Women with signs and symptoms of preterm labor with intact membranes are managed similarly to those with PPROM. If possible, delivery before 34 weeks’ gestation is delayed. Drugs used to abate or suppress preterm uterine contractions are subsequently discussed.
Amniocentesis to Detect Infection
Several tests have been used to diagnose intraamnionic infection (Andrews, 1995; Romero, 1993; Yoon, 1996). Although such infection can be confirmed with a positive test result, there is little utility for routine amniocentesis (American College of Obstetricians and Gynecologists (2017b).
Corticosteroids for Fetal Lung Maturation
Because glucocorticosteroids were found to accelerate lung maturation in preterm sheep fetuses, Liggins and Howie (1972) evaluated them to treat women. Corticosteroid therapy was effective in lowering the incidence of RDS and neonatal mortality rates if birth was delayed for at least 24 hours after initiation of betamethasone. Infants exposed to corticosteroids in these early studies have now been followed to age 31 years with no ill effects detected. In 1995, a National Institutes of Health (NIH) Consensus Development Conference panel recommended corticosteroids for fetal lung maturation in threatened preterm birth. In a subsequent meeting, another NIH Conference (2000) concluded that data were insufficient to assess corticosteroid effectiveness in pregnancies complicated by hypertension, diabetes, multifetal gestation, fetal-growth restriction, or fetal hydrops. It was concluded, however, that it was reasonable to administer corticosteroids to these women.
A recent metaanalysis by Roberts and associates (2017) of 30 studies totaling 7774 women and 8158 infants quantified the benefit of a single course of corticosteroids. Treatment was associated with lower rates of perinatal death, neonatal death, RDS, intraventricular hemorrhage, necrotizing enterocolitis, need for mechanical ventilation, and systemic infection in the first 48 hours of life. No obvious benefits were gained for chronic lung disease, death in childhood, or neurodevelopmental delay in childhood. Therapy was not associated with chorioamnionitis. Parenthetically, corticosteroids given prophylactically to women at risk of preterm birth in low- and middle-income countries actually increase perinatal mortality rates (Althabe, 2015).
A single course of corticosteroids is currently recommended by the American College of Obstetricians and Gynecologists (2017a) for women between 24 and 34 weeks who are at risk for delivery within 7 days. This recommendation for premature twins has been challenged (Viteri, 2016). Boundaries of gestational age for corticosteroid administration are also now being explored. For pregnancies at 23 weeks and at risk of delivery within 7 days, a single course of corticosteroids may be considered (Late-Preterm Birth). Administration of corticosteroids during the periviable period is linked to a family’s decision regarding resuscitation and should be considered in that context (American College of Obstetricians and Gynecologists, 2017e).
Betamethasone and dexamethasone appear to be equivalent for fetal lung maturation (Murphy, 2007). These two drugs are comparable in reducing rates of major neonatal morbidities in preterm newborns (Elimian, 2007). A treatment course may be two 12-mg doses of betamethasone, and each dose is given intramuscularly 24 hours apart. With dexamethasone, 6-mg doses are given intramuscularly every 12 hours for four doses. Because treatment for less than 24 hours may be beneficial and reduce neonatal morbidity and mortality rates, a first dose of antenatal corticosteroids is administered regardless of the ability to complete additional doses before delivery (American College of Obstetricians and Gynecologists, 2017a).
Women at Risk for Late-Preterm Delivery
The MFMU Network conducted a randomized trial to assess whether administration of antenatal betamethasone to women who were likely to deliver in the late-preterm period would decrease respiratory and other neonatal complications (Gyamfi-Bannerman, 2016). Even though only 60 percent of the study cohort of 2831 women received both injections, the rate of respiratory complications measured as a composite outcome was lower with corticosteroid use compared with placebo—11.6 versus 14.4 percent. Because of these findings, consideration for administration of a single course of betamethasone for women between 340/7 and 366/7 weeks has been recommended by both the American College of Obstetricians and Gynecologists (2017a) and the Society for Maternal-Fetal Medicine (2016a).
Adoption of this practice has not been universal. Both short- and long-term neonatal safety are concerns (Crowther, 2016; Kamath-Rayne, 2016). Specifically, in the newborns receiving betamethasone, rates of hypoglycemia were significantly greater (Gyamfi-Bannerman, 2016). Neonatal hypoglycemia is particularly worrisome for possible adverse long-term consequences that include developmental delay (Kerstjens, 2012). Another caveat is that the largest effects of betamethasone included a reduction in transient tachypnea of the newborn—a self-limited condition with little clinical significance (Kamath-Rayne, 2016). Specifically, the rates of transient tachypnea of the newborn were 6.7 and 9.9 percent in those given betamethasone and placebo, respectively. These rates are three- to fourfold higher than those reported by the Consortium on Safe Labor (2010), which was a retrospective, observational study that abstracted detailed labor and delivery information from 19 hospitals across the United States on 233,844 deliveries. Because of these issues, we do not provide corticosteroids beyond 34 weeks at Parkland Hospital at this time.
Single versus additional courses of intramuscular corticosteroids for lung maturation has been the topic of two major trials. Although both found repeated courses to be beneficial in reducing neonatal respiratory morbidity rates, the long-term consequences were much different. In one randomized study by Crowther and associates (2007), all women at risk for preterm birth were given a primary course of betamethasone. Women were then given serial weekly doses of 11.4 mg of betamethasone for persistent risk or were given placebo. These investigators found no adverse effects in the infants followed to age 2 years. Wapner and coworkers (2007) studied infants born to 495 women who were randomly assigned to receive a single corticosteroid course that contained two doses or assigned to repeated courses that were given weekly. A nonsignificant rise in the cerebral palsy rate was identified in infants exposed to repeated courses. The doubled betamethasone dose in this study was worrisome because some experimental evidence supports the view that adverse effects are dose dependent (Bruschettini, 2006). Stiles (2007) summarized these two studies as “early gain, long-term questions.” We agree, and at Parkland Hospital, we follow the recommendation by the American College of Obstetricians and Gynecologists (2017a) for single-course therapy.
This refers to administration of a second corticosteroid dose when delivery becomes imminent and more than 7 days have elapsed since the initial dose. In one randomized trial, 326 women received placebo or a single 12-mg dose of betamethasone (Peltoniemi, 2007). Paradoxically, the rescue dose of betamethasone increased the risk of RDS. In another randomized study of 437 women with gestations <33 weeks, Garite and associates (2009) reported significantly lower rates of respiratory complications and neonatal composite morbidity with rescue corticosteroids versus placebo. Rates of perinatal mortality and other morbidities, however, did not differ. Last, McEvoy and colleagues (2010) found that treated infants had improved respiratory compliance.
Garite and coworkers (2009) randomly assigned 437 women with singletons or twins <33 weeks’ gestation and with intact membranes to one rescue course of either betamethasone or dexamethasone or placebo. These women had all previously completed a single course of corticosteroids before 30 weeks’ gestation and at least 14 days before the rescue course. RDS developed in 41 percent of the newborns given rescue corticosteroids compared with 62 percent of those randomized to placebo. Rates of other morbidities attributable to prematurity did not differ. In a metaanalysis, Crowther and colleagues (2011) concluded that a single course of corticosteroids should be considered in women whose prior course was administered at least 7 days previously and who were <34 weeks’ gestation. The American College of Obstetricians and Gynecologists (2017a) has taken the position that a single rescue course of antenatal corticosteroids be considered in women before 34 weeks whose prior course was administered at least 7 days previously. Effects of rescue therapy beyond 34 weeks are currently unknown. At Parkland Hospital, we currently do not provide additional courses of corticosteroids beyond the initial single-course therapy.
Magnesium Sulfate for Neuroprotection
Very-low-birthweight neonates whose mothers were treated with magnesium sulfate for preterm labor or preeclampsia were found to have a reduced incidence of cerebral palsy at 3 years (Grether, 2000; Nelson, 1995). Because of this, randomized trials were designed to investigate this hypothesis. In one trial, 1063 women at risk of delivery before 30 weeks were given magnesium sulfate or placebo (Crowther, 2003). Magnesium exposure improved some perinatal outcomes. Namely, rates of both neonatal death and cerebral palsy were lower in the magnesium-treated group—but this study was not sufficiently powered. The multicenter French trial reported by Marret and associates (2008) had similar problems.
More convincing evidence for magnesium neuroprotection came from the MFMU Network study—Beneficial Effects of Antenatal Magnesium Sulfate—BEAM—Study (Rouse, 2008). This was a placebo-controlled trial in 2241 women at imminent risk for preterm birth between 24 and 31 weeks. Women randomized to magnesium sulfate were given a 6-g bolus over 20 to 30 minutes followed by a maintenance infusion of 2 g per hour. Magnesium sulfate was actually infusing at the time of delivery in approximately half of the treated women. A 2-year follow-up was available for 96 percent of the children. Results are shown in Table 42-10. This trial can be interpreted differently depending on statistical methodologies employed. Some interpret these findings to mean that magnesium infusion prevents cerebral palsy regardless of the gestational age at which therapy is given. Those with a differing view conclude that this trial only supports use of magnesium sulfate for prevention of cerebral palsy before 28 weeks.
TABLE 42-10Magnesium Sulfate for the Prevention of Cerebral Palsya ||Download (.pdf) TABLE 42-10 Magnesium Sulfate for the Prevention of Cerebral Palsya
| ||Treatment |
|Perinatal Outcomea ||Magnesium Sulfate No. (%) ||Placebo No. (%) ||Relative Risk (95% CI) |
|Infants with 2-year follow-up ||1041 (100) ||1095 (100) ||— |
|Fetal or infant death ||99 (9.5) ||93 (8.5) ||1.12 (0.85–1.47) |
|Moderate or severe cerebral palsy: || || || |
| Overall ||20/1041 (1.9) ||38/1095 (3.5) ||0.55 (0.32–0.95) |
| <28–31 weeksb ||12/442 (2.7) ||30/496 (6) ||0.45 (0.23–0.87) |
| ≥24–27 weeksb ||8/599 (1.3) ||8/599 (1.3) ||1.00 (0.38–2.65) |
Subsequent to these studies, Doyle and associates (2009) reviewed five randomized trials to assess neuroprotective effects. A total of 6145 infants were studied, and these reviewers concluded that magnesium exposure compared with no exposure significantly lowered risks for cerebral palsy. Rates of other neonatal morbidity did not differ significantly. It was calculated that treatment given to 63 women would prevent one case of cerebral palsy.
Controversy surrounding magnesium efficacy for neuroprotection prompted a debate at the 2011 annual meeting of the Society for Maternal-Fetal Medicine. Rouse (2011) spoke for the benefits of magnesium sulfate, whereas Sibai (2011) challenged that the reported benefits were false positive due to random statistical error in the metaanalysis by Doyle (2009). Another peculiarity is the apparent lack of dose-response for efficacy (McPherson, 2014). Because none of the individual studies found a benefit from magnesium sulfate for fetal neuroprotection, the American College of Obstetricians and Gynecologists (2016a) concluded that those electing prophylaxis should develop specific guidelines. To guide such therapy, the American College of Obstetricians and Gynecologists (2012) issued a Patient Safety Checklist for use of magnesium sulfate for neuroprotection. For those with PPROM, prophylaxis may similarly be considered. At Parkland Hospital, we provide magnesium sulfate for neuroprotection with threatened preterm delivery from 240/7 to 276/7 weeks.
Results have been disappointing in studies of antimicrobials given to arrest preterm labor. From one Cochrane metaanalysis, antimicrobial prophylaxis given to women with intact membranes did not reduce preterm birth rates or affect other clinically important short-term outcomes (Flenady, 2013). However, rates of short- and longer-term harm were higher for children of mothers exposed to antibiotics. Kenyon (2001) reported the ORACLE Collaborative Group study of 6295 women with spontaneous preterm labor and intact membranes, but without evidence of infection. Women were randomly assigned to receive antimicrobial or placebo therapy. The primary outcomes of neonatal death, chronic lung disease, and major cerebral abnormality were similar in both groups. In a follow-up of the ORACLE II trial, fetal exposure to antimicrobials in this clinical setting was associated with an increased cerebral palsy rate at age 7 years compared with that in children without fetal exposure (Kenyon, 2008b). Importantly, antimicrobial use described here is distinct from that given for group B streptococcal prophylaxis (Chap. 64, Methicillin-Resistant Staphylococcus aureus).
This is one of the most often prescribed interventions during pregnancy, yet one of the least studied. One systematic review concluded that evidence neither supported nor refuted bed rest for prevention of preterm birth (Sosa, 2004). Goulet and coworkers (2001) randomly assigned 250 Canadian women to either home care or hospitalization after treatment of an acute episode of preterm labor and found no benefits. There have, however, been reports of possible harm. Kovacevich and associates (2000) reported that bed rest for 3 days or more increased thromboembolic complications to 16 per 1000 women compared with only 1 per 1000 with normal ambulation. Promislow and colleagues (2004) observed significant bone loss in pregnant women prescribed outpatient bed rest. More recently, Grobman and associates (2013) noted that women with activity restriction were nearly 2.5 times more likely to have a preterm birth before 34 weeks. This finding, however, may reflect ascertainment bias. That is, women with restricted activity may have been assigned to bed rest because they were viewed to be at more imminent risk of preterm delivery. McCall and coworkers (2013) summarized the literature on bed rest, and they found insufficient evidence to support its use. The American College of Obstetricians and Gynecologists (2017d) suggests that, although frequently prescribed, bed rest is only rarely indicated, and ambulation should be considered in most cases.
Silicone rings, such as the Arabin pessary, are being used to support the cervix in women with a sonographically short cervix. For 385 Spanish women with a cervical length ≤25 mm, Goya and associates (2012) provided a silicone pessary or expectant management. Newborns spontaneous delivered before 34 weeks’ gestation in 6 percent of women in the pessary group compared with 27 percent in the expectant management group. Another trial randomly assigned almost 100 women with a cervix <25 mm at 20 to 24 weeks to silicone pessaries or expectant management (Hui, 2013). The pessary did not lower the rate of delivery <34 weeks. Similar findings were reported by Nicolaides and colleagues (2016). The Society for Maternal-Fetal Medicine (2017b) recently recognized the conflicting published reports and lack of an FDA-approved pessary for the indication of preterm birth prevention. They currently recommend pessary prophylaxis only within research protocols.
Emergency or Rescue Cerclage
Some evidence supports the concept that cervical incompetence and preterm labor lie along a spectrum leading to preterm delivery. Consequently, investigators have evaluated cerclage placement after preterm labor begins to manifest clinically. Althuisius and colleagues (2003) randomly assigned 23 women with cervical incompetence before 27 weeks to bed rest, with or without emergency McDonald cerclage. Delivery delay was significantly greater in the cerclage group compared with those assigned to bed rest—54 versus 24 days, respectively. Terkildsen and coworkers (2003) studied 116 women who underwent second-trimester emergency cerclage. Nulliparity, membranes extending beyond the external cervical os, and cerclage before 22 weeks were associated with a significantly decreased chance of significant pregnancy continuation. For women facing a poor pregnancy prognosis due to cervical dilation at midgestation, it seems reasonable to offer emergency or rescue cerclage with appropriate counseling. However, it is unclear if such interventions truly confer a benefit or merely increase the risk of membrane rupture and infection (Hawkins, 2017).
Tocolysis to Treat Preterm Labor
Although several drugs and other interventions have been used to prevent or inhibit preterm labor, none is completely effective. The American College of Obstetricians and Gynecologists (2016b) has concluded that tocolytic agents do not markedly prolong gestation but may delay delivery in some women for up to 48 hours. This may allow transport to an obstetrical center with higher-level neonatal care and permit time for a course of corticosteroid therapy. Although delivery may be delayed to administer corticosteroids, treatment has not improved perinatal outcome rates (Gyetvai, 1999).
Beta-adrenergic agonists, magnesium sulfate, calcium-channel blockers, or indomethacin are the recommended tocolytic agents for this short-term use. The gestational age range for tocolytic use is debatable. But, because corticosteroids are not generally used after 34 weeks, and because the perinatal outcomes in preterm neonates are generally good after this time, most do not recommend use of tocolytics after 33 weeks’ gestation (Goldenberg, 2002).
In many women, tocolytics stop contractions temporarily but rarely prevent preterm birth. The College (2016b) notes that maintenance therapy with tocolytics is ineffective for preventing preterm birth. Importantly, no trial has ever convincingly shown reductions in rates of any important adverse outcome by a tocolytic drug compared with placebo (Walker, 2016). Maintenance tocolysis after acute therapy is not recommended.
β-Adrenergic Receptor Agonists
Several compounds react with β-adrenergic receptors to reduce intracellular ionized calcium levels and prevent activation of myometrial contractile proteins (Chap. 21, G-Protein–Coupled Receptors). Of β-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 β-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 (Merkatz, 1980). In a randomized trial at Parkland Hospital, intravenous ritodrine delayed delivery for 24 hours but without other benefits (Leveno, 1986b). Additional studies confirmed a delivery delay up to 48 hours (Canadian Preterm Labor Investigators Group, 1992).
β-Agonist drug infusion has resulted in serious and even fatal maternal side effects. Pulmonary edema is a special concern, and its contribution to morbidity is discussed in Chapter 47 (Acute Pulmonary Edema). 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. Risk factors include tocolytic therapy with β-agonist drugs, multifetal gestation, concurrent corticosteroid therapy, tocolysis for more than 24 hours, and intravenous infusion of large volumes of crystalloid. β-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.
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 long-term by subcutaneous pump (Lam, 1988; Perry, 1995). But, randomized trials have shown no benefit for terbutaline pump therapy (Guinn, 1998; Wenstrom, 1997). Oral terbutaline given to prevent preterm delivery is also ineffective (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 effects, 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. Terbutaline, used as a tocolytic prior to external cephalic version, is discussed in Chapter 28 (Tocolysis).
Ionic magnesium in a sufficiently high concentration can 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 as a 4-g loading dose and followed by a continuous infusion of 2 g/hr, usually arrests labor (Steer, 1977). Like β-mimetic agents, magnesium treatment can cause pulmonary edema (Samol, 2005). However, this has not been our experience at Parkland Hospital 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 (Pharmacology and Toxicology).
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 differences 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 ineffective 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.
These compounds are intimately involved in contractions of normal labor (Chap. 21, Uterotonins in Parturition Phase 3). 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.
Indomethacin, a nonselective cyclooxygenase inhibitor, was first used as a tocolytic in one study of 50 women (Zuckerman, 1974). Studies that followed reported the efficacy 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 difference in their efficacy 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 ineffective.
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 fluid is monitored, oligohydramnios can be detected early, and it is reversible with drug discontinuation.
In a study of neonates born before 30 weeks, Norton and coworkers (1993) identified 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 effects of antenatal indomethacin on neonatal outcomes had conflicting findings (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 tocolytic agent.
These potent smooth-muscle relaxants affect 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 effect (Bisits, 2004; El-Sayed, 1999; Lees, 1999).
Discussed in Chapter 21 (Actin-Myosin Interactions), myometrial activity 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 preterm labor has been evaluated.
From study results, calcium-channel blockers, especially nifedipine, are safer and more effective tocolytic agents than β-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 differences in efficacy or adverse effects. 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).
Flenady and coworkers (2014b) reviewed 38 trials of calcium- channel blockers (mainly nifedipine) for preterm labor. These investigators suggested that calcium-channel blockers have benefits 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.
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 effects 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 benefit nor harm was found (How, 2006).
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 significant neonatal morbidity (Moutquin, 2000; Romero, 2000). The FDA has denied approval of atosiban because of concerns regarding efficacy and fetal–newborn safety. Further, in 2014, a metaanalysis did not demonstrate superiority of ORAs (largely atosiban) as a tocolytic compared with placebo, β-mimetic drugs, or calcium-channel blockers in terms of pregnancy prolongation or neonatal outcomes. But, ORAs were associated with fewer maternal adverse effects (Flenady, 2014a). 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 differences were reported between the two study groups.
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 intensify some of the neonatal complications usually attributed to preterm delivery. For example, Morgan and associates (2017) found that metabolic acidemia significantly 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, Neonatal Encephalopathy). Group B streptococcal infections are common and dangerous in the preterm neonate, and antimicrobial prophylaxis should be provided (Chap. 64, Methicillin-Resistant Staphylococcus aureus).
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. Staff proficient in resuscitative techniques commensurate with the gestational age and fully oriented to any specific problems should be present at delivery. Principles of resuscitation described in Chapter 32 (Resuscitation Protocol) 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
Preterm newborns frequently have intracranial germinal matrix bleeding that can extend to more serious intraventricular hemorrhage (Chap. 34, Retinopathy of Prematurity). It was hypothesized that cesarean delivery to obviate trauma from labor and vaginal delivery might prevent these complications. This 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 firmly established.