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Abstract

The preterm birth rate in the USA is nearing 13%. The recent rise has been attributed to increased indicated preterm births and multiple births following artificial conceptions. There are few obstetrical interventions that successfully delay or prevent spontaneous preterm birth or reduce the risk factors leading to indicated preterm birth. On the other hand, there are many strategies that have improved outcomes for those infants who are born preterm. These include the use of corticosteroids for fetal maturation and regionalization of perinatal care for high-risk mothers and their infants. Several interventions, including progesterone use and cerclage, demonstrate promise in reducing spontaneous preterm births. The most pressing need is to better define the populations of pregnant women for whom these and other interventions will effectively reduce preterm birth.

Keywords

perinatal mortality prematurity preterm birth preterm delivery prevention

In developed countries, preterm birth is the leading cause of perinatal mortality as well as morbidity [1]. As much as two-thirds of the perinatal mortality and a half of long-term neurologic disabilities, including cerebral palsy, are associated with a preterm birth. Infants are born preterm following spontaneous labor with intact membranes (~45% of cases), preterm membrane rupture (~30%) and after labor induction or cesarean delivery for maternal or fetal indications (~25%) [1,2]. The frequency of preterm birth is approximately 12.7% in the USA and 4.4–8.2% in many other developed countries, such as Australia, New Zealand, Sweden and Japan [3 –5]. The rate of preterm birth has increased in many locations, predominantly because of increasing indicated preterm births and preterm delivery of artificially conceived multiple pregnancies [6 –8]. Although all births before 37 week' gestation are classified as premature, births occurring prior to 32 week' gestation (~2% of all births) account for most neonatal deaths and long-term handicaps [9].

Common reasons for indicated preterm births include pre-eclampsia/eclampsia and intrauterine growth restriction [10,11]. Births following spontaneous preterm labor and spontaneous preterm premature rupture of the membranes (pPROM) – together called spontaneous pre-term births – are considered a syndrome caused by multiple etiologies, including infection/inflammation, vascular disease, uterine over-distension and immunological disorders [1]. Important risk factors for spontaneous preterm birth include Black race, low socioeconomic status, short interpregnancy interval, periodontal disease and maternal thinness [1]. By far, a woman's most significant risk factor is having a history of a prior preterm birth [12]. A short cervical length diagnosed by ultrasound and an elevated cervical–vaginal fetal fibronectin concentration are the strongest medical-test predictors of spontaneous preterm birth [13,14]. It is apparent that different causes and predictors are more common or have a stronger relationship with preterm birth at various gestational ages. For example, infection is by far the most common cause of preterm birth at less than 30 weeks, but plays a less important role nearer to term [15]. Similarly, a positive cervical–vaginal fetal fibronectin test is a much stronger predictor of preterm birth at 24 weeks than a positive test later in pregnancy [13,14].

Preterm birth is consequential, predominantly because it results in morbidity or death in some infants. Preterm babies are at increased risk for death when compared with their term counterparts. However, preterm birth is of lesser consequence if the infant does not have any acute or long-term disorders or experiences a prolonged hospitalization and is sent home with the parents. It should also be noted that some full-term infants may die or exhibit evidence of neurologic damage as a result of problems occurring later in the pregnancy. Thus, although delaying birth would be desirable in the majority of situations, there are cases in which facilitating a preterm delivery, whether by induction or cesarean, may lead to improved maternal and neonatal outcomes.

Interventions to improve outcomes in infants who are born preterm

Among the interventions that ameliorate prematurity-associated morbidity and mortality, the most successful is regionalization of perinatal care – organizing a system of care so that infants destined to be born preterm are delivered in a labor ward with an adjacent newborn intensive care unit with appropriate facilities and personnel whose training and experience facilitate a good standard of care. Effective antenatal interventions include prophylactic intra-partum antibiotics that reduce neonatal sepsis – especially to cover group B streptococcus – the use of antenatal steroids to accelerate fetal lung maturation and, finally, prevention as well as prompt management of intra-partum fetal hypoxia [16 –18]. Effective neonatal management protocols include various methods for mechanical ventilation, antibiotics, judicious fluid and electrolyte management and exogenous-surfactant therapy. As a result of these and other effective interventions, the neonatal mortality of very low birthweight neonates born in the USA and elsewhere in developed countries has decreased significantly. In spite of the dramatically lower mortality rates, approximately 50–60% of all neonatal deaths occur in the 1–2% of all infants who are born weighing less than 1 kg [19]. Oddly, the improvement in survival has not been associated with a concomitant reduction in risk of prematurity-associated neurologic handicaps [20].

Antenatal steroids are one of the most effective tools in the hands of the obstetrician to prevent or reduce associated morbidity and mortality of preterm birth. An NIH consensus conference recommended the use of corticosteroids in pregnant women between 24 and 34 week' gestational age who are at risk for preterm delivery within 7 days; conditions meeting such criteria include diagnoses of preterm labor, pPROM, severe pre-eclampsia necessitating preterm delivery and other maternal–fetal indications [21]. In fact, recent data suggest that as early as 23 weeks gestation, a complete course of antenatal steroids is associated with an 82% reduction in the risk of neonatal death [22]. The American College of Obstetricians and Gynecologists (ACOG) recommends using either β-methasone or dexamethasone since they are both extensively studied and widely used to affect antenatal fetal organ maturation [23]. However, several studies suggest that there may be less morbidity and mortality with β-methasone; specifically, recently published data associate use of dexamethasone with increased risk for intraventricular hemorrhage, retinopathy of prematurity and neonatal death [24,25].

Risk assessment for preterm birth

Using standardized questionnaires in order to assess one's risk for a preterm birth has been included in many prematurity-prevention strategies. Overall, these scoring systems identified women with risk of preterm birth that was approximately double the so-called background risk; this relationship was predominantly a result of having a history of preterm birth [26]. Although these systems identify those at risk, their use has generally resulted in an increased use of interventions with no significant reduction in preterm birth rates.

There have been many attempts to use various biomarkers, either alone or in combination, to predict preterm birth [27,28]. Some of these, such as vaginal or cervical fetal fibronectin, when performed at approximately 24 weeks, even in a general population of pregnant women, are very powerful predictors of preterm birth [13,14]. Serum corticotrophin-releasing factor, serum a-fetoprotein and many other proteins in amniotic fluid, serum, plasma, cervical fluid and vaginal fluid are also relatively strong predictors of preterm birth [29]. More recently, studies using proteomic methodology have identified additional proteins that predict preterm birth [30,31]. However, to date, knowledge of abnormal levels of these potential markers of preterm birth has not led to the development of an effective treatment strategy leading to a reduction in preterm birth. In addition, various genetic markers, now more commonly identified through microarrays, have been associated with preterm birth. Gene–environmental interactions, perhaps mediated by epigenetic associations, may also be important in the causation of preterm birth. While these findings are likely to be important in identifying pathways leading to preterm birth, to date, as with the proteins discussed above, their identification has not led to a treatment or intervention that reduces preterm birth.

Perinatal & prenatal care

Women who either seek prenatal care early or have more prenatal visits exhibit a lower incidence of preterm birth than women who seek less care or care later in pregnancy [32 –39] Consequently, a liberal provision of prenatal care has been advocated as a means to reduce preterm birth. Unfortunately, there is no simple cause–effect relationship to be inferred from this association. First, women at lower risk take advantage of receiving prenatal care more often than those women at higher risk. Second, women who deliver early often have fewer prenatal visits, simply because routine prenatal visits are scheduled at shorter intervals in late pregnancy. The association of lower rates of preterm birth with early registry for care has led investigators to study improvement of access to standard prenatal care in areas of need. However, such investigations have generally not demonstrated a positive effect on the rate of preterm births. Enhanced prenatal care (e.g., the March of Dimes Multicenter trial) or early access to care has not generally resulted in a reduction in premature birth [38]. Literature reviews including many of these trials has likewise failed to demonstrate a significant benefit in reducing preterm birth from either strategy [32 –34].

Increasing availability of prenatal care to the expectant mother has not proven effective in reducing the incidence of preterm delivery. By the same token, enhancing prenatal care by the addition of nutrition counseling, home visitation, case management and patient education appeared to suggest benefit in some randomized trials but not in the majority. Since the enhancements to prenatal care have varied from study to study and because the associated reductions in preterm birth have been inconsistent, it is not clear which specific additions to prenatal care, if any, will result in a reduction in preterm births.

Interpregnancy interval

There is a raised risk of preterm birth in pregnancies arising within close temporal proximity to a previous delivery. An inter-pregnancy interval of less than 6 months confers a greater than twofold increased risk of preterm birth after adjustment for confounding variables [40,41]. Furthermore, women whose first births were preterm are more likely to have a short interval than women who had a term first birth, thus compounding the risk. Although the mechanism is not clear, one potential explanation is that the uterus takes time to return to its normal state, including resolution of the inflammatory status associated with the previous pregnancy. Maternal depletion may be another cause, because pregnancy consumes maternal stores of essential vitamins, minerals and amino acids. A short interval decreases the opportunity to replenish these nutrients. Thus, increasing pregnancy spacing through the use of counseling and provision of contraceptives, especially in women with a prior preterm birth, is likely to reduce the risk of subsequent preterm birth. However, there is little clinical trial evidence to support this recommendation.

Nutritional interventions

In developed countries, risk factors for spontaneous preterm birth include being underweight before pregnancy as well as gaining below-average weight during pregnancy [42]. Nutritional status during pregnancy can be described by indicators, such as the BMI, nutritional intake and serum assessments for various analytes [42 –45]. For example, a low pre-pregnancy BMI is associated with a high risk of spontaneous preterm birth, whereas obesity can be protective for this outcome [42]. Women with low serum concentrations of iron, folate or zinc have more preterm births than those with measurements within the normal range [42 –45]. There are many potential mechanisms by which maternal nutritional status might affect preterm birth – for example, spontaneous preterm birth can be related to maternal thinness by decreased blood volume and reduced uterine blood flow. Thin women might also consume fewer vitamins and minerals, low concentrations of which are associated with decreased blood flow and increased maternal infections [46,47]. Obese women are more likely to have infants with congenital anomalies, such as neural-tube defects, and these infants are more likely to be delivered preterm [48].

To date, nutritional interventions that have been studied include nutritional counseling, caloric supplementation, protein supplementation and vitamin or mineral supplementation. There is a paucity of convincing evidence of nutritional counseling changing eating habits of gravid females, much less the outcome of pregnancy [43]. Data from the US Special Supplementation Program for Women, Infants and Children (WIC), which provides a calorically enriched diet to low-income pregnant women, has demonstrated that caloric supplementation is associated with small increases in birthweight but no decrease in preterm birth. Greater increases in birthweight and reductions in preterm birth are seen with the provision of caloric supplementation in areas of relative famine [49]. Protein supplementation during pregnancy appears to increase adverse pregnancy outcomes including preterm birth [50].

The association between maternal iron status and its surrogate – iron deficiency anemia – and prematurity is complicated. Owing to the unequal rates of expansion of plasma volume and red cell mass during pregnancy, women in the second or early third trimester routinely have lower hematocrit values than those at term [51 –54]. Failure to correct for gestational age has therefore resulted in a misleading association between anemia and prematurity. Except at the lowest limits of hematocrit levels, studies accounting for gestational age have demonstrated little correlation between anemia and preterm birth. Accordingly, iron supplementation may raise hematocrit levels, but does not consistently change the incidence of preterm birth [53–54]. Low maternal zinc levels have been associated with an increased risk of restricted fetal growth and possibly preterm birth [55]. Several, but not most, trials of zinc supplementation have demonstrated an increase in birthweight, and some, including a previous study of ours [56,57], suggested that zinc supplementation may reduce the rate of preterm birth, especially among thin women in a low-income minority population of US women with moderately low serum zinc values. Studies of folate supplementation to reduce the rate of pre-term birth have also had conflicting results. The *Cochrane review of data from ten trials found no overall effect of calcium supplementation on the risk of preterm birth [58]. The efficacy of combined vitamin and mineral supplementation, which is used in many Western countries in attempts to lower the risk of preterm birth has not been rigorously evaluated [59,60]. In inner-city populations, women who used a vitamin–mineral supplement had significantly fewer preterm births than those who did not [59]. However, because this analysis was not derived from a randomized trial, factors other than supplementation, such as self-selection, may have accounted for the observed differences on the outcome of pregnancy. Increased intake of the antioxidant vitamins C and E had no effect on the preterm birth rate in recent large, placebo-controlled trials of these vitamins intended to assess their effect on the rate of pre-eclampsia [61]. Thus, although a few observational studies suggested reduced rates of preterm birth in women taking dietary supplements, in most prospective trials, vitamin or mineral supplementation as well as protein and calorie supplementation had no consistent benefit.

In populations with a high dietary intake of omega-3 polyunsaturated fatty acids (PUFAs), low preterm birth rates have been observed [62,63]. This effect is believed to occur because omega-3 PUFAs reduce levels of proinflammatory cytokines. Dietary supplementation has been associated with reduced production of inflammatory mediators, and a randomized trial of omega-3 supplements conducted in women at risk of preterm birth found a 50% decrease in preterm birth [64]. This has not been confirmed in other populations, and no benefit to PUFAs were observed in a recently completed trial by the NIH Maternal–Fetal Medicine Network [201].

In summary, women with an adequate nutritional status and a normal BMI have better pregnancy outcomes than other women. Although nutritional interventions in developing countries have promise in improving certain pregnancy outcomes, it remains unclear whether any nutritional intervention is associated with a reduction in the rate of preterm birth.

Periodontal care

In a number of studies, the risk of preterm birth rose with increasing severity of periodontal disease and with progression of periodontal disease during pregnancy [65 –72]. However, the basis for this association remains uncertain. It may arise from hematogenous transmission of oral microbial pathogens to the genital tract, but is more likely the result of an increase in an overall systemic inflammatory response [69,72]. The best treatment appears to be scaling and root planing accomplished over one to four visits, depending on the severity of the periodontal disease. Several small, randomized trials of scaling and root planing have suggested benefit in reducing preterm birth, but the largest and most recently published study demonstrated no benefit [70]. Several larger trials are ongoing. Therefore, to date, based on existing data, most authorities do not believe that treatment of periodontal disease during pregnancy, solely to reduce preterm birth, should be undertaken [71]. Treating periodontal disease in the interpregnancy interval is also being studied; however, effects on preterm birth rates have yet to be reported. On the other hand, no harm from periodontal treatment during pregnancy has been demonstrated. Therefore, while treatment of periodontal disease is not proven to reduce preterm birth, because of the general adverse effect of periodontal disease on health, there appears to be minimal risk of harm and some benefit to its treatment in the preconception period or during pregnancy.

Intervention in women with a history of previous preterm birth

Women with a prior preterm birth have increased risk of recurrence of preterm birth regardless of whether their prior preterm birth was spontaneous or indicated [12]. A thorough review of a patient's obstetrical history may enable the clinician to identify avenues through which risk may be either reduced or completely eliminated. For example, those with histories of spontaneous second trimester loss may be given progesterone supplementation beginning at 16 weeks. If identified, other risks for preterm delivery, such as a uterine septum, may be corrected preconception. As much as 40% of pre-term deliveries have been associated with preconception risk factors; this suggests that there may be a significant role for pre-pregnancy interventions in reducing preterm birth [73] Examples of treatable disorders whose treatment may decrease the risk of preterm birth include diabetes, asthma, hypertension and seizures. However, evidence that these steps can actually influence the preterm birth rate is lacking.

Progesterone

Both animal and human studies provide evidence that maternal progesterone concentrations decline before labor [74 –78]. Hence, many randomized studies have evaluated the effect of exogenous progestin supplementation, including weekly injections of 17 α-hydroxyprogesterone caproate, in women considered at risk of pre-term birth. In clinical trials, progesterone has been administered as vaginal suppositories as well as intramuscular injections [79,80]. In women with a history of preterm birth, risk of preterm delivery was reduced by approximately a third in two trials of progesterone supplementation, administered as weekly intramuscular injections of 17 α-hydroxprogesterone caproate 250 mg or as daily vaginal progesterone [79,80]. In meta-analyses of these studies with data from earlier trials, the risk of recurrent preterm birth was reduced by 40–55% (relative risk [RR]: 0.58; 95% CI: 0.48–40.70) [81].

Progesterone was also found to be of benefit when used for threatened preterm labor; this trial found a reduction in delivery prior to 37 weeks gestation (RR: 0.29; 95% CI: 0.12–10.69), but not at 34 weeks gestation [82]. However, Rouse et al. reported that 17 α-hydroxyprogesterone caproate had no effect on the rate of preterm birth in women with twins in a randomized, placebo-controlled trial [83]. Another study reported similar results [84].

The exact mechanism of action of progestins on reducing preterm birth is speculative at this point. The absence of effect in twin pregnancy together with the positive results in women with historical risk, short cervix and the recent cerclage data, suggests that progesterone's effect on preterm birth rates may be related to reducing inflammation rather than acting as a tocolytic agent [76]. More information is needed not only regarding the mechanism of action, but also in regard to maternal outcomes following antenatal therapy, preference by patient in terms of mode of delivery, satisfaction of care, optimal dose, optimal route of administration and optimal gestational age at which to begin therapy. The ACOG has echoed this need [85].

Cerclage

In approximately 0.5–1% of pregnancies, pregnant women are diagnosed as having an incompetent cervix, usually based on a history of early pregnancy loss, often accompanied by painless dilatation. More recently, an incompetent cervix is diagnosed by cervical ultrasound – usually for being ‘short’. A cerclage – a circumferential stitch placed in the cervix – has has been studied for a variety of obstetrical indications, including a history of three or more preterm births, second trimester loss, cervical shortening on ultrasound, preterm cervical dilation and being assessed as high risk for a preterm birth. The Royal College of Obstetricians and Gynaecologists conducted a randomized, controlled trial investigating 1292 women and demonstrated that cerclage reduced delivery prior to 37 weeks from 53 to 32% in women with either a prior second trimester loss or at least three previous preterm deliveries [86]. The Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT) published data supporting the screening of women with history of preterm delivery or second trimester losses via ultrasound to obtain transvaginal cervical length; these authors concluded that cerclage was indicated when cervical length was less than 2.5 cm [87]. Berghella et al. performed a meta-analysis of ultrasound-indicated cerclage and reported that when cervical length was less than 2.5 cm between 14–23 6/7 weeks gestational age, a 40% reduction in preterm birth was observed in singletons receiving a cerclage [88]. However, they found an increase in preterm birth when the same indication was used for cerclage placement in women with multiple pregnancies. Evidence of cervical inflammation as determined by a high IL-8 level may divide the population at risk into those that may benefit and those that may be harmed by cerclage placement [89]. A large NIH-sponsored trial of cerclage in women with a prior preterm birth and a short cervix is currently underway, with the results expected soon.

Early identification of preterm labor

On the premise that labor-inhibiting drugs are effective only if administered before preterm labor has been fully established, a number of strategies have evolved to identify women in early preterm labor. Typically, pregnant women receive instruction in detecting contractions or other signs of labor, such as pelvic pressure, vaginal discharge and back pain [90]. The March of Dimes prematurity-prevention program, which included instruction in uterine self-palpation and detection of signs of labor, did not reduce preterm births when tested prospectively in five different settings [91]. Another method of detecting uterine contractions before the onset of active preterm labor is home uterine activity monitoring, in which a contraction monitor records data on uterine activity and transfers the information to a central site for analysis [92 –95].

The monitor was approved by the US FDA primarily because it can detect contractions, the data can be transmitted to a central location and contractions are associated with an increased risk of preterm birth. However, in most randomized trials, this approach has failed to prevent preterm births. One study of home uterine-activity monitoring demonstrated that this intervention not only failed to reduce pre-term births, but its use was also associated with an increased number of unscheduled hospital visits and increased use of tocolytic drugs [95]. Strategies using home uterine-activity monitoring have often included daily contact with a nurse, and several authors have suggested that this interaction may result in a reduced rate of preterm birth. These data are, at best, conflicting and there is little evidence that daily contact with a nurse, as compared with routine prenatal care, reduces preterm births [96].

Tocolytic drugs

Tocolytic drugs reduce or stop uterine contractions. Some of these drugs, such as β-mimetic agents, have been thoroughly evaluated, whereas others, including magnesium sulfate, calcium-channel blockers, oxytocin antagonists, nitroglycerin and COX inhibitors, have not. In general, data from randomized trials suggest that tocolytic drugs may prolong pregnancy up to 48 h [97]. However, if a benefit is defined as a reduction in preterm delivery or even a delay in delivery for more than 1 week, the effect of tocolytic therapy appears to be minimal. Furthermore, the use of most tocolytic agents has not been associated with a reduction in neonatal mortality or respiratory distress syndrome. Magnesium sulfate, which in the USA has been a mainstay of treatment used to reduce preterm birth, was found to be ineffective in terms of preventing preterm delivery [98]. However, recent data from a trial involving 2241 women at 24–32 weeks gestation suggests a reduction in the incidence of cerebral palsy with the use of magnesium sulfate (1.9%) versus placebo (3.5%); RR: 0.55; 95% CI: 0.32–30.95 [99].

Cochrane analysts also stated that administration of β-mimetics – ritodrine and terbutaline – may facilitate a 48 h delay in delivery in comparison with no treatment/placebo, but do so at the cost of placing both the mother and fetus/neonate at greater risk of unwanted side effects than other types of tocolytics. Specifically, use of β-mimetic agents has been associated with an increased risk of many neonatal side effects including neonatal intraventricular hemorrhage [100 –102]. Other reviews and metaanalyses have been used to evaluate efficacy of the remaining tocolytic classes. For example, a Cochrane meta-analysis of tocolytic agents suggested that calcium-channel blockers and the oxytocin antagonist atosiban may delay delivery by 2–7 days [103,104]. COX inhibitors have been used to inhibit contractions based on their ability to block inflammatory processes triggering labor. However, their use has been associated with undesirable neonatal side effects – intraventricular hemorrhage, necrotizing enterocolitis, oligohydramnios in utero, bronchopulmonary dysplasia and patent ductus arteriosus requiring ligation. As a result of these effects, which are more common when used at or beyond 32 weeks gestation, COX inhibitors are generally used for preterm labor at earlier gestational ages in comparison with other tocolytic agents [105 –109].

Usage of tocolytics in Europe probably varies from that of the USA. Europeans more often employ the use of tractocile (atosiban), which is an oxytocin receptor antagonist. While atosiban has been shown to delay preterm birth up to 48 h, it has not reduced the incidence of preterm birth at less than 37 weeks any more than placebos have done. Currently in the USA, atosiban is not available for use outside of research protocols since it is not approved by the FDA.

Nevertheless, the delay in delivery afforded by some tocolytic drugs may have a benefit. Antenatal administration of corticosteroid drugs for as few as 12–24 h before delivery is associated with significant reductions in neonatal respiratory distress syndrome, intraventricular hemorrhage and mortality. Since the apparent benefit of tocolytic drugs is to delay delivery for 48 h, the combined use of tocolytic drugs and corticosteroids has become widespread. Even though this approach has not been adequately tested in randomized studies, several retrospective observational studies suggest that it improves outcome [110].

Bed rest & hydration

Although bed rest and hydration are therapies employed upon presentation to the delivery ward with either threatened or diagnosed preterm labor, no valid data have ever demonstrated either approach to have therapeutic benefit [112,113]. In fact, in two randomized trials involving twins, hospitalization with bed rest was associated with increased rates of preterm birth. In addition, there are other possible adverse outcomes associated with these interventions, including venous thrombosis and pulmonary edema [113].

Behavioral modification

Maternal psychosocial

Mothers experiencing high levels of psychological or social stress have been found in many studies to be at increased risk of preterm birth (generally less than twofold) even after adjustment for the effects of sociodemographic, medical and behavioral risk factors [114]. Furthermore, exposure to objectively stressful conditions, such as housing instability and severe material hardship, has also been associated with preterm birth. The mechanism underlying the association between psychological or social stress and increased risk of preterm birth is unknown. Clinical depression during pregnancy has been reported in up to 16% of women, with up to 35% having some depressive symptoms [115]. Although the results are inconsistent, several reports suggest a relationship (risks generally rose less than twofold) between depression and pre-term birth [116,117]. Depression is associated with an increase in smoking and drug and alcohol use; therefore, the relationship between depression and preterm birth might be mediated by these behaviors. Nevertheless, in some studies that adjusted for smoking and drug and alcohol use, the association between depression and preterm birth remained. To date, there is little evidence that any intervention reduces preterm birth in women diagnosed with stress, anxiety or depression. Various trials of social support and counseling have not produced consistently positive results.

Substance abuse

Tobacco use increases the risk of preterm birth (less than twofold) after adjustment for other factors [118,119]. The mechanism(s) by which smoking is related to preterm birth has not been elucidated. There are thousands of chemical agents in cigarette smoke of which the in vivo effects of most are not clear. However, both nicotine and carbon monoxide are powerful vasoconstrictors, which have been shown to correlate with placental damage and suboptimal uteroplacental blood flow; these effects lead to fetal growth restriction and, consequently, indicated preterm deliveries; for example, abruption and intrauterine growth restriction. Smoking is also associated with a systemic inflammatory response and may increase spontaneous preterm birth via triggering inflammatory pathways leading to labor. Heavy alcohol consumption – defined as the equivalent of seven alcoholic beverages daily – correlates with preterm birth [120]. Cocaine and heroin use have been associated with preterm birth in several studies. Programs for cessation of tobacco, drug and alcohol use have been recommended as part of a strategy to reduce preterm births. However, the use of these substances is more closely linked to restricted fetal growth than to preterm birth. Moreover, these programs all achieve, at best, relatively low rates of cessation; thus, it is not likely that these interventions will have a substantial impact on preterm birth [121 –123].

Treatment of infection & antibiotics

Substantial progress has been made in understanding the relationship between maternal intra-uterine infection and preterm birth [15,124–129]. Microbiological studies suggest that intrauterine infection might account for 25–40% of preterm births; however, this might be a minimum estimate because at least several types of intrauterine infection are difficult to detect with conventional culture techniques. Intrauterine infection can be confined to the decidua, extend to the space between the amnion and chorion and reach the amniotic cavity and the fetus. Bacteria in the membranes and an associated inflammatory response in the amniotic fluid have been identified in more than 80% of women in early pre-term labor with intact membranes who underwent cesarean section. In spite of these findings, most trials of antibiotic therapy in women with preterm labor have failed to prevent premature birth [15]. It is unknown whether this failure is due to the selection of inappropriate antibiotics, the initiation of treatment too late in the cascade of events leading to spontaneous preterm delivery or other factors.

Bacterial vaginosis, a polymicrobial overgrowth of predominantly anaerobic bacteria, has been consistently associated with a risk of spontaneous preterm birth that is increased by a factor of 1.5–3 [15,130]. Furthermore, in several randomized trials involving women at high risk for preterm birth (predominantly because of prior preterm birth), treatment of bacterial vaginosis with metronidazole either alone or in combination with erythromycin resulted in substantial reductions in rates of spontaneous preterm birth [131]. How attributable such results are to gravidas at lower risk remains to be established. However, since so many premature births are related to infection, antibiotic treatment has promise in reducing early spontaneous preterm births, especially among Black women, who have significantly higher rates of bacterial vaginosis compared with other women (30 vs 10%, respectively) [132]. Furthermore, recent evidence suggests that treatment of abnormal vaginal flora with either oral or topical clindamycin may have efficacy in reducing preterm birth [133 –135].

A 2007 Cochrane review of 15 trials concluded that although antimicrobial treatment can reduce the incidence of bacterial vaginosis in pregnancy, it does not reduce the risk of preterm birth or pre-term membrane rupture before 37 weeks for all women or in women with a prior preterm birth [136]. However, the reviewers noted evidence that treatment before 20 week' gestation may reduce the risk of preterm birth. One potential reason for the failure of antibiotics to reduce preterm birth is that they may not effectively prevent or treat chorioamnionitis.

Nearly four decades ago, antibiotic treatment for asymptomatic urinary tract infections (UTIs) was found to result in fewer spontaneous preterm deliveries in comparison with untreated UTIs [137,138]. Both symptomatic and asymptomatic UTIs have been associated with an increased risk of preterm delivery, and several randomized trials have provided confirmation that treating asymptomatic bacteriuria not only reduces the risk of maternal pyelonephritis, but may also reduce the risk of preterm birth.

Identification of other infections that may have a causal role in spontaneous preterm birth is the focus of much current research. For example, nearly every sexually transmitted disease has been associated with increased preterm births [139]. However, women with sexually transmitted diseases often have other risk factors for preterm birth, which have rarely been evaluated as confounding factors. Owing to the inconsistency of the association between infection and preterm birth and the relatively low prevalence of most infections, their elimination in pregnant women, although otherwise beneficial, is not likely to have a major effect on the overall rate of preterm birth.

Preterm premature rupture of the membranes

Spontaneous preterm birth is customarily defined as any delivery following either spontaneous preterm labor or pPROM. Even though these events are defined as distinct entities; there is considerable evidence that the risk factors for their occurrence are similar and the distinction maybe largely a matter of semantics. Most prevention strategies for spontaneous preterm birth target both conditions and these will not be discussed separately for pPROM.

In the absence of clinical evidence suggesting infection, delaying the delivery after diagnosis of pPROM at less than 34 weeks gestation becomes the obstetrician's primary goal. Such delay increases the likelihood of fetal organ maturation, especially that of the lungs. However, this delay concomitantly increases the fetus's risk of in utero infection. As these infections pose risk to both the mother and fetus/neonate, pPROM was historically an indication for expeditious delivery, regardless of gestational age. Even without induction, most women diagnosed with pPROM have spontaneous labor and, subsequently, deliver within a week. Rather than trying to reduce the rate of preterm delivery in the context of pPROM, the goal of treatment in these pregnancies has been to lengthen the time from preterm rupture of the membranes to delivery (i.e., to facilitate more time for fetal maturation) or reducing morbidity and mortality in mothers and infants. To date, no strategies have been identified that reduce the occurrence of preterm birth after pPROM; thus, most pregnancies complicated by pPROM end in preterm birth.

With the availability of more potent antibiotics and a better understanding of the risk of infection as compared with the risk of complications of prematurity, management of preterm rupture of the membranes at less than 32 or 34 weeks of gestation has evolved into a policy of watchful waiting with antibiotics, with delivery at any sign of infection. Prophylactic antibiotic therapy has been found to be effective in prolonging the period between preterm rupture of the membranes and delivery [140 –143]. The largest studies to date have also demonstrated that antibiotic treatment reduces the risks of maternal chorioamnionitis, neonatal respiratory distress syndrome and neonatal sepsis [142,143]. Thus, antibiotics are beneficial in prolonging the interval between pPROM and delivery, as well as in reducing neonatal morbidity. Corticosteroids may augment this benefit. It is worth noting that most practice algorithms adopt the use of antibiotics for latency between 24 and 34 weeks and steroids within the same time interval. The combined use of corticosteroids and antibiotics has been associated with a reduced risk of respiratory distress syndrome, as compared with the use of corticosteroids alone [144].

Conclusion

A large literature describes retrospective and prospective trials of interventions applied after conception to prevent or reduce the risk of indicated and/or spontaneous preterm birth. The available data on the effectiveness of various interventions aimed at reducing premature births provide an explanation for the epidemiologic observation that the rate of preterm birth is not declining. Studies of interventions aimed at reducing idiopathic/spontaneous preterm birth have typically been disappointing. Most interventions designed to prevent preterm birth do not work, and the few that do, including treatment of UTI and possibly the treatment of bacterial vaginosis in high-risk women, are not universally effective and are probably applicable to only a small percentage of women at risk for preterm birth. Other interventions such as cerclage and the use of progestins are still being evaluated. In many cases, the women most likely to see benefit are unknown and only now is this issue being evaluated.

Future perspective

Historically, our attempts to effect a reduction in the incidence of preterm birth have been aimed at removing associated risk factors in the hope that removing the risk would, in turn, thwart the onset of preterm labor or membrane rupture. Such attempts have generally failed. Additional research focusing on contributing factors and how they lead toward preterm or term parturition will help us identify targets for prevention or treatment. Such knowledge will facilitate the design of clinical trials to ascertain potentially effective treatments. Until we have a better understanding of the underlying mechanisms on a cellular and molecular level, both derivation of effective treatments and achieving substantial reductions in preterm delivery are unlikely to occur. For instance, many recent studies have focused on the role of inflammatory processes in facilitating preterm births. Progesterone, a known anti-inflammatory agent, has been demonstrated to both reduce rates of preterm birth in select populations and to prevent inflammation-induced preterm birth in animal models [93]. Studies directed toward inflammation-mediated preterm labor by use of either immune or hormonal modulation may prove useful. More trials are needed in order to determine whether such agents will prove to affect the overall incidence of preterm birth.

Executive summary

Infants are born preterm following spontaneous labor with intact membranes (~45% of cases), preterm membrane rupture (~30%) and after labor induction or cesarean delivery for maternal or fetal indications (~25%).

Preterm birth is consequential, predominantly because it results in short- and long-term morbidity or death in some infants.

Antibiotic treatment in preterm premature rupture of the membranes at less than 34 weeks reduces the risks of maternal chorioamnionitis, neonatal respiratory distress syndrome and neonatal sepsis.

Regionalization of perinatal care ensures that preterm infants are delivered at units with appropriate resources; this has proven effective in reducing morbidity and mortality associated with preterm birth.

The observed benefit of increased birthweight in mothers receiving caloric supplementation is most probably attributable to improved fetal growth rather than prolonging pregnancy or preventing preterm birth.

Although the risk of preterm birth rises with increased severity of periodontal disease and with progression of periodontal disease during pregnancy, treatment of periodontal disease has not been shown to decrease the rate of preterm birth.

Progestin supplementation is associated with a significant reduction in the rate of preterm birth in women with a history of preterm birth and in women with threatened preterm labor.

Cervical cerclage in women with a short (<15 mm) cervix who do not have a prior preterm birth has not reduced the rate of spontaneous preterm birth.

Cerclage may benefit women with short cervix who have a prior preterm birth but the evidence is not conclusive. Selection of the appropriate candidates for cerclage is uncertain.

Prophylactic cerclage for women with a history of prior preterm birth without sonographic demonstration of short cervix in the current pregnancy is not justified by the current literature.

Antenatal administration of corticosteroid drugs for as few as 12–24 h before delivery is associated with significant reductions in neonatal respiratory distress syndrome, intraventricular hemorrhage and mortality.

Since the apparent benefit of tocolytic drugs is to delay delivery for 48 h, the combined use of tocolytic drugs and corticosteroids has become widespread.

Although bed rest and hydration are widely used in women in preterm labor, there is no convincing evidence of a reduction in preterm delivery with either approach.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Prevention of Preterm Birth

Abstract

Keywords

Interventions to improve outcomes in infants who are born preterm

Risk assessment for preterm birth

Perinatal & prenatal care

Interpregnancy interval

Nutritional interventions

Periodontal care

Intervention in women with a history of previous preterm birth

Progesterone

Cerclage

Early identification of preterm labor

Tocolytic drugs

Bed rest & hydration

Behavioral modification

Maternal psychosocial

Substance abuse

Treatment of infection & antibiotics

Preterm premature rupture of the membranes

Conclusion

Future perspective

Footnotes

References