this setting, amnioinfusion with saline has been shown to decrease the risk of cesarean for non-reassuring fetal testing (but has not necessarily been shown to improve perinatal outcome). Preterm PROM complicates 2%-4% of singleton and 7%-10% of twin pregnancies. It is associated with 30%-40% of preterm births and 10% of all perinatal mortality.204 Risk factors include prior preterm PROM, unexplained vaginal bleeding, placental abruption (seen in 10%-15% of women with preterm PROM, but may be a result rather than a cause),205 cervical insufficiency, vaginal or intra-amniotic infection, amniocentesis, smoking, multiple pregnancy, polyhydramnios, chronic steroid treatment, connective tissue diseases (systemic lupus erythematosus, Ehlers-Danlos syndrome), anemia, low socioeconomic status and unmarried marital status. Factors which are not associated with preterm PROM include coitus, cervical examinations, maternal exercise and parity. The recurrence risk is 20%-30%.204 Complications Neonatal complications are related primarily to prematurity, including RDS, IVH, sepsis, pulmonary hypoplasia (especially with preterm PROM <22 weeks) and skeletal deformities/limb strictures (related to severity and duration of preterm PROM). Overall, preterm PROM is associated with a 4-fold increase in perinatal mortality and a 3-fold increase in neonatal morbidity.204, 206 The fetus is at risk for developing chorioamnionitis, stillbirth from cord accident or placental abruption, non-reassuring fetal heart rate tracings or precipitous delivery. Maternal complications include increased rates of cesarean delivery, intra-amniotic infection and postpartum endometritis.
Preterm PROM

2.) Antibiotics. Prophylactic broad-spectrum antibiotic therapy has consistently been shown to prolong latency in the setting of preterm PROM,208, 209 and this appears to translate into an improvement in perinatal outcome. There is currently no evidence to recommend 1 antibiotic regimen over another. The most commonly used antibiotic regimen is ampicillin and erythromycin for 7 days.

1.) Tocolysis. Preterm PROM is a relative contraindication to tocolysis to prevent undue exposure of fetuses to infected in utero environment, with subsequent postnatal risk of neurologic injury and cerebral palsy.207 Tocolytic agents may delay delivery by 24-48 hours in the setting of intact membranes, but do not appear to delay delivery or improve perinatal outcome in pregnancies complicated by preterm PROM.204

amniotic infection. Patients should be placed on pelvic rest (no tampons, no douching, no sexual intercourse). A screening sonogram should be performed to determine fetal presentation as non-vertex presentation places the fetus at risk for umbilical cord prolapse. Hospitalization, bed rest and fetal surveillance have been the mainstay of management of preterm PROM.204 Areas of controversy in the management of preterm PROM include:

3.) Antenatal corticosteroids. A single course of antenatal glucocorticoids is recommended for all pregnancies at high risk of delivering before 34 weeks gestation with intact membranes and before 32 weeks with preterm PROM with a view to decreasing the incidence of RDS, IVH and NEC.68-70 The benefit of antenatal corticosteroids in pregnancies complicated by preterm PROM at 32-34 weeks gestation is not clear.70 4.) Fetal surveillance. Fetuses in pregnancies complicated by preterm PROM are at risk for ascending infection, cord accident, placental abruption and (possibly) uteroplacental insufficiency. Amniocentesis may be considered in the setting preterm PROM to test for evidence of intra-amniotic infection and to confirm fetal lung maturity with a view to affecting an earlier delivery. In some cases, vaginal pooled amniotic fluid can be aspirated and tested for fetal lung maturation. Loss of fetal breathing in the BPP was

Management Management of preterm PROM should be individualized. The risk of prematurity should be weighed against the risk of expectant management, primarily intra-amniotic infection.204, 206 Amniotic fluid can be used to assess fetal lung maturity by testing for the lethicin/sphingomyelin (L/S) ratio and presence of phosphatidyl glycerol (PG). In the setting of expectant management for preterm PROM, new onset uterine contractions may portend the development of intra-

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9. Antepartum Hemorrhage
previously hailed as an early sign of intrauterine infection, but more recent studies have refuted this idea.210 In the absence of evidence of uteroplacental insufficiency, fetal surveillance has not been demonstrated to reliably diagnose or predict intra-amniotic infection. Fetal surveillance should therefore be instituted only for the usual obstetric indications, such as fetal nonstress testing (NST) to assess for variable decelerations in the setting of oligohydramnios.

Antepartum hemorrhage is defined as vaginal bleeding after 24 weeks gestation and before labor, and complicates 4%-5% of all pregnancies. Placenta previa (20%) and placental abruption (30%) are the most common causes of antepartum hemorrhage. Other causes include vasa previa, early labor and lesions/lacerations of the lower genital tract.
Placenta Previa

Complications Maternal complications include placenta accreta, which refers to abnormal attachment of placental villi to the uterine wall in which chorionic villi are directly attached to the myometrium due to a poorly developed decidua basalis, and Nitabuch’s layer that normally separates the placenta from the uterine myometrium.214 In the absence of placenta previa, placenta accreta is rare (1 in 7000 pregnancies). However, it complicates 5%-15% of pregnancies with placenta previa, 25% with previa and 1 prior cesarean, and 60% with previa and 2 or more prior cesareans.215 Neonatal complications include preterm birth and malpresentation. Fetal anemia may result from vasa previa associated with a placenta previa, which is an indication for an emergent delivery to prevent exsanguination of the fetus.216 Placenta previa is not associated with IUGR.217
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Placenta previa refers to implantation of the placenta over the cervical os in advance of the fetal presenting part, and complicates 1 in 200 pregnancies.211 Risk factors include multiparity, advanced maternal age, prior placenta previa, prior cesarean delivery and smoking. Placenta previa may be asymptomatic or may present clinically with painless, bright-red vaginal bleeding. Fetal malpresentation due to the inability of the presenting part to engage the pelvis may further suggest the diagnosis. Placenta previa is primarily a sonographic diagnosis. Transvaginal sonogram can be safely performed in the setting of abnormal placentation to quantify the distance from the leading edge of the placenta to the internal os of the cervix. If the leading edge of the placenta crosses the cervical os, a complete previa is diagnosed. If the leading edge of the placenta is within 2 cm of the cervical os, a marginal previa is diagnosed.212 Low-lying placenta is defined as a placenta with its leading edge between 2-3 cm from the internal cervical os. As the lower uterine segment develops with advancing gestational age, the leading edge of the placenta may appear to “move” further from the internal os.213

Management The goal of antepartum management is to maximize fetal maturation while minimizing risk to mother and fetus. Blind digital vaginal examination should be avoided in all women with antepartum hemorrhage until placenta previa is excluded. Non-reassuring fetal testing and excessive maternal hemorrhage are contraindications to expectant management, and may necessitate immediate cesarean delivery irrespective of gestational age. However, most episodes of antenatal bleeding are not life-threatening. With careful monitoring, delivery can be safely delayed in most cases. Placenta previa may resolve with time due to cephalic growth of the lower uterine segment, drawing the leading edge of the placenta away from the internal os, thereby allowing vaginal delivery to proceed. Indeed, only 5% of low-lying placentae identified by ultrasound at 14-20 weeks gestation persist to term (although complete placenta previa is unlikely to resolve).218 Cesarean delivery is generally performed by 37 weeks gestation due to active maternal hemorrhage or concern over impending risk of maternal hemorrhage. If elective delivery of an asymptomatic patient is planned prior to 39 weeks gestation, it should be done only after documentation of fetal lung maturity. Placental abruption refers to premature separation of the placenta from the underlying maternal decidua, and complicates 1 in 120 pregnancies.219, 220 Risk factors include hypertension, prior placental abruption, trauma, smoking, cocaine, uterine anomaly or fibroids, multiparity, advanced maternal age, preterm PROM, bleeding diathesis and an overdistended uterus (multifetal gestations, polyhydramnios).220 Placental abruption is a clinical diagnosis that may include vaginal bleeding (80%), painful uterine contractions (35%), and abdominal tenderness (70%), with or without non-reassuring fetal testing (50%). The amount of vaginal bleeding is not a reliable indicator of the severity of the condition, because bleeding may be concealed. A retroplacental collection of ≥300 mL is necessary for sonographic visualization, and only 2% of placental abruptions can be visualized on ultrasound. Serial measurements of fundal height and abdominal girth are useful to monitor large retroplacental blood collections.
Placental Abruption

Complications. Maternal complications include mortality (due to hemorrhage, cardiac failure or renal failure [0.5%-5%]) and coagulopathy (10%). Fetal complications include IUFD in 10%-35% of cases due primarily to fetal hypoxia, exsanguination and/or complications of prematurity. Chronic abruption is also associated with an increased rate of congenital anomalies and IUGR.219, 221 Management. Hospitalization is indicated to evaluate maternal and fetal condition. Mode and timing of delivery depends on the condition of the mother and fetus, and on gestational age. In the setting of hemodynamic instability, invasive monitoring and immediate delivery may be necessary. If the abruption is mild and pregnancy is remote from term, expectant management may be appropriate. Placental abruption is a relative contraindication to tocolysis, particularly with beta-agonists that may cause maternal tachycardia and increased pulse pressure to the site of the abruption. The risk of cesarean delivery is increased primarily due to fetal compromise.
Vasa Previa

Vasa previa refers to the presence of fetal vessels coursing through the membranes (velamentous insertion) overlying the internal os ahead of presenting part of the fetus. Vasa previa is usually asymptomatic, but may present with painless bright-red vaginal bleeding, often associated with diminished fetal movement. Since bleeding is from the umbilical vessels and is fetal in origin, fetal mortality is >75%, due primarily to fetal exsanguination. Diagnosis is by the bedside Apt test (hemoglobin alkaline denaturation test), which involves adding 2-3 drops of an alkaline solution (NaOH) to 1 mL of blood. If the blood is maternal, erythrocytes will rupture and the mixture will turn brown. Fetal erythrocytes, on the other hand, are resistant to rupture and the mixture will remain red. Emergent cesarean delivery is indicated regardless of gestational age if the fetus is viable. Brisk vaginal bleeding temporally related to spontaneous or artificial rupture of the membranes, particularly in light of a placenta previa or low-lying placenta, and acute changes in fetal heart rate tracing, should prompt consideration of this diagnosis.222

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132. Spinillo A, Capuzzo E, Piazzi G, Nicola S, Colonna L, Iasci A. Maternal high-risk factors and severity of growth deficit in small for gestational age infants. Early Hum Dev. 1994;38(1):35-43. 133. Wapner RJ, Lewis D. Genetics and metabolic causes of stillbirth. Semin Perinatol. 2002;26(1):70-74.

142. Romero R, Duffy TP, Berkowitz RL, Chang E, Hobbins JC. Prolongation of a preterm pregnancy complicated by death of a single twin in utero and disseminated intravascular coagulation. Effects of treatment with heparin. N Engl J Med. 1984;310(12):772-774. 143. Benirschke K. Intrauterine death of a twin: mechanisms, implications for surviving twin, and placental pathology. Semin Diagn Pathol. 1993;10(3):222-231.

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137. Reid DE, Weiner AE, Roby CC, Diamond LK. Maternal afibrinogenemia associated with longstanding intrauterine fetal death. Am J Obstet Gynecol. 1953;66(3):500-506. 138. Pritchard JA. Fetal death in utero. Obstet Gynecol. 1959;14:573-580.

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139. Carlson NJ, Towers CV. Multiple gestation complicated by the death of one fetus. Obstet Gynecol. 1989;73(5:1):685-9.

147. Lin CC, Santolaya-Forgas J. Current concepts of fetal growth restriction: part I. Causes, classification, and pathophysiology. Obstet Gynecol. 1998;92(6):1044-1055. 148. Clausson B, Gardosi J, Francis A, Cnattingius S. Perinatal outcome in SGA births defined by customised versus population-based birthweight standards. Bjog. 2001;108(8):830-834. 149. Pollack RN, Divon MY. Intrauterine growth retardation: definition, classification, and etiology. Clin Obstet Gynecol. 1992;35(1):99-107.

150. Kazzi GM, Gross TL, Sokol RJ. Fetal biparietal diameter and placental grade: predictors of intrauterine growth retardation. Obstet Gynecol. 1983;62(6):755-759.

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152. Lee MJ, Conner EL, Charafeddine L, Woods JR, Jr., Priore GD. A critical birth weight and other determinants of survival for infants with severe intrauterine growth restriction. Ann NY Acad Sci. 2001;943:326-339. 153. Godfrey KM, Barker DJ. Fetal programming and adult health. Public Health Nutr. 2001;4(2B):611-624.

151. Lin CC, Santolaya-Forgas J. Current concepts of fetal growth restriction: part II. Diagnosis and management. Obstet Gynecol. 1999;93(1): 140-146.

160. Winn HN, Gabrielli S, Reece EA, Roberts JA, Salafia C, Hobbins JC. Ultrasonographic criteria for the prenatal diagnosis of placental chorionicity in twin gestations. Am J Obstet Gynecol. 1989;161(6:1):1540-1542. 161. Scardo JA, Ellings JM, Newman RB. Prospective determination of chorionicity, amnionicity, and zygosity in twin gestations. Am J Obstet Gynecol. 1995;173(5):1376-1380.

154. Odibo AO, Quinones JN, Lawrence-Cleary K, Stamilio DM, Macones GA. What antepartum fetal test should guide the timing of delivery of the preterm growth-restricted fetus? A decisionanalysis. Am J Obstet Gynecol. 2004;191(4):1477-1482. 155. Simchen MJ, Alkazaleh F, Adamson SL, et al. The fetal cardiovascular response to antenatal steroids in severe early-onset intrauterine growth restriction. Am J Obstet Gynecol. 2004;190(2):296-304.

162. Wood SL, St Onge R, Connors G, Elliot PD. Evaluation of the twin peak or lambda sign in determining chorionicity in multiple pregnancy. Obstet Gynecol. 1996;88(1):6-9. 163. Kovacs BW, Kirschbaum TH, Paul RH. Twin gestations: I. Antenatal care and complications. Obstet Gynecol. 1989;74(3:1):313-317. 164. Haning RV, Jr., Seifer DB, Wheeler CA, Frishman GN, Silver H, Pierce DJ. Effects of fetal number and multifetal reduction on length of in vitro fertilization pregnancies. Obstet Gynecol. 1996;87(6):964-968.

156. Mordel N, Ezra Y, Dorembus D, Benshushan A, Schenker JG, Sadovsky E. Triplets are not so rare any more. J Perinat Med. 1992;20(2):117122.
Multiple Gestation

165. Hendricks CH. Twinning in relation to birth weight, mortality, and congenital anomalies. Obstet Gynecol. 1966;27(1):47-53.

157. Norwitz E. Multiple Pregnancies: Trends past, present and future. Philadelphia, PA: WB Saunders Company; 1998. 158. Derom C, Vlietinck R, Derom R, Van den Berghe H, Thiery M. Increased monozygotic twinning rate after ovulation induction. Lancet. 1987;1(8544):1236-1238.

166. Erkkola R, Ala-Mello S, Piiroinen O, Kero P, Sillanpaa M. Growth discordancy in twin pregnancies: a risk factor not detected by measurements of biparietal diameter. Obstet Gynecol. 1985;66(2):203-206.

167. Peek MJ, McCarthy A, Kyle P, Sepulveda W, Fisk NM. Medical amnioreduction with sulindac to reduce cord complications in monoamniotic twins. Am J Obstet Gynecol. 1997;176(2):334336. 168. Carr SR, Aronson MP, Coustan DR. Survival rates of monoamniotic twins do not decrease after 30 weeks gestation. Am J Obstet Gynecol. 1990;163(3):719-722. 169. Gonzalez MC, Reyes H, Arrese M, et al. Intrahepatic cholestasis of pregnancy in twin pregnancies. J Hepatol. 1989;9(1):84-90.

159. Barss VA, Benacerraf BR, Frigoletto FD, Jr. Ultrasonographic determination of chorion type in twin gestation. Obstet Gynecol. 1985;66(6):779-783.

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170. Fick AL, Feldstein VA, Norton ME, Wassel Fyr C, Caughey AB, Machin GA. Unequal placental sharing and birth weight discordance in monochorionic diamniotic twins. Am J Obstet Gynecol. 2006;195(1):178-183. 171. Danskin FH, Neilson JP. Twin-to-twin transfusion syndrome: what are appropriate diagnostic criteria? Am J Obstet Gynecol. 1989;161(2): 365-369.

172. Reisner DP, Mahony BS, Petty CN, et al. Stuck twin syndrome: outcome in thirty-seven consecutive cases. Am J Obstet Gynecol. 1993;169(4):991-995. 173. Urig MA, Clewell WH, Elliott JP. Twin-twin transfusion syndrome. Am J Obstet Gynecol. 1990;163(5 Pt 1):1522-1526.

180. O’Brien JE, Dvorin E, Yaron Y, et al. Differential increases in AFP, hCG, and uE3 in twin pregnancies: impact on attempts to quantify Down syndrome screening calculations. Am J Med Genet. 1997;73(2):109-112.

179. ACOG Practice Bulletin #56: Multiple gestation: complicated twin, triplet, and high-order multifetal pregnancy. Obstet Gynecol. 2004;104(4):869-883.

174. Gonsoulin W, Moise KJ, Jr., Kirshon B, Cotton DB, Wheeler JM, Carpenter RJ, Jr. Outcome of twin-twin transfusion diagnosed before 28 weeks of gestation. Obstet Gynecol. 1990;75(2):214-216.

182. Boulot P, Hedon B, Pelliccia G, Peray P, Laffargue F, Viala JL. Effects of selective reduction in triplet gestation: a comparative study of 80 cases managed with or without this procedure. Fertil Steril. 1993;60(3):497-503.

181. Melgar CA, Rosenfeld DL, Rawlinson K, Greenberg M. Perinatal outcome after multifetal reduction to twins compared with nonreduced multiple gestations. Obstet Gynecol. 1991;78(5:1):763-767.

176. Elliott JP, Urig MA, Clewell WH. Aggressive therapeutic amniocentesis for treatment of twintwin transfusion syndrome. Obstet Gynecol. 1991;77(4):537-540.

175. Ville Y, Hyett J, Hecher K, Nicolaides K. Preliminary experience with endoscopic laser surgery for severe twin-twin transfusion syndrome. N Engl J Med. 1995;332(4):224-227.

183. Smith-Levitin M, Kowalik A, Birnholz J, et al. Selective reduction of multifetal pregnancies to twins improves outcome over nonreduced triplet gestations. Am J Obstet Gynecol. 1996;175(4:1):878-882. 184. Evans MI, Dommergues M, Timor-Tritsch I, et al. Transabdominal versus transcervical and transvaginal multifetal pregnancy reduction: international collaborative experience of more than one thousand cases. Am J Obstet Gynecol. 1994;170(3):902-909. 185. Evans MI, May M, Drugan A, Fletcher JC, Johnson MP, Sokol RJ. Selective termination: clinical experience and residual risks. Am J Obstet Gynecol. 1990;162(6):1568-1572; discussion 72-75.

177. Wittmann BK, Farquharson DF, Thomas WD, Baldwin VJ, Wadsworth LD. The role of feticide in the management of severe twin transfusion syndrome. Am J Obstet Gynecol. 1986;155(5):1023-1026. 178. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-totwin transfusion syndrome. N Engl J Med. 2004;351(2):136-144.

186. Malone FD, Craigo SD, Chelmow D, D’Alton ME. Outcome of twin gestations complicated by a single anomalous fetus. Obstet Gynecol. 1996;88(1):1-5.

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187. Evans MI, Goldberg JD, Dommergues M, et al. Efficacy of second-trimester selective termination for fetal abnormalities: international collaborative experience among the world’s largest centers. Am J Obstet Gynecol. 1994;171(1): 90-94. 188. Wald N, Cuckle H, Wu TS, George L. Maternal serum unconjugated oestriol and human chorionic gonadotrophin levels in twin pregnancies: implications for screening for Down’s syndrome. Br J Obstet Gynaecol. 1991;98(9): 905-908.

196. Davison L, Easterling TR, Jackson JC, Benedetti TJ. Breech extraction of low-birthweight second twins: can cesarean section be justified? Am J Obstet Gynecol. 1992;166(2):497-502.

197. Dommergues M, Mahieu-Caputo D, Mandelbrot L, Huon C, Moriette G, Dumez Y. Delivery of uncomplicated triplet pregnancies: is the vaginal route safer? A case-control study. Am J Obstet Gynecol. 1995;172(2:1):513-517.
Preterm Premature Rupture of Membranes

189. Neveux LM, Palomaki GE, Knight GJ, Haddow JE. Multiple marker screening for Down syndrome in twin pregnancies. Prenat Diagn. 1996;16(1):29-34. 190. Tabor A, Philip J, Madsen M, Bang J, Obel EB, Norgaard-Pedersen B. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet. 1986;1(8493):1287-1293.

198. Capeless EL, Mead PB. Management of preterm premature rupture of membranes: lack of a national consensus. Am J Obstet Gynecol. 1987;157(1):11-12.

191. Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. 1983;249(15):2034-2038. 192. Rodis JF, Egan JF, Craffey A, Ciarleglio L, Greenstein RM, Scorza WE. Calculated risk of chromosomal abnormalities in twin gestations. Obstet Gynecol. 1990;76(6):1037-1041.

199. Bengtson JM, VanMarter LJ, Barss VA, Greene MF, Tuomala RE, Epstein MF. Pregnancy outcome after premature rupture of the membranes at or before 26 weeks gestation. Obstet Gynecol. 1989;73(6):921-927.

200. Park JS, Yoon BH, Romero R, et al. The relationship between oligohydramnios and the onset of preterm labor in preterm premature rupture of membranes. Am J Obstet Gynecol. 2001;184(3):459-462. 201. Bianco AT, Stone J, Lapinski R, Lockwood C, Lynch L, Berkowitz RL. The clinical outcome of preterm premature rupture of membranes in twin versus singleton pregnancies. Am J Perinatol. 1996;13(3):135-138. 202. Duff P, Huff RW, Gibbs RS. Management of premature rupture of membranes and unfavorable cervix in term pregnancy. Obstet Gynecol. 1984;63(5):697-702.

193. Meyers C, Adam R, Dungan J, Prenger V. Aneuploidy in twin gestations: when is maternal age advanced? Obstet Gynecol. 1997;89(2):248-251. 194. Strong TH, Jr., Phelan JP, Ahn MO, Sarno AP, Jr. Vaginal birth after cesarean delivery in the twin gestation. Am J Obstet Gynecol. 1989;161(1):29-32.

195. Gocke SE, Nageotte MP, Garite T, Towers CV, Dorcester W. Management of the nonvertex second twin: primary cesarean section, external version, or primary breech extraction. Am J Obstet Gynecol. 1989;161(1):111-114.

203. Hannah ME, Hodnett ED, Willan A, Foster GA, Di Cecco R, Helewa M. Prelabor rupture of the membranes at term: expectant management at home or in hospital? The TermPROM Study Group. Obstet Gynecol. 2000;96(4):533-538.

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204. ACOG Practice Bulletin No. 80: premature rupture of membranes. Clinical management guidelines for obstetrician-gynecologists. Obstet Gynecol. 2007;109(4):1007-1019. 205. Vintzileos AM, Campbell WA, Nochimson DJ, Weinbaum PJ. Preterm premature rupture of the membranes: a risk factor for the development of abruptio placentae. Am J Obstet Gynecol. 1987;156(5):1235-1238. 206. Ohlsson A. Treatments of preterm premature rupture of the membranes: a meta-analysis. Am J Obstet Gynecol. 1989;160(4):890-906. 207. Wu YW, Colford JM, Jr. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA. 2000;284(11):1417-1424.

214. Gielchinsky Y, Mankuta D, Rojansky N, Laufer N, Gielchinsky I, Ezra Y. Perinatal outcome of pregnancies complicated by placenta accreta. Obstet Gynecol. 2004;104(3):527-530. 215. Ananth CV, Smulian JC, Vintzileos AM. The association of placenta previa with history of cesarean delivery and abortion: a metaanalysis. Am J Obstet Gynecol. 1997;177(5):1071-1078. 216. Oyelese Y, Smulian JC. Placenta previa, placenta accreta, and vasa previa. Obstet Gynecol. 2006;107(4):927-941.

213. Predanic M, Perni SC, Baergen RN, Jean-Pierre C, Chasen ST, Chervenak FA. A sonographic assessment of different patterns of placenta previa “migration” in the third trimester of pregnancy. J Ultrasound Med. 2005;24(6):773-780.

208. Mercer BM, Arheart KL. Antimicrobial therapy in expectant management of preterm premature rupture of the membranes. Lancet. 1995;346(8985):1271-1279. 209. Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE Collaborative Group. Lancet. 2001;357(9261):979988.

217. Wolf EJ, Mallozzi A, Rodis JF, Egan JF, Vintzileos AM, Campbell WA. Placenta previa is not an independent risk factor for a small for gestational age infant. Obstet Gynecol. 1991;77(5):707-709.

210. Ghidini A, Salafia CM, Kirn V, Doria V, Spong CY. Biophysical profile in predicting acute ascending infection in preterm rupture of membranes before 32 weeks. Obstet Gynecol. 2000;96(2):201-206.
Antepartum Hemorrhage

218. Zelop CC, Bromley B, Frigoletto FD, Jr., Benacerraf BR. Second trimester sonographically diagnosed placenta previa: prediction of persistent previa at birth. Int J Gynaecol Obstet. 1994;44(3):207-210.

219. Ananth CV, Wilcox AJ. Placental abruption and perinatal mortality in the United States. Am J Epidemiol. 2001;153(4):332-337.

211. Sauer M, Parsons M, Sampson M. Placenta previa: an analysis of three years’ experience. Am J Perinatol. 1985;2(1):39-42. 212. Bhide A, Prefumo F, Moore J, Hollis B, Thilaganathan B. Placental edge to internal os distance in the late third trimester and mode of delivery in placenta praevia. Bjog. 2003;110(9):860-864.

220. Ananth CV, Smulian JC, Demissie K, Vintzileos AM, Knuppel RA. Placental abruption among singleton and twin births in the United States: risk factor profiles. Am J Epidemiol. 2001;153(8):771-778.

221. Ananth CV, Berkowitz GS, Savitz DA, Lapinski RH. Placental abruption and adverse perinatal outcomes. JAMA. 1999;282(17):1646-1651. 222. Oyelese KO, Turner M, Lees C, Campbell S. Vasa previa: an avoidable obstetric tragedy. Obstet Gynecol Surv. 1999;54(2):138-145.

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11. Questions
1. A 27-year-old woman presents for her first prenatal visit at 8 weeks gestation. She has a number of risk factors for cervical insufficiency. On review of her medical and obstetrical history, you conclude that she is a good candidate for elective cervical cerclage. Which of the following elements of her history support this conclusion? A. B. C. D. A history of in utero DES exposure. 3 prior first trimester elective pregnancy terminations. Regarding the management of preterm labor, which of the following statements are true? (More than 1 statement may be true.) A.

B. C. D.

You should recommend strict bed rest and aggressive intravenous hydration as these interventions have been shown to prevent preterm birth.

A prior 20 week pregnancy loss characterized by painless cervical dilatation. A triplet pregnancy conceived through in vitro fertilization.

You should start IV magnesium sulfate as this is the only drug approved by the FDA for the treatment of preterm labor. You should start broad-spectrum antibiotic therapy as this has been shown to prolong latency. You should administer antenatal corticosteroids.

2. A nulliparous woman presents at 18 weeks gestation complaining of a watery vaginal discharge. Sterile speculum examination reveals a cervix which is 1-2 cm dilated and 80% effaced. After reviewing the respective risks and benefits, the patient elects emergent cerclage placement over bed rest. At the time of cerclage placement, however, you notice something which causes you to cancel the procedure. Which of the following clinical findings would explain this change in plans? A. B. C. D. Evidence of uterine contractions. Evidence of a vaginal yeast infection.

Fetal membranes visible through the open cervical os.

4. A 28-year-old G4P3 is admitted to labor and delivery at 29-3/7 weeks gestation with regular painful uterine contractions every 3 minutes. Bimanual examination shows her cervix to be long and to admit a fingertip. Fetal heart rate tracing is formally reactive with a baseline of 130 bpm. A diagnosis of preterm contractions is made. She has had 3 prior spontaneous preterm deliveries at 28-31 weeks gestation, and is very concerned that this pregnancy will also end prematurely. Which of the following statements about screening for preterm labor are true? (More than 1 statement may be true.) A. B. C. D. Her history is highly predictive of preterm birth. As such, no further screening tests are available. A negative test for fetal fibronectin (fFN) in cervicovaginal secretions is reassuring.

A large cervical ectropion (cervical erosion).

3. A 36-year-old G7P1233 presents at 32-1/7 weeks gestation complaining of increasing abdominal pain and diminished fetal movement for 12 hours. Bimanual examination shows her cervix to be 4 cm dilated and 90% effaced. Fetal cardiotocography shows evidence of uterine contractions every three minutes. Fetal heart rate tracing is formally reactive, with a baseline of 140 bpm and no decelerations. A diagnosis of preterm labor is made.
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Transvaginal sonography reveals a cervical length of 3.6 cm. This finding should be viewed as reassuring.

Given her increased risk of preterm birth, she is a good candidate for home uterine activity monitoring.

5. A 21-year-old G3P2 with two prior vaginal deliveries is admitted to labor and delivery at 41-4/7 weeks gestation complaining of decreased fetal movement. Fetal cardiotocography shows the fetal heart rate to be formally reactive with a baseline of 140 bpm, and the patient reports that she is again feeling fetal movements. Bimanual examination shows her cervix to be 1 cm dilated and 80% effaced. Estimated fetal weight is 4,400 g. As you are about to leave, she says: “My sister’s baby died at 41 weeks. Why can’t you induce my labor now, Doctor?” Which of the following statements are true? (More than 1 statement may be true.) A. B. C. D. Induction of labor is appropriate, because her pregnancy is post-term.

7. A 36-year-old G6P2 calls the office complaining of no fetal movement for 8 hours. She is at 37 weeks gestation. On arrival, you confirm an IUFD. Which of the following statements regarding the management of IUFD at term are true? (More than 1 statement may be true.) A. B. C. D. It is highly likely that a cause for the IUFD can be identified after delivery.

Immediate induction of labor is indicated to prevent coagulopathy.

Pathologic examination of the fetus and placenta/fetal membranes is the single most useful test to identify a cause for the IUFD. A Kleihauer-Betke test should be sent to identify fetomaternal hemorrhage.

Induction of labor is appropriate to minimize maternal and fetal risks. Induction of labor is appropriate for the indication of impending macrosomia. Induction of labor will not increase her risk of cesarean delivery.

6. A 43-year-old G1P0 presents to your office at 345/7 weeks gestation complaining of a severe headache and flashing lights in front of her eyes. Her supine BP is 140/90 and there is 3+ proteinuria. A diagnosis of preeclampsia is made. Which of the following statements regarding the management of preeclampsia are true? (More than 1 statement may be true.) A. B. C. D. She should be delivered immediately by cesarean for a diagnosis of moderate preeclampsia.

8. An 18-year-old G1P0 presents for her first prenatal visit. She is complaining of severe morning sickness. On examination, uterine size is greater than expected for gestational age. You perform an ultrasound examination and confirm a monochorionic/monoamniotic twin gestation. Which of the following complications of multiple gestations is specific to monochorionic/monoamniotic pregnancies? A. B. C. Malpresentation. Twin-to-twin transfusion syndrome. Cord entanglement. Preterm delivery.

D.

You should measure her BP sitting and not lying.

You should start antihypertensive therapy in an attempt to improve perinatal outcome. Regional anesthesia is contraindicated.

9. A 27-year-old G3P1 with a strong family history of multiple pregnancy presents for her first prenatal visit at 12 weeks gestation. Ultrasound examination confirms a monochorionic/diamniotic twin pregnancy. Which of the following statements regarding twin pregnancy are true? (More than 1 statement may be true.)

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A. B. C. D.

Monozygous twinning is not influenced by epidemiologic or genetic factors. 80% of twin pregnancies are dizygous. Perinatal mortality is higher with monozygous than with dizygous twins. Perinatal mortality is highest with monochorionic/monoamniotic twins.

DES exposure remains controversial. Most clinicians believe that a history of in utero DES exposure alone (without a history of prior pregnancy loss) is not an indication for prophylactic cerclage placement. Similarly, elective cerclage has not been shown to be beneficial in women with multiple pregnancies without a prior history of cervical insufficiency.

10. A 30-year-old G4P2 presents at 19 weeks gestation with vaginal spotting. She has a history of 2 prior cesarean deliveries. Ultrasound examination reveals a low-lying placenta covering the cervical os. Fetal well-being is confirmed. Which of the following statements regarding the management of placenta previa are true? (More than 1 statement may be true.) A. B. C. D. There is a high probability that the placenta will move away from the cervix as the pregnancy progresses.

Given placenta previa and 2 prior cesarean deliveries, the likelihood of placenta accreta is 25%.

Fetal nonstress testing is indicated after 32 weeks, because placenta previa is associated with uteroplacental insufficiency and IUGR. Pelvic examination should be deferred in all patients presenting with antepartum hemorrhage until placenta previa can be excluded.

2. A. The presence of uterine contractions suggests preterm labor and not cervical insufficiency, and are an absolute contraindication to cervical cerclage. Indeed, the presence of persistent uterine contractions requires the removal of any cerclage to avoid cervical laceration and/or uterine rupture. Although intra-amniotic infection is an absolute contraindication to cerclage placement, vaginal yeast infection is not. Cervical ectropion represents a physiologic extrusion of columnar epithelium out of the cervical canal under the influence of steroid hormones, and should not interfere with cervical cerclage placement. If the fetal membranes are found to be prolapsing through the external os at the time of cerclage placement, the risk of iatrogenic rupture of the fetal membranes may be as high as 50%. Although this is not an absolute contraindication to cerclage placement, the surgeon should proceed with care. A number of techniques have been described in an attempt to reduce the fetal membranes prior to cerclage placement, including Trendelenburg position, back-filling the bladder, placement of a 30 mL Foley catheter or moistened sponge forceps into the cervical os, and/or therapeutic amniocentesis. 3. D. You should administer antenatal corticosteroids. A single course of antenatal corticosteroids decreases the incidence of RDS, IVH, and (possibly) NEC by 50%, and is recommended for all pregnancies at highrisk of delivering before 34 weeks gestation with intact membranes and before 32 weeks with preterm PROM. Maximal benefit is achieved 24-48 hours after the initial dose. This effect lasts for 7 days, but it is unclear what happens thereafter. Repeated courses of steroids are not generally recommended. Bed rest is recommended in up to 20% of all pregnancies, with an estimated cost of >$250 million per year in the United States alone. Despite these recommendations, there is no proven benefit to bed rest in women at risk for preterm labor. Intravenous hydration is also commonly recommended in the acute setting, but without

Answers

1. C. A history suggestive of cervical insufficiency (ie, acute, painless dilatation of the cervix usually in the mid-trimester culminating in prolase and/or PROM with resultant preterm and often previable delivery) is the only proven indication for elective cervical cerclage. If the prior preterm delivery was the result of preterm labor and not cervical insufficiency, cerclage placement is not indicated. Prophylactic cerclage for
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proven benefit. Broad-spectrum antibiotic therapy has been shown to delay preterm birth and prolong latency in the setting of preterm PROM < 34 weeks. However, there is no consistent evidence of prolonged latency in the setting of preterm labor with intact membranes. As such, broad-spectrum antibiotics are not recommended for this indication. Pharmacologic tocolytic therapy remains the cornerstone of modern management. Although a number of alternative agents are now available for tocolysis, the only agent that is approved by the FDA for the treatment of preterm labor is ritodrine hydrochloride (which has been off formulary in North America for over 10 years, because it is too dangerous to administer in pregnancy). Although the ultimate goal of tocolysis is to delay delivery to term, there is no reliable data to suggest that any tocolytic agents are able to delay delivery for longer than 24-48 hours. As such, the most realistic goal of tocolysis is to delay delivery for 48 hours to allow administration of antenatal corticosteroids. No single tocolytic agent has a clear therapeutic advantage. As such, the side effect profile of each of the drugs will often determine which to use in a given clinical setting. Magnesium sulfate (which acts both to suppress nerve transmission to uterine smooth muscle and to lower the concentration of intracellular calcium within myometrial cells, which is necessary for activation of the myosinactin contractile unit) has traditionally been regarded as the first-line tocolytic agent for use in preterm labor. More recent data suggests that nifedipine (a calcium channel blocker) is equally effective and safer, and can be administered orally. In Europe, the first-line tocolytic agent is atosiban, an oxytocin receptor antagonist. 4. B. and C. It is clear from this patient’s history that she is at high risk of preterm delivery. The screening tests currently available for prediction of preterm birth fall into 5 broad categories: 1.) Risk factor scoring. A number of risk factors for preterm labor have been identified. However, reliance on risk factors alone will fail to identify over 50% of pregnancies which deliver preterm, and most women designated at risk will deliver at term.

2.) Home uterine activity monitoring (HUAM). An increase in uterine contractility is a prerequisite for preterm labor. However, use of HUAM in women at high risk does not reduce the incidence of preterm delivery, but does lead to over-diagnosis of preterm labor, increased obstetric intervention, and increased cost. 3.) Assessment of cervical maturation. Serial digital evaluation of the cervix is useful if the examination remains normal. However, an abnormal cervical finding (shortening and/or dilatation) is associated with preterm delivery in only 4% of low-risk women and 12%-20% of high-risk women. Sonographic evaluation of the cervix has demonstrated a strong inverse correlation between cervical length and preterm delivery. If the cervical length is below the 10th percentile for gestational age, the pregnancy is at a six-fold increased risk of delivery prior to 35 weeks gestation. 4.) Biochemical markers. Although a number of biochemical markers have been associated with preterm delivery, only fetal fibronectin (fFN) is established as a screening test for preterm delivery. Elevated levels of fFN in cervicovaginal secretions at 22-34 weeks gestation are associated with premature delivery. The real value of this test lies in its negative predictive value (99% of patients with a negative fFN test will not deliver within 7 days).

5.) Endocrine markers. The detection of elevated levels of estriol in maternal saliva (≥2.1 ng/mL) is predictive of delivery prior to 37 weeks gestation in a high-risk population with a sensitivity of 68%87%, a specificity of 77% and a false positive rate of 23%. Serial (weekly) measurments may be more accurate in predicting pretermbirth than a single measurement. This test is not currently available in the United States. 5. B. and D. Post-term (prolonged) pregnancy refers to a pregnancy that has extended to or beyond a gestational age of 42.0 weeks (294 days) from the first day of the last menstrual period. As such, this patient’s pregnancy is currently at term, not post-term. Clearly, accurate pregnancy dating is critical to the diagnosis. Post-term pregnancy is associated with both fetal and maternal
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risks. Perinatal mortality (stillbirths plus early neonatal deaths) at ≥ 42 weeks of gestation is twice that at term and increases 4-fold at 43 weeks and 5- to 7-fold at 44 weeks. Chronic uteroplacental insufficiency, asphyxia and intrauterine infection all contribute to the excess perinatal deaths. Post-term infants are larger than term infants, with a higher incidence of macrosomia (defined as a sonographic EFW >4500 g). Complications associated with fetal macrosomia include prolonged labor, cephalopelvic disproportion, and shoulder dystocia with resultant risks of orthopedic or neurologic injury. Post-term pregnancies are at increased risk of umbilical cord compression from oligohydramnios, nonreassuring fetal antepartum or intrapartum assessment, meconium aspiration, shortterm neonatal complications (hypoglycemia, seizures) and long-term neurologic sequelae. For these reasons, there does appear to be a small advantage to routine induction of labor at 41 weeks gestation, regardless of parity or method of induction. However, induction of labor for the indication of “impending macrosomia” is not appropriate, and such an approach has not been shown to decrease cesarean delivery rates or improve perinatal outcome. Routine induction of labor at 41 weeks will not increase the cesarean rate for multipara and nullipara with a favorable cervical exam (although the cesarean delivery rate of primipara with an unfavorable cervical exam is likely to be increased).

preeclampsia (in the absence of thrombocytopenia) with close attention to volume expansion and anesthetic technique. The use of antihypertensive agents to control mildly elevated BP in the setting of preeclampsia has not been shown to alter the course of the disease nor to diminish perinatal morbidity or mortality, and may indeed reduce uteroplacental perfusion. Moreover, the use of such agents may serve to remove the most sensitive index of worsening preeclampsia. For these reasons, antihypertensive therapy is not recommended for mild-to-moderate hypertension in the setting of preeclampsia. 7. C. and D. Causes of unexplained IUFD at term can be identified in only around 50% of cases. Pathologic examination of the fetus and placenta/fetal membranes is the single most useful test to identify a cause for the IUFD. Fetal karyotyping should be considered in all cases of fetal death to identify chromosomal abnormalities, particularly in cases with documented fetal structural abnormalities. Fetal-maternal hemorrhage occurs in all pregnancies, but is usually minimal. In rare instances, fetal-maternal hemorrhage may be massive, leading to fetal demise. The Kleihauer-Betke (acid elution) test allows an estimate of the volume of fetal blood in the maternal circulation and should be sent as soon as possible since fetal cells are very rapidly cleared from the maternal circulation. Intra-amniotic infection resulting in fetal death is usually evident on clinical exam. Placental culture and histologic examination of the fetus, placenta/fetal membranes, and umbilical cord may be useful. Immediate delivery is not necessary. Overall, >90% of women will go into labor within 2 weeks of fetal death. Around 20%-25% of women that retain a dead singleton fetus for longer than 3 weeks will develop disseminated intravascular coagulopathy (DIC) due to excessive consumption of clotting factors. Therefore, delivery should be effected within this time period.

6. B. Preeclampsia is a clinical diagnosis encompassing 3 elements: 1.) new-onset hypertension (defined as a sustained BP ≥140/90 in a previously normotensive woman); 2.) new-onset proteinuria (>300 mg/24 h or ≥2+ on a clean-catch urinalysis in the absence of urinary infection); and 3.) non-dependent edema (although this is not a prerequisite for diagnosis). BP should always be measured in the sitting position using the 5th Korotkoff sound (disappearance of pulsation) to describe the diastolic BP. Preeclampsia is classified as either “mild” or “severe” (there is no moderate preeclampsia). This patient has severe preeclampsia by symptoms (headache, visual changes) and should be delivered immediately. However, immediate delivery need not necessarily mean cesarean delivery. Cervical ripening agents may be used if the cervix is not favorable prior to induction, but prolonged inductions should be avoided. Regional analgesia can be safely administered in the setting of
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8. C. Multiple pregnancy should be suspected in women at high risk, excessive symptoms of pregnancy or uterine size larger than expected. Overall, antepartum complications develop in 80% of multiple pregnancies as compared with around 30% of singleton gestations. Preterm delivery is the most common complication, and the risk of preterm delivery increases as fetal number increases. Malpresentation is a common com-

plication of multiple pregnancies. Cord entanglement, on the other hand, is specific to monochorionic/monoamniotic pregnancies. Overall, it is a rare complication (1 in 25,000 births), but may occur in up to 70% of monochorionic/monoamniotic pregnancies and is thought to account for >50% of perinatal mortality in this subgroup. Twin polyhydramnios/oligohydramnios sequence results from an imbalance in blood flow from the “donor” twin to the “recipient.” Both twins are at risk for adverse events. Twin-to-twin transfusion is a subset of poly/oligo sequence seen in 15% of monochorionic pregnancies, and is due to unbalanced vascular communications between the fetal circulations. Overall perinatal mortality is 40%-80%. Treatment options include expectant management, serial amniocentesis, indomethacin (to decrease fetal urine output), laser obliteration of the placental vascular communications or selective fetal reduction. 9. All are correct. Of pregnancies with placenta previa, 25% with previa and 1 prior cesarean, and 60% with previa and 2 or more prior cesareans. Neonatal complications include preterm birth and malpresentation. However, placenta previa is not associated with IUGR. Elective cesarean delivery is generally recommended at 36-37 weeks gestation. 80% of twin pregnancies are dizygous (derived from 2 separate embryos). Dizygous twinning is influenced by a number of epidemiologic factors, including a family or personal history of multiple pregnancy, advanced maternal age, multiparity, African American, and ART. Monozygous twinning, on the other hand, is a random event that occurs in around 1 in 300 pregnancies (although the risk may be increased 2- to 3-fold with in vitro fertilization). Perinatal mortality is higher with monozygous(30%50%) than with dizygous twins (10%-20%). Chorionicity refers to the arrangement of membranes in multiple pregnancies. In monozygous twinning, the timing of the cell division determines the chorionicity. If the zygote divides within 3 days of fertilization, the result is dichorionic/diamniotic placentation (30% of all monozygous pregnancies); if the division occurs between day 3 and day 8, the result is a monochorionic/diamniotic pregnancy (65%); between day 8 and day 13, a monochorionic/ monoamniotic pregnancy ensues (<5%); and if the division occurs on or after day 13, incomplete separation (conjoined twins) is the rule (<0.5%). Chorionicity correlates directly with

perinatal mortality, which is especially high with monochorionic/monoamniotic twins (65%-70%). Chorionicity is determined most accurately by examination of the membranes after delivery. Antenatal diagnosis is more difficult. Identification of separate sex fetuses or two separate placentae confirms dichorionic/diamniotic placentation.

10. A. and D. Placenta previa refers to implantation of the placenta over the cervical os in advance of the fetal presenting part. In any patient presenting with antepartum hemorrhage, pelvic and/or rectal examinations should be avoided until placenta previa is excluded. Placenta previa is primarily a sonographic diagnosis. Placenta previa may resolve with time, thereby permitting vaginal delivery. Indeed, only 5% of low-lying placentae identified by ultrasound at 14-20 weeks gestation persist to term. Maternal complications include placenta accreta, which refers to abnormal attachment of placental villi to the uterine wall. In the absence of placenta previa, placenta accreta is rare. However, it complicates 5%-15% of pregnancies with placenta previa, 25% with previa and 1 prior cesarean, and 60% with previa and 2 or more prior cesareans. Neonatal complications include preterm birth and malpresentation. However, placenta previa is not associated with IUGR. Elective cesarean delivery is generally recommended at 36-37 weeks gestation.

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