Obstentrics_Williams

Obstentrics_Williams. Several compounds react with 3-adrenergic receptors to reduce intracellular ionized calcium levels and prevent activation of myometrial contractile proteins (Chap. 21, p. 406). Of 3-mimetic drugs in the United States, ritodrine and terbutaline have been used in obstetrics, but only ritodrine is approved for preterm labor by the FDA. Ritodrine was voluntarily withdrawn from the United States market in 2003, but a discussion of ritodrine is included here to present issues with 3-mimetic drug use. In one early trial, neonates whose mothers were treated with ritodrine for threatened preterm labor had lower rates of preterm birth and its complications (NIerkatz, 1980). In a randomized trial at Parkland Hospital, intravenous ritodrine delayed delivery for 24 hours but without other beneits (Leveno, 1986b). Additional studies confirmed a delivery delay up to 48 hours (Canadian Preterm Labor Investigators Group, 1992).


Obstentrics_Williams

Obstentrics_Williams. 3-Agonist drug infusion has resulted in serious and even fatal maternal side efects. Pulmonary edema is a special concern, and its contribution to morbidity is discussed in Chapter 47 (p. 917). In one early study, tocolysis was the third most common cause of acute respiratory distress and death in pregnant women during a 14-year period in Mississippi (Perry, 1998). The cause of pulmonary edema is multifactorial. isk factors include tocolytic therapy with 3-agonist drugs, multifetal gestation, concurrent corticosteroid therapy, tocolysis for more than 24 hours, and intravenous infusion of large volumes of crystalloid. 3-Agonist agents cause retention of sodium and water, and with time-usually 24 to 48 hours-these can cause volume overload (Hankins, 1988). The drugs have been implicated in increased capillary permeability, cardiac rhythm disturbances, and myocardial ischemia.


Obstentrics_Williams

Obstentrics_Williams. Terbutaline is commonly used in the United States to forestall preterm labor. Like ritodrine, it may cause pulmonary edema (Angel, 1988). Low-dose terbutaline can be administered longterm by subcutaneous pump (Lam, 1988; Perry, 1995). But, randomized trials have shown no beneit for terbutaline pump therapy (Guinn, 1998; Wenstrom, 1997). Oral terbutaline given to prevent preterm delivery is also inefective (How, 1995; Parilla, 1993). In one trial, 203 women with arrested preterm labor at 24 to 34 weeks' gestation were randomly assigned to receive 5-mg terbutaline tablets or placebo every 4 hours (Lewis, 1996). Of outcomes, delivery rates at 1 week, median latency duration, mean gestational age at delivery, and incidence of preterm labor relapse were similar in both groups. Because of reports of serious maternal side efects, the FDA (2011) issued a warning regarding the use of terbutaline to treat preterm labor. The American College of Obstetricians and Gynecologists (2016b) recommends


Obstentrics_Williams

Obstentrics_Williams. of serious maternal side efects, the FDA (2011) issued a warning regarding the use of terbutaline to treat preterm labor. The American College of Obstetricians and Gynecologists (2016b) recommends only short-term inpatient use of terbutaline as a tocolytic or as acute therapy of uterine tachysystole. Subcutaneous dosages of 0.25 mg are commonly used for the latter indication. T erbutaline, used as a tocolytic prior to external cephalic version, is discussed in Chapter 28 (p. 550).


Obstentrics_Williams

Obstentrics_Williams. Ionic magnesium in a suiciently high concentration n alter myometrial contractility. Its role is presumably that of a calcium antagonist, and when given in pharmacological doses, it may inhibit labor. Intravenous magnesium sulfate, given s a 4-g loading dose and followed by a continuous inusion of 2 g/hr, usually arrests labor (Steer, 1977). Like 3-mimetic agents, magnesium treatment can cause pulmonary edema (Samol, 2005). However, this has not been our experience at Parkland Hospitl in the treatment of tens of thousands of preeclamptic women with intravenous magnesium sulfate. Pharmacology and toxicology of magnesium are considered in more detail in Chapter 40 (p. 737).


Obstentrics_Williams

Obstentrics_Williams. Only two randomized studies have evaluated tocolysis with magnesium sulfate. Cotton and colleagues (1984) compared magnesium sulfate, ritodrine, and placebo in 54 women with preterm labor. They identified few diferences in outcomes. Cox and coworkers (1990) randomly assigned 156 women to receive magnesium sulfate or infusions of normal saline. Magnesium-treated women and their neonates had identical outcomes compared with those given placebo. Because of these findings, this method of tocolysis was abandoned at Parkland Hospital. Similarly, Crowther and associates (2014) reviewed magnesium sulfate as a tocolytic agent and concluded it was inefective and potentially harmful. Last, the FDA (2013) has warned against prolonged use of magnesium sulfate given to arrest preterm labor because of bone thinning and fractures in fetuses exposed for more than 5 to 7 days. This was attributed to low calcium levels in the fetus.


Obstentrics_Williams

Obstentrics_Williams. hese compounds are intimately involved in contractions of normal labor (Chap. 21, p. 416). Antagonists act by inhibiting prostaglandin synthesis or by blocking their action on target organs. A group of enzymes collectively termed prostaglandin synthase is responsible for the conversion of free arachidonic acid to prostaglandins. Several drugs block this system, including acetylsalicylate and indomethacin.


Obstentrics_Williams

Obstentrics_Williams. Indomethacin, a nonselective cyclooxygenase inhibitor, was first used as a tocolytic in one study of 50 women (Zuckerman, 1974). Studies that followed reported the eicacy of indomethacin in halting contractions and delaying preterm birth (Muench, 2003; Niebyl, 1980). Morales and coworkers (1989, 1993a), however, compared indomethacin with either ritodrine or magnesium sulfate and found no diference in their eicacy to forestall preterm delivery. Berghella and associates (2006) reviewed four trials of indomethacin given to women with a sonographically determined short cervix and found such therapy to be inefective. Indomethacin is administered orally or rectally. Most studies have limited indomethacin use to 24 to 48 hours because of concerns for oligohydramnios, which can develop with therapeutic doses. If amnionic luid is monitored, oligohydramnios can be detected early, and it is reversible with drug discontinuation.


Obstentrics_Williams

Obstentrics_Williams. In a study of neonates born before 30 weeks, Norton and coworkers (1993) identiied necrotizing enterocolitis in 30 percent of 37 indomethacin-exposed newborns compared with 8 percent of 37 control newborns. Higher incidences of intraventricular hemorrhage and patent ductus arteriosus were also documented in the indomethacin group. Several investigators have challenged the association between indomethacin exposure and necrotizing enterocolitis (Muench, 2001; Parilla, 2000). Similarly, Gardner (1996) and Abbasi (2003) and their colleagues found no link between indomethacin use and intraventricular hemorrhage, patent ductus arteriosus, sepsis, necrotizing enterocolitis, or neonatal death. Two metaanalyses of the efects of antenatal indomethacin on neonatal outcomes had conflicting indings (Amin, 2007; Loe, 2005). Reinebrant and colleagues (2015) in a review of 20 studies reported no clear benefit from cyclooxygenase inhibitors, including indomethacin, compared with placebo or any other


Obstentrics_Williams

Obstentrics_Williams. 2007; Loe, 2005). Reinebrant and colleagues (2015) in a review of 20 studies reported no clear benefit from cyclooxygenase inhibitors, including indomethacin, compared with placebo or any other tocolytic agent.


Obstentrics_Williams

Obstentrics_Williams. These potent smooth-muscle relaxants afect the vasculature, gut, and uterus. In randomized clinical trials, nitroglycerin administered orally, transdermally, or intravenously was ineffective or showed no superiority over other tocolytics. In addition, maternal hypotension was a common side efect (Bisits, 2004; EI-Sayed, 1999; Lees, 1999). Discussed in Chapter 21 (p. 404), myometrial aCtlVIty is directly related to cytoplasmic free calcium, and reduced calcium concentrations inhibit contractions. Calcium-channel blockers act to inhibit, by various mechanisms, calcium entry through cell membrane channels. Although they were developed to treat hypertension, their ability to arrest pre term labor has been evaluated.


Obstentrics_Williams

Obstentrics_Williams. From study results, calcium-channel blockers, especially nifedipine, are safer and more efective tocolytic agents than 3-agonist drugs (King, 2003; Papatsonis, 1997). Lyell and colleagues (2007) randomized 192 women at 24 to 33 weeks' gestation to either magnesium sulfate or nifedipine and found no substantial diferences in eicacy or adverse efects. In another randomized study, 145 women with preterm labor between 24 and 33 weeks received nifedipine or atosiban. Neither proved superior to delay delivery, and neonatal morbidity was equivalent (Salim, 2012).


Obstentrics_Williams

Obstentrics_Williams. Flenady and coworkers (20 14b) reviewed 38 trials of calciumchannel blockers (mainly nifedipine) for preterm labor. These investigators suggested that calcium-channel blockers have beneits compared with placebo or no treatment. But, this conclusion stemmed from a trial with unclear risk of selection bias and a three-arm study of 84 women that was not blinded (Ara, 2008; Zhang, 2002). We are currently performing a randomized, double-blind, placebo-controlled trial of nifedipine for acute tocolysis of preterm labor at Parkland Hospital.


Obstentrics_Williams

Obstentrics_Williams. Importantly, the combination of nifedipine with magnesium for tocolysis is potentially dangerous. Ben-Ami (1994) and Kurtzman (1993) and their coworkers reported that nifedipine enhances the neuromuscular blocking efects of magnesium, which can interfere with pulmonary and cardiac function. In one small study of 54 women with preterm labor who received either magnesium sulfate plus nifedipine or no tocolytic, neither beneit nor harm was found (How, 2006).


Obstentrics_Williams

Obstentrics_Williams. This nonapeptide oxytocin analogue is an oxytocin-receptor antagonist (ORA). Goodwin and colleagues (1995) described its pharmacokinetics in pregnant women. In randomized clinical trials, atosiban failed to improve relevant neonatal outcomes and was linked with signiicant neonatal morbidity (Moutquin, 2000; Romero, 2000). he FDA has denied approval of atosiban because of concerns regarding eicacy and fetal-newborn safety. Further, in 2014, a metaanalysis did not demonstrate superiority of ORAs (largely atosiban) as a tocolytic compared with placebo, 3-mimetic drugs, or calcium-channel blockers in terms of pregnancy prolongation or neonatal outcomes. But, ORAs were associated with fewer maternal adverse efects (Flenady, 20 14a). Recently, van Vliet and coworkers (2016) conducted a randomized trial comparing nifedipine with atosiban in 510 women with threatened preterm birth. Using a composite of adverse perinatal outcomes, no diferences were reported between the two study groups.


Obstentrics_Williams

Obstentrics_Williams. Whether preterm labor is induced or spontaneous, abnormalities of fetal heart rate and uterine contractions are sought. We prefer continuous electronic monitoring. Fetal tachycardia, especially with ruptured membranes, is suggestive of sepsis. Some evidence supports that intrapartum acidemia may intensiy some of the neonatal complications usually attributed to preterm delivery. For example, Morgan and associates (2017) found that metabolic acidemia signiicantly raised the risks related to prematurity in neonates delivered prior to 34 weeks' gestation. Low and colleagues (1995) observed that intrapartum acidosis-umbilical artery blood pH <7.0-had an important role in neonatal complications (Chap. 33, p. 621). Group B streptococcal infections are common and dangerous in the preterm neonate, and antimicrobial prophylaxis should be provided (Chap. 64, p. 1222).


Obstentrics_Williams

Obstentrics_Williams. In the absence of a relaxed vaginal outlet, an episiotomy for delivery may be necessary once the fetal head reaches the perineum. Perinatal outcome data do not support routine episiotomy or forceps delivery to protect the "fragile" preterm fetal head. Staf proicient in resuscitative techniques commensurate with the gestational age and fully oriented to any speciic problems should be present at delivery. Principles of resuscitation described in Chapter 32 (p. 608) are applicable. The importance of specialized personnel and facilities for preterm newborn care is underscored by the improved survival rates of these neonates when delivered in tertiary-care centers. • Prevention of Intracranial Hemorrhage


Obstentrics_Williams

Obstentrics_Williams. • Prevention of Intracranial Hemorrhage Preterm newborns frequently have intracranial germinal matrix bleeding that can extend to more serious intraventricular hemorrhage (Chap. 34, p. 639). It was hypothesized that cesarean delivery to obviate trauma from labor and vaginal delivery might prevent these complications. his has not been validated by subsequent studies. Malloy (1991) analyzed 1765 newborns with birthweights < 1500 g and found that cesarean delivery did not lower the risk of mortality or intracranial hemorrhage. Anderson and colleagues (1988), however, made an interesting observation regarding the role of cesarean delivery in intracranial hemorrhage prevention. These hemorrhages correlated with exposure to active-phase labor. However, they emphasized that avoidance of active-phase labor is impossible in most preterm births because decisions for delivery route are not required until active labor is irmly established.


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Obstentrics_Williams. Aagaard K, Riehle K, Ma ], et al: A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. PLoS One (6):e36466, 2012 Abbasi S, Gerdes ]S, Sehdev HM, et al: Neonatal outcomes after exposure to indomethacin in utero: a retrospective case cohort study. Am ] Obstet Gynecol 189:782,n2003 Akgul Y, Word RA, Ensign LM, et al: Hyaluronan in cervical epithelia protects against infection-mediated preterm birth.] Clin Invest 124(12):5481,2014 Alexander ]M, Gilstrap LC, Cox SM, et al: Clinical chorioamnionitis and the prognosis for very low birthweight infants. Obstet Gynecol 25, 1998 Alexander ]M, Mercer BM, Miodovnik M, et al: he impact of digital cervical examination on expectantly managed preterm tuptured membranes. Amn] Obstet Gynecol 183: 1 003, 2000 Alirevic Z, Milan S], Livio S: Caesarean section versus vaginal delivery for preterm birth in singletons. Cochrane Database Syst Rev 9:CD000078, 2013


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Obstentrics_Williams. Alirevic Z, Milan S], Livio S: Caesarean section versus vaginal delivery for preterm birth in singletons. Cochrane Database Syst Rev 9:CD000078, 2013 Althabe F, Belizan ]M, McClure EM, et al: A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortaliry due to preterm birth in lowincome and middle-income countries: the ACT cluster-randomised trial. Lancet 385(9968):629,n2015 Althuisius SM, Dekker G, Hummel P, et al: Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone. Am] Obstet Gynecol 189:907,n2003 Althuisius SM, Dekker GA, Hummel P, et al: Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest versus bed rest alone. Am ] Obstet Gynecol 185:1106,n2001


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Obstentrics_Williams. American College of Obstetricians and Gynecologists: Magnesium sulfate before anticipated preterm birth for neuroprotection. Patient Safety Checklist No.n7, August 2012 American College of Obstetricians and Gynecologists: Magnesium sulfate use in obstetrics. Committee Opinion No. 652, January 2016a American College of Obstetricians and Gynecologists: Management of preterm labor. Practice Bulletin No. 171, October 2016b American College of Obstetricians and Gynecologists: Prediction and prevention of preterm birth. Practice Bulletin No. 130, October 2012, Reairmed 2016c American College of Obstetricians and Gynecologists: Premature rupture of membranes. Practice Bulletin No. 172, October 2016d American College of Obstetricians and Gynecologists: Antenatal corticosteroid therapy for fetal maturation. Committee Opinion No. 713, August 2017a


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Obstentrics_Williams. American College of Obstetricians and Gynecologists: Antenatal corticosteroid therapy for fetal maturation. Committee Opinion No. 713, August 2017a American College of Obstetricians and Gynecologists: Intrapartum management of intraamniotic infection. Committee Opinion No. 712, August 2017b American College of Obstetricians and Gynecologists: Medically indicated late-preterm and early-term deliveries. Committee Opinion No. 560, April 2013, Reairmed 2017c American College of Obstetricians and Gynecologists: Physical activity and exercise during pregnancy and the postpartum period. Committee Opinion No. 650, December 2015, Reairmed 2017d American College of Obstetricians and Gynecologists, Society for MaternalFetal Medicine: Periviable birth. Obstetric Care Consensus No.n6, 2017e Amin SB, Sinkin RA, Glantz C: Metaanalysis of the efect of antenatal indo methacin on neonatal outcomes. Am ] Obstet Gynecol :486, 2007


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Obstentrics_Williams. Ananth CV, Joseph KS, Oyelese Y, et al: Trends in pre term birth and perinatal mortality among singletons: United States, 1989 through 2000. Obstet GynecoIn105:1084,n2005 Ananth CV, Liu S, Joseph KS, et al: A comparison of foetal and infant mortality in the United States and Canada. Intn] Epidemiol 38(2):480, 2009 Anderson GD, Bada HS, Sibai BM, et al: The relationship berween labor and route of delivery in the preterm infant. Am] Obstet Gynecol158: 1382, 1988 Andrews W, Goldenberg L, Hauth ]C, et al: Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized clinical trial. Am ] Obstet Gynecol 194:617, 2006 Andrews W, Hauth ]C, Goldenberg L, et al: Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery. Amn] Obstet Gynecol 173:606, 1995


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Obstentrics_Williams. Andrews WW, Sibai BM, Thon A, et al: Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal ibronectin-positive women. Obstet GynecoIn101:847, 2003 Angel ]L, O'Brien F, Knuppel RA, et al: Carbohydrate intolerance in patients receiving oral tocolytics. m ] Obstet Gynecol 159:762, 1988 Annas G]: Extremely preterm birth and parental authority to refuse treatmentthe case of Sidney Miller. N Engl ] Med 35:2118, 2004 Anum A, Springel EH, Shriver MD, et al: Genetic contributions to disparities in preterm birth. Pediatr Res 65(1): 1, 2009 Ara I, Banu H: A prospective randomised trial of nifedipine versus placebo in preterm labour. Bangladesh] Obstet Gynaecol 23(2):61, 2008


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Obstentrics_Williams. Ara I, Banu H: A prospective randomised trial of nifedipine versus placebo in preterm labour. Bangladesh] Obstet Gynaecol 23(2):61, 2008 Arechavaleta-Velasco F, Mayon-Gonzalezn], Gonzalez-]imenez M, et al: Association of type II apoptosis and 92-kDa type IV collagenase expression in human amniochorion in prematurely ruptured membranes with tumor necrosis factor receptor-1 expression. ] Soc Gynecol Investig 9:60, 2002 Attardi B], Zeleznik A, Simhan H, et al: Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17 -alpha hydroxyprogesterone caproate, and related progestins. Am] Obstet GynecoIn197(6):599.e1, 200


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Obstentrics_Williams. Aune 0, Schlesinger S, Henriksen T, et al: Physical activity and the risk of preterm birth: a systematic review and meta-analysis of epidemiological studies. B]OG 124(12):1816,n2017 Ball S], Pereira G, Jacoby P, et al: Re-evaluation oflink berween interpregnancy interval and adverse birth outcomes: retrospective cohort study matching rwo intervals per mother. BM] 349:g4333, 2014 Barth H ] r: Lost in translation: the changing language of our specialty. Obstet Gynecol 127(3):423,n2016 Beigi RH, Austin MN, Meyn A, et al: Antimicrobial resistance associated with the treatment of bacterial vaginosis. Am ] Obstet Gynecol 191: 1124, 2004 Ben-Ami M, Giladi Y, Shalev E: The combination of magnesium sulphate and nifedipine: a cause of neuromuscular blockade. B]OG 101n:262, 1994 Berghella V, Odibo AO, Tolosa ]E: Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial. Amn] Obstet Gynecol 191:131n1,n2004


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Obstentrics_Williams. Berghella V, Rafael T], Szychowski ]M, et al: Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis. Obstet Gynecol (3):663, 2011 Berghella V, Rust OA, Althuisius SM: Short cervix on ultrasound: does indomethacin prevent preterm birth? m] Obstet Gynecol 195:809,n2006 Bisits A, Madsen G, Knox M, et al: The randomized nitric oxide tocolysis trial (RNOTT) for the treatment of preterm labor. Amn] Obstet Gynecol 191:683,n2004 Bloom SL, Leveno K]: Unproven technologies in maternal-fetal medicine and the high cost of US health care.]AMA 317(10):1025,n2017 Bloom SL, Yost NP, McIntire DD, et al: Recurrence of preterm birth in singleton and rwin pregnancies. Obstet Gynecol 98:379, 2001


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Obstentrics_Williams. Bloom SL, Yost NP, McIntire DD, et al: Recurrence of preterm birth in singleton and rwin pregnancies. Obstet Gynecol 98:379, 2001 Bond OM, Middleton P, Levett , et al: Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy outcome. Cochrane Database Syst Rev 3:CD004735, 2017 Borgida AF, Mills A, Feldman DM, et al: Outcome of pregnancies complicated by ruptured membranes after genetic amniocentesis. Am ] Obstet Gynecol 183(4):937,n2000 Bruschettini M, van den Hove DL, Gazzolo D, et al: Lowering the dose of antenatal steroids: the efects of a single course of betamethasone on somatic growth and brain cell proliferation in the rat. Amn] Obstet Gynecol 194:1341,n2006 Buekens P, Alexander S, Boutsen M, et al: Randomised controlled trial of routine cervical examinations in pregnancy. Lancet 344:841, 1994


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Obstentrics_Williams. Buekens P, Alexander S, Boutsen M, et al: Randomised controlled trial of routine cervical examinations in pregnancy. Lancet 344:841, 1994 Buxton IL, Singer CA, Tichenor ]N: Expression of stretch-activated rwo-pore potassium channels in human myometrium in pregnancy and labor. PLoS One 5(8):e12372, 2010 Callaghan M, MacDorman MF, Shapiro-Mendoza CK, et al: Explaining the recent decrease in US infant mortality rate, 2007-2013. Amn] Obstet GynecoIn216(1):73.el,2017 Canadian Preterm Labor Investigators Group: Treatment of preterm labor with the beta-adrenergic agonist ritodrine. N Engl ] Med 327:308, 1992 Cantonwine DE, Zhang Z, Rosenblatt K, et al: Evaluation of proteomic biomarkers associated with circulating micro particles as an efective means to stratiy the risk of spontaneous preterm birth. Am ] Obstet Gynecol 214(5):631.e1,t2016 Careyt]C, Klebanof A: Is a change in the vaginal flora associated with an increased risk of preterm birth? Am ] Obstet Gynecol 192(4): 1341, 2005


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Obstentrics_Williams. Careyt]C, Klebanof A: Is a change in the vaginal flora associated with an increased risk of preterm birth? Am ] Obstet Gynecol 192(4): 1341, 2005 Caritis SN, Rouse D], Peaceman M, et al: Prevention of preterm birth in triplets using 17alpha-hydroxyprogesterone caproate. Obstet Gynecol 113:285, 2009 Caritis SN, Sharma S, Venkataramanan R, et al: Pharmacology and placental transport of 17 -hydroxyprogesterone caproate in singleton gestation. Am ] Obstet GynecoIt207(5):398.e1, 2012 Caritis SN, Venkataramanan R, Thon E, et al: Relationship berween 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth. Am] Obstet GynecoI210(2):128.e1, 2014 Carlan S], O'Brien WF, Parsons MT, et al: Preterm premature rupture of membranes: a randomized study of home versus hospital management. Obstet GynecoIt81:61, 1993 Carroll SG, Blott M, Nicolaides KH: Preterm prelabor amniorrhexis: outcome of live births. Obstet Gynecol 86: 18, 1995


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Obstentrics_Williams. Carroll SG, Blott M, Nicolaides KH: Preterm prelabor amniorrhexis: outcome of live births. Obstet Gynecol 86: 18, 1995 Carroll SG, Papaionnou S, Ntumazah IL, et al: Lower genital tract swabs in the prediction of intrauterine infection in preterm prelabour rupture of the membranes. B]OG 103:54, 1996 Casanueva E, Ripoll C, Meza-Camacho C, et al: Possible interplay berween vitamin C deficiency and prolactin in pregnant women with premature rupture of membranes: facts and hypothesis. Med Hypotheses 64:241, 2005 Casey ML, Cox SM, Word A, et al: Cyrokines and infection-induced preterm labour. Reprod Fertil Devel 2:499, 1990 Casey ML, MacDonald PC: Transforming growth factor-beta inhibits progesterone-induced enkephalinase expression in human endometrial stromal cells. ] Clin Endocrinol Metab 81 :4022, 1996 Chat], Bartos A, Egashira M, et al: Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions. ] Clin Invest 123(9):4063, 2013


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Obstentrics_Williams. Chat], Bartos A, Egashira M, et al: Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions. ] Clin Invest 123(9):4063, 2013 Chaim W, Mazor M: Intraamniotic infection with fusobacteria. Arch Gynecol Obstet 251:1,t1992 Challis ]R, Sloboda OM, Alfaidy N, et al: Prostaglandins and mechanisms of preterm birth. Reproduction 124: 1, 2002 Chao TT, Bloom SL, Mitchell ]S, et al: he diagnosis and natural history of false preterm labor. Obstet Gynecol 118(6):1301,t2011 Chuang TH, Ulevitch R]: Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8, and hTLR9. Eur Cyrokine Nerw 11:372,t2000 Cnattingius S, Villamor E, Johansson S, et al: Maternal obesity and risk of preterm delivery.t]AMA 309(22):2362, 2013


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Obstentrics_Williams. Cnattingius S, Villamor E, Johansson S, et al: Maternal obesity and risk of preterm delivery.t]AMA 309(22):2362, 2013 Cohen A W, Copel ]A, Macones GA, et al: Unjustiied increase in cost of care resulting from U.S. Food and Drug Administration approval of Makena (17a-hydroxyprogesterone caproate). Obstet Gynecol 117(6): 1408, 2011 Collaborative Home Uterine Monitoring Study Group: A multicenter randomized controlled trial of home uterine monitoring: active versus sham device. Am] Obstet Gynecol 173: 1170, 1995 Collins ]W ]r, David R], Simon DM, et al: Preterm birth among African American and white women with a lifelong residence in high-income Chicago neighborhoods: an exploratory study. Ethn Dis 17(1): 113, 2007 Conde-Agudelo A, Rosas-Bermudez A, Kafury-Goeta AC: Birth spacing and risk of adverse perinatal outcomes: a meta-analysis. ]MA 295: 1809, 2006 Consortium on Safe Labor: Respiratory morbidity in late preterm births. ]MA 304(4):419,t2010


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Obstentrics_Williams. Cook CM, Ellwood DA: A longitudinal study of the cervix in pregnancy using transvaginal ultrasound. B]OG 103:16, 1996 Copper L, Goldenberg L, Dubard MB, et al: Cervical examination and tocodynamometry at 28 weeks' gestation: prediction of spontaneous preterm birth. Am J Obstet Gynecol 172:666, 1995 Cotton DB, Strassner HT, Hill LM, et al: Comparison berween magnesium sulfate, terbutaline and a placebo for inhibition of preterm labor: a randomized study. ] Reprod Med 29:92, 1984 Cox SM, Leveno K]: Intentional delivery versus expectant management with preterm ruptured membranes at 30-34 weeks' gestation. Obstet Gynecol 86:875, 1995


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Obstentrics_Williams. Cox SM, Leveno K]: Intentional delivery versus expectant management with preterm ruptured membranes at 30-34 weeks' gestation. Obstet Gynecol 86:875, 1995 Cox SM, Sherman ML, Leveno K]: Randomized investigation of magnesium sulfate for prevention of pre term birth. Am] Obstet GynecoIt163:767, 1990 Cox SM, Williams ML, Leveno K]: The natural history of preterm ruptured membranes: what to expect of expectant management. Obstet GynecoI71:558, 1988 Creasy RK, Gummer BA, Liggins GC: System for predicting spontaneous pre term birth. Obstet Gynecol 55(6):692, 1980 Crowley AE, Grivell M, Dodd ]M: Sealing procedures for preterm prelabour rupture of membranes. Cochrane Database Syst Rev 7:CD010218, 2016 Crowther CA, Brownt], �l1cKinlay C], et al: Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev 8:CD001060, 2014


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Obstentrics_Williams. Crowther CA, Brownt], �l1cKinlay C], et al: Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev 8:CD001060, 2014 Crowther CA, Doyle L W, Haslam RR, et al: Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Englt] Med 357: 1179, 2007 Crowther CA, Harding ]E: Antenatal glucocorticoids for late preterm birth. N Engl] Med 374(14):1376, 2016 Crowther CA, Hiller ]E, Doyle L W, et al: Efect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. ]AMA 290:2669, 2003 Crowther CA, McKinlay C], Middleton P, et al: Repeat doses of prenatal corticosteroids for women at risk for preterm birth for improving neonatal health outcomes. Cochran Database Syst Rev 6:CD003935, 2011 Culhane ]F, Rauh V, McCollum KF, et al: Exposure to chronic stress and ethnic diferences in rates of bacterial vaginosis among pregnant women. Am ] Obstet 2,t2002


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Obstentrics_Williams. Culhane ]F, Rauh V, McCollum KF, et al: Exposure to chronic stress and ethnic diferences in rates of bacterial vaginosis among pregnant women. Am ] Obstet 2,t2002 Delnord M, Hindori-Mohangoo AD, Smith LK, et al: Variations in very preterm birth rates in 30 high-income countries: are valid international comparisons possible using routine data. B]OG 124(5):785,t201 Di Mascio D, Magro-Malosso ER, Saccone G, et al: Exercise during pregnancy in normal-weight women and risk of preterm birth: a systematic review and meta-analysis of randomized controlled trials. Am ] Obstet Gynecol 215(5):561,t2016 Dolan SM, Gross S], Merkatz lR, et al: The contribution of birth defects to preterm birth and low birth weight. Obstet Gynecol 110:318, 2007 Donders GG, Van Calsteren K, Bellen G, et al: Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the irst trimester of pregnancy. B]OG 116(10): 1315, 2009


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Obstentrics_Williams. Smith SB, Ravel ]: The vaginal microbiota, host defence and reproductive physiology.] PhysioI595(2):451, 2017 Society for Maternal-Fetal Medicine: Implementation of the use of antenatal corticosteroids in the late preterm birth period in women at risk for preterm delivery. Amt] Obstet GynecoIt215(2):B13, 2016a Society for Maternal-Fetal Medicine: The choice of progestogen for the prevention of preterm birth in women with singleton pregnancy and prior preterm birth. Am J Obstet Gynecol 216(3):B11, 2017a Society for Maternal-Fetal Medicine: The role of cervical pessary placement to prevent preterm birth in clinical practice. Am] Obstet GynecoI216(3):B8, 2017b Society for Maternal-Fetal Medicine, McIntosh ], Feltovich H, et al: he role of routine cervical length screening in selected high-and low-risk women for preterm birth prevention. Am] Obstet GynecoI215(3):B2, 2016b


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Obstentrics_Williams. Young A, Thomson A], Ledingham M, et al: Immunolocalization of proinlammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. BioI Reprod 66:445, 2002 Young D: Clinical trials and tribulations: 170HPC and preventing recurrent preterm birth. Am] Obstet GynecoI216(6):543, 2017 Younge N, Goldstein RF, Bann CM, et al: Survival and neurodevelopmental outcomes among periviable infants. N Engl ] Med 376(7):617, 2017 Zhang X, Liu M: Clinical observations on the prevention and treatment of premature labor with nifedipine. [Chinese] Hua i Yi Ke Da Xue Xue Bao 33(2):288, 2002 Zuckerman H, Reiss U, Rubinstein I:


Obstentrics_Williams

Obstentrics_Williams. Zuckerman H, Reiss U, Rubinstein I: Inhibition of human premature labor by indomethacin. Obstet , 1974 t must be admitted that the duration ofpregnancy not infrequenty exceeds 280 days rom the last menstrual period and that when it lasts much longer large children are developed which are frequenty delivered ony after great dficuly. Thus, whenever the menstrual history of the patient indicates that she has passed much beyond the tenth and is approaching the eleventh lunar month, we should consider the pro priey of the induction of labour, provided that examination shows the child is larger than usual. -J. Whitridge Williams (1903) he above passage from Williams shows that pregnancies exceeding the expected normal length were problematic more than 100 years ago. These postterm pregnancies remain so today.


Obstentrics_Williams

Obstentrics_Williams. The adjectives postterm, prolonged, postdates, and postmature are often loosely used interchangeably to describe pregnancies that have exceeded a duration considered to be the upper limit of normal. We eschew use of the term postdates because the real issue in many postterm pregnancies is "post-what dates?" Post mature is reserved for the relatively uncommon speciic clinical fetal syndrome in which the newborn has recognizable features indicating a pathologically prolonged pregnancy. herefore, postterm or prolonged pregnancy is our preferred expression for an extended pregnancy.


Obstentrics_Williams

Obstentrics_Williams. The international definition of prolonged pregnancy, endorsed by the American College of Obstetricians and Gynecologists (2016b,d) is one that exceeds 42°/7 weeks, namely, 294 days or more from the first day of the last menstrual period. Importantly, this is 42 "completed weeks," as pregnancies between 41 weeks 1 day and 41 weeks 6 days, although in the 42nd week, do not complete 42 weeks until the seventh day has elapsed. The method that we use widely in this book is to divide the 42nd week into 7 days, that is, 42°/7 through 426' weeks.


Obstentrics_Williams

Obstentrics_Williams. The current deinition of postterm pregnancy assumes that the last menses was followed by ovulation 2 weeks later. hat said, some pregnancies may not actually be postterm. Instead, the because of faulty menstrual date recall or delayed ovulation. Thus, the two categories of pregnancies that reach 42 completed weeks are those truly 40 weeks past conception and those of less-advanced gestation but with inaccurately estimated gestational age. Even with exactly recalled menstrual dates, there still is imprecision, and the American College of Obstetricians and Gynecologists (2016d, 20 17b) considers first-trimester sonography to be the most accurate method to establish or confirm gestational age. Several clinical studies support this practice (Bennett, 2004; Blondel, 2002; Joseph, 2007).


Obstentrics_Williams

Obstentrics_Williams. Of the 3.93 million neonates born in the United States during 2015, 0.4 percent were delivered at 42 weeks or later (11artin, 2017). In the past, the proportion was much higher. This trend suggests earlier intervention, however, the added accuracy from earlier sonographic dating ofgestational age is another factor. To identiy potential predisposing factors for postterm pregnancy, Olesen and associates (2006) analyzed various characteristics in the Danish Birth Cohort. Only prepregnancy body mass index (BMI) :25 and nulliparity were signiicantly associated with prolonged pregnancy. Mission (2015) and Arrowsmith (2011) and their coworkers also reported similar associations. In nulliparas, those whose cervical length at midpregnancy is longer, that is, in the third or fourth quartile, are twice as likely to deliver after 42 weeks (van der Ven, 2016).


Obstentrics_Williams

Obstentrics_Williams. The tendency for some mothers to have repeated postterm births suggests that some prolonged pregnancies are biologically determined. Oberg and colleagues (2013) reported that when mother and daughter had a prolonged pregnancy, the risk for the daughter to have a subsequent postterm pregnancy was signiicantly increased. Laursen and associates (2004) found that maternal, but not paternal, genes inluenced prolonged pregnancy. As discussed in Chapter 5 (p. 105), rare fetal-placental factors that predispose to postterm pregnancy include anencephaly, adrenal hypoplasia, and X-linked placental sulfatase deiciency (Ayyavoo, 2014; MacDonald, 1965).


Obstentrics_Williams

Obstentrics_Williams. Rates of stillbirth, neonatal death, and infant morbidity all rise after the expected due date has passed. This is best seen when perinatal mortality rates are analyzed from times before widespread intervention for postterm pregnancies. In two large Swedish studies shown in Figure 43-1, after reaching a nadir at � 7.2 4.0 c 2.32.4 ing to gestational age of all births in Sweden during 1943-1952 compared with those during 1977-1o978. The partially compressed scale is used for convenience in depiction. (Adapted from Bakketeig, 1991; Lindell, 1956.) TABLE 43-1 . Adverse Maternal and Perinatal Outcomes Associated with Postterm Pregnancy NICU = neonatal intensive care unit. 39 to 40 weeks, the perinatal mortality rate rose as pregnancy duration exceeded 41 weeks. his trend is also reported for the United States (Cheng, 2008; MacDorman, 2009). As shown in


Obstentrics_Williams

Obstentrics_Williams. 39 to 40 weeks, the perinatal mortality rate rose as pregnancy duration exceeded 41 weeks. his trend is also reported for the United States (Cheng, 2008; MacDorman, 2009). As shown in Table 43-1, the major cause of death in these studies includes gestational hypertension, prolonged labor with cephalopelvic disproportion, birth injuries, and hypoxic-ischemic encephalopathy. Similar outcomes were reported by Olesen and colleagues (2003) in 78,022 women with postterm pregnancies delivered before routine labor induction was adopted in Denmark. Moster and associates (2010) found higher rates of cerebral palsy in postterm births, and Yang and coworkers (2010) reported lower intelligence quotient (IQ) scores at age 6.5 years in children born :42 weeks' gestation. Conversely, autism was not associated with postterm birth (Gardener, 2011).


Obstentrics_Williams

Obstentrics_Williams. Alexander and colleagues (2000a) reviewed 56,317 consecutive singleton pregnancies delivered at :40 weeks between 1988 and 1998 at Parkland Hospital. Labor was induced in 35 percent of pregnancies completing 42 weeks. he rate of cesarean delivery for dystocia and fetal distress was signiicantly greater at 42 weeks compared with earlier deliveries. More newborns of postterm pregnancies were admitted to intensive care units. Importantly, the incidence of neonatal seizures and deaths was doubled at 42 weeks. Smith (2001) has challenged analyses such as these because the population at risk for perinatal mortality in a given week consists ofall ongoing pregnancies rather than just the births in a givenweek. He calculated perinatal mortality rates calculated using only births in a given week of gestation from 37 to 43 completedweeks comparedwith the cumulative probabilitythe perinatal index-of death when all ongoing pregnancies are included in the denominator. Using this computation,


Obstentrics_Williams

Obstentrics_Williams. of gestation from 37 to 43 completedweeks comparedwith the cumulative probabilitythe perinatal index-of death when all ongoing pregnancies are included in the denominator. Using this computation, delivery at 38 weeks had the lowest risk index for perinatal death.


Obstentrics_Williams

Obstentrics_Williams. The postmature newborn is unique, and features include wrinkled, patchy, peeling skin; a long, thin body suggesting wasting; and advanced maturity in that the infant is open-eyed, unusually alert, and appears old and worried 43-2). Skin wrinkling can be particularly prominent on the palms and soles. The nails are typically long. Most postmature neonates are not technically FIGURE 43-2 Postmaturity syndrome. Neonate delivered at 43 weeks' gestation with thick, viscous meconium coating the desquamating skin. Note the long, thin appearance and wrinkling of the hands. growth restricted because their birthweight seldom falls below the 10th percentile for gestational age (Chap. 44, p. 847). On the other hand, severe growth restriction-which logically must have preceded completion of 42 weeks-may be present.


Obstentrics_Williams

Obstentrics_Williams. he incidence of postmaturity syndrome in newborns at 41, 42, or 43 weeks, respectively, has not been conclusively determined. From data, the syndrome complicates 10 to 20 percent of pregnancies at 42 completed weeks (American College of Obstetricians and Gynecologists, 2016d). Associated oligohydramnios substantially raises the likelihood of postmaturity. Trimmer and associates (1990) reported that 88 percent of fetuses were postmature if there was oligohydramnios deined by a sonographic maximal vertical amnionic fluid pocket that measuredr; 1 cm at 42 weeks. Many believe that postterm pregnancy is an abnormal state. Redman and Staf (2015) posit that limited placental capacity, which is characterized by dysfunctional syncytiotrophoblast, explains the greater risks of the postmaturity syndrome.


Obstentrics_Williams

Obstentrics_Williams. Cliford (1954) proposed that the associated skin changes were due to loss of the protective efects of vernix caseosa. He also attributed the postmaturity syndrome to placental senescence, although he did not ind placental degeneration histologically. Still, the concept that postmaturity stems from placental insuiciency has persisted despite an absence of morphological or signiicant quantitative findings (Larsen, 1995; Redman, 2015; Rushton, 1991). here are indings that the


Obstentrics_Williams

Obstentrics_Williams. FIGURE 43-3 Mean daily fetal growth during previous week of gestation. (Redrawn from Hendricks CH: Patterns of fetal and placental growth: the second half of pregnancy. Obstet Gynecol 24:357, 1964.) rate of placental apoptosis-programmed cell death-is significantly greater at 41 to 42 completed weeks compared with that at 36 to 39 weeks (Smith, 1999). Several proapoptotic genes such as kisspeptin are upregulated in postterm placental explants compared with the same genes in term placental explants (Torricelli, 2012). The clinical significance of such apoptosis is currently unclear.


Obstentrics_Williams

Obstentrics_Williams. Jazayeri and coworkers (1998) investigated cord blood erythropoietin levels in 124 appropriately grown newborns delivered from 37 to 43 weeks. he only known stimulator of erythropoietin is decreased partial oxygen pressure. Thus, they sought to assess whether fetal oxygenation was compromised due to placental aging in postterm pregnancies. All women had an uncomplicated labor and delivery. These investigators found that cord blood erythropoietin levels were significantly higher in pregnancies reaching 41 weeks or more. Although Apgar scores and acid-base studies were normal, these researchers concluded that fetal oxygenation was decreased in some postterm gestations.


Obstentrics_Williams

Obstentrics_Williams. Another scenario is that the postterm fetus may continue to gain weight and thus be unusually large at birth. This at least suggests that placental function is not severely compromised. Indeed, continued fetal growth is the norm-albeit at a slower rate beginning at 37 completed weeks (Fig. 43-3). Nahum and colleagues (1995) conirmed that fetal growth continues until at least 42 weeks. However, Link and associates (2007) showed that umbilical blood low did not increase concomitantly. The principal reasons for increased risks to postterm fetuses were described by Leveno and associates (1984). Both antepartum fetal jeopardy and intrapartum fetal distress were found to be the consequence of cord compression associated with oligohydramnios. In their analysis of 727 postterm pregnancies, intrapartum fetal distress detected with electronic monitoring was not associated with late decelerations characteristic of uteroplacental insuiciency. Instead, one or more prolonged 1008060 -.0 100f80 -0


Obstentrics_Williams

Obstentrics_Williams. FIGURE 43-4 A. Prolonged fetal heart rate deceleration before emergency cesarean delivery in a postterm pregnancy with oligohydramnios. B. Severe-less than 70 bpm for 60 seconds or longer-variable decelerations in a postterm pregnancy with oligohydramnios. C. Saltatory baseline fetal heart rate showing oscillations exceeding 20 bpm and associated with oligohydramnios in a postterm pregnancy. (Reproduced with permission from Leveno J, Quirk JG, Cunningham FG, et al: Prolonged pregnancy, I. Observations concerning the causes of fetal distress, Am J Obstet Gynecol. 1984 Nov 1 ;1o50(5 Pt 1 ):465-473.) decelerations such as shown in of emergency cesarean deliveries for nonreassuring fetal heart rate tracings. In all but two cases, there were also variable decelerations. Another common fetal heart rate pattern, although not ominous by itself, was the saltatory baseline. As described in Chapter 24 (p. 468), these indings are consistent with cord occlusion as the proximate cause of the