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预防早产和新生儿死亡：探寻流行病学、病因和干预措施
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Preventing Preterm Birth and Neonatal Mortality: Exploring the Epidemiology, Causes, and Interventions
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LaVone E. Simmons, Craig E. Rubens, Gary L. Darmstadt and Michael G. Gravett |
2010/11/24 21:08:00
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Seminars in Perinatology |
2010 |
Volume 34
Issue 6 |
打印|
推荐给好友
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Globally, each year, an estimated 13 million infants are born before 37 completed weeks of gestation. Complications from these preterm births are the leading cause of neonatal mortality. Preterm birth is directly responsible for an estimated one million neonatal deaths annually and is also an important contributor to child and adult morbidities. Low- and middle-income countries are disproportionately affected by preterm birth and carry a greater burden of disease attributed to preterm birth. Causes of preterm birth are multifactorial, vary by gestational age, and likely vary by geographic and ethnic contexts. Although many interventions have been evaluated, few have moderate-to high-quality evidence for decreasing preterm birth: smoking cessation and progesterone treatment in women with a high risk of preterm birth in low- and middle-income countries and cervical cerclage for those in high-income countries. Antepartum and postnatal interventions (eg, antepartum maternal steroid administration, or kangaroo mother care) to improve preterm neonatal survival after birth have been demonstrated to be effective but have not been widely implemented. Further research efforts are urgently needed to better understand context-specific pathways leading to preterm birth; to develop appropriate, efficacious prevention strategies and interventions to improve survival of neonates born prematurely; and to scale-up known efficacious interventions to improve the health of the preterm neonate.
Keywords: prematurity; preterm birth; preterm birth prevention
The United Nations Millennium Development Goals (MDGs) 4 and 5 target a two-thirds' reduction of under-five deaths and a 75% reduction in the maternal mortality ratio between 1990 and 2015. Complications of preterm birth are the leading direct cause and major risk factor for neonatal deaths.1 Although neonatal mortality rates have decreased in recent years, neonatal deaths remain a significant global health care problem.2 There are an estimated 3.1 million neonatal deaths annually, accounting for more than 40% of all deaths in children younger than 5 years of age.1 Low- and middle-income countries (LMICs) are disproportionately affected, with 99% of the neonatal deaths occurring in these locales, making it a major global health priority.[1] and [2]
Achieving MDG 4 is dependent on high coverage of evidence-based interventions to prevent preterm delivery and to improve survival for preterm newborns. In some high-income countries (HICs), preterm birth has been on the maternal, newborn, and child health agenda for 2 decades but is now starting to receive wider public attention, particularly in the United States. However, only recently has this issue started to reach the attention of higher-level policymakers in LMICs. Many countries, particularly in Latin America, have recognized the importance of preterm birth and are searching for solutions in prevention as well as improved care. Understanding and improving the current data are critical to setting priorities for action and for tracking progress. Furthermore, more than three million stillbirths remain invisible on global policy agendas, are not included in MDG targets and are often not tracked. (See article on stillbirths.)
A recent Institute of Medicine report highlighted 3 recurring themes and challenges in an analysis of preterm birth.3 First, there is a need for clarity in preterm birth definitions, including gestational age and distinguishing between spontaneous preterm birth (which occurs naturally because of preterm labor or preterm rupture of fetal membranes) and indicated preterm birth (in which labor is initiated by medical intervention because of pregnancy complications). Second, there is consistent evidence of long-standing disparities in the rates of preterm birth among varied racial-ethnic and socioeconomic groups in HICs. Further research into these disparities will likely provide insight into some of the variation observed in preterm birthrates on a global level. Third, it is clear that preterm birth is not one disease for which there is one solution. Rather, preterm birth is a cluster of problems that comprise a set of interrelated factors of influence. Because of this complexity, a collaborative effort is imperative to both understand the relevant factors and design thoughtful, successful interventions.
The following section provides an overview of preterm birth on a global level, including regional variations in the preterm birthrate, short- and long-term consequences, and known causes and current pathway-specific interventions. A prevailing theme is notable: more research and improved access to safe, timely health care are desperately needed if we are to achieve the United Nations' (UN) goals of improving maternal, neonatal and child health outcomes.
Regional Variation in Preterm Birth
The preterm birthrate is defined as the percentage of babies born before 37 completed weeks of gestation. For improved specificity, it can be subdivided into “moderately or late preterm” (32-36 completed weeks of gestation), “very preterm” (>28 and <32 weeks), and “extremely preterm” (<28 weeks). Separate distinctions between spontaneous and medically indicated preterm birth are also used. This level of specificity is important for understanding the prevalence and etiologies of preterm birth and to guide intervention strategies. It is estimated there are approximately 13 million preterm infants born each year worldwide.4 However, this is a best estimate because more than 95% of the world's births occur in countries with incomplete vital registration. Sixty million of the world's births occur outside of facilities with little or no information on birth weight, gestational age, or even survival.5 Known data rely on household surveys and modeled estimates, limiting the accuracy. Gestational age is rarely recorded and, where recorded, tends to be determined by the often-imprecise method of self-reported last menstrual period.6 Birth weight may be recorded for those born in health care facilities, but birth weight is only an indirect surrogate for gestational age Pregnancies complicated by fetal growth restriction and neonates with low birth weight may be incorrectly classified as preterm, and large-for-gestational age preterm neonates may be incorrectly classified as term.
The regional variance in the preterm birthrates in the published literature range from 5% in HICs to 25% in LMICs.7 The WHO Special Programme of Research, Development and Research Training in Human Reproduction has recently published estimates of preterm prevalence at global and regional levels (Table 1). Rates are greatest in least developed regions, especially Africa, but are also high in North America. Reported preterm birthrates among HICs have been increasing for the past 3 decades. A significant contribution to the increase of preterm birthrates spanning the last few decades in HICs reflects an increase in medically indicated preterm birth. In absolute terms, however, medically indicated preterm births made up less than one-half of all preterm births in the year 2000 in the United States.[8] and [9] In LMICs, data on trends in preterm birth are limited and inconsistent. In general, preterm birthrates in LMICs tend to be greater than in HICs. In Latin America, an analysis of more than 1.7 million births from 51 facilities demonstrated that rates of preterm birth were the same between 1985 and 2003 (approximately 9%). However, there was a marked increase in the proportion of preterm births associated with induction/elective Cesarean deliveries during this period from 6.8% to 11%.10 For countries outside of Latin America, such as China, Indonesia, Bangladesh, and sub-Saharan Africa, the available studies use subnational samples and should be interpreted with caution. The recording of births and deaths, as well as the likelihood of medical intervention, is affected by economic and social factors, the availability of neonatal care, and by perceptions of viability. In resource-poor areas, very preterm infants may be less likely to be registered, have limited access to neonatal intensive care, or may be recorded as stillbirths even if born alive.
Table 1. Regional Variation in the Estimated Preterm Birth Prevalence Rates
Source: reprinted from Beck et al4 with permission from WHO Press.
Consequences of Preterm Birth
Prematurity is the leading direct cause of early neonatal death, responsible for 27% or approximately 1 million annual neonatal deaths.1 Preterm birth also increases the risk of dying from other causes. The proportion of deaths that are directly related to preterm birth is lower in LMICs than in HICs. However, other factors related to neonatal deaths, such as neonatal sepsis and birth asphyxia (Fig. 1), are often indirectly related to preterm birth. Overall, prematurity and its consequences contribute to an estimated 50% of neonatal deaths.1 Preterm birth also leads to significant neonatal morbidities. Compared with infants born at term, preterm infants have greater rates of temperature instability, respiratory distress, infections, apnea, hypoglycemia, seizures, jaundice, kernicterus, feeding difficulties, necrotizing enterocolitis, periventricular leukomalacia, and rehospitalizations.11 Mortality rates increase proportionally with decreasing gestational age (and hence decreasing birth weight) and are greatest among infants born at less than 32 weeks. Infants born from 32 to 36 weeks represent approximately 75% of all preterm births and the group of infants who make up the fastest-growing proportion of the preterm births in HICs, with a 25% increase during 1990-2005.3 Although improvements in medical care have led to improved survival and long-term outcomes among moderately and extremely preterm babies in HICs, these babies still account for the majority of deaths. For example, in the United States, the 2% of neonates born at less than 32 weeks' gestation account for more than 50% of neonatal deaths.3 Similar observations have been made in LMICs. In one South African hospital, the 3% of very low birth weight (<1000 g) neonates accounted for 55% of early neonatal deaths.12 Finally, neonatal mortality associated with prematurity extends beyond the early neonatal period. Barros et al13 found that in southern Brazil, preterm infants had an infant mortality rate 13 times greater than infants born at term, and that a significant proportion of this excess mortality beyond the early neonatal period was attributable to infectious complications (Table 2).
Figure 1.
Global causes of neonatal death.
(Source: Reprinted with modifications from Lawn et al,1 with permission from Elsevier.)
Table 2. Infant Mortality Rate (per 1000) and Cause Among Term and Preterm Infants in Southern Brazil
Source: modified from Barros et al13 with permission from American Academy Pediatrics.
Preterm infants experience increased neurodevelopmental impairments and behavioral sequelae, have greater rates of hospital admissions, and experience a greater rate of cardiovascular, pulmonary, and vision and hearing impairments compared with their term cohorts. One recent study found a 23% risk of severe neurodevelopmental impairments, for example, among surviving infants born at less than 33 weeks' gestation in Bangladesh.11 These outcomes are influenced by the etiology of the preterm birth, genetic and environmental factors, and are more prevalent with decreasing gestational age. A 2008 cohort study of more than 900,000 preterm and term infants in Norway demonstrated an increased prevalence of cerebral palsy, developmental delay, and medical disability with decreasing gestational age.14 Preterm birth was also associated with increased perinatal and infant mortality, diminished long-term survival, and lower rates of reproduction.15 Thus, the true costs of prematurity, especially on a long-term global level, are poorly understood and likely grossly underestimated.
Causes of Preterm Birth
Although preterm birth is recognized to be an adverse outcome of parturition, parturition itself remains incompletely understood. Two compelling principles emerge from the current understanding of pregnancy and parturition. First, labor represents a natural continuum of processes that begin at implantation and culminate with the return of the uterus to its nonpregnant state. The continuum involves 5 well-defined phases: implantation, uterine quiescence, activation, stimulation and involution (Fig. 2).16
Figure 2.
Phases of parturition as a continuum of pregnancy. After implantation, most pregnancy is spent in a state of quiescence, with uterine growth without uterine contractions. Activation is characterized by a biochemical and physiological maturation favoring uterine contractions. Stimulation, or labor, constitutes less than 0.5% of gestation.
(Source: Reprinted with modifications from Gravett et al,16 with permission from BioMed Central.)
The overwhelming majority of pregnancy is spent in quiescence or activation whereas less than 0.5% is spent in active labor. However, most interventions and research have focused upon stimulation, or active labor. Only recently has attention been directed toward factors important in maintaining uterine quiescence, or relaxation that characterizes most pregnancy. The second compelling principle is that preterm birth is not a single pathologic process but rather the outcome of multifactorial etiologies, each with distinct biological pathways. The etiologies differ according to gestational age, ethnicity, and characteristics unique to each population. Preterm birth may result from preterm labor with intact fetal membranes, preterm rupture of the fetal membranes, or from iatrogenic preterm delivery for maternal or fetal indications. In high-income countries, approximately 40% to 45% of preterm births follow preterm labor, 25% to 40% follow preterm premature rupture of the fetal membranes (preterm premature rupture of membranes (PPROM)), and 30% to 35% are indicated deliveries.8 In contrast, studies from countries in Latin America have shown that almost 60% are spontaneous preterm births, 16% to 21% involve PPROM, and 11% to 15% have medically induced causes.[17] and [10] PPROM often represents a final common pathway to preterm birth. PPROM has been associated with intrauterine infection, tobacco use, abruption, multiple gestations, previous PPROM, previous cervical surgery or laceration, a short cervix by ultrasound, genetic connective tissue disorders, and vitamin C deficiency.
Commonly recognized etiologies and pathways leading to spontaneous preterm birth are listed in Table 3 and are summarized below. Regional- or ethnic-specific variations in the contribution of specific pathways are not completely understood and reflect the need for further research efforts. Nonetheless, while there may be many pathway-specific unique upstream initiators of labor, there are few common downstream effectors (Fig. 3). An understanding of these etiologies provides the opportunity to develop interventions that target these unique upstream initiators in pathway-specific interventions.
Table 3. Commonly Recognized Etiologies and Pathways Leading to Spontaneous Preterm Birth
Figure 3.
Overview of major pathways leading to preterm labor and delivery. Although there are multiple unique upstream initiators of preterm birth, there a few common downstream effectors. This suggests that interventions targeting unique upstream initiators coupled with interventions targeting common downstream effectors may have enhanced efficacy in treating preterm labor when compared with interventions that target only downstream effectors. (Color version of figure is available online.)
(Source: Reprinted from Behrman3 with permission from National Academies Press.)
Each pathway to prematurity may be influenced by gene-environment interactions and by genetic variability. Although a single candidate gene has not been identified, it is important to recall preterm birth is a complex phenotype, with many etiologic and pathophysiological pathways that likely cannot be explained by genetic variation alone. As such, selective candidate gene studies have focused upon single nucleotide polymorphisms (SNPs) within selected genes. It is estimated that 10 million SNPs may regularly occur within the human genome and constitute 90% of the variation in a population. The most common patterns of these polymorphisms are being assessed and more than 30 SNPs have been associated with increased or decreased risks of preterm birth or preterm premature rupture of the membranes (PPROM).[18] and [19] Important ethnic differences in SNP frequencies may help explain racial disparities in preterm birth.
Infection/Inflammation
From a global health perspective, infection is one of the most important and potentially preventable causes of early preterm birth. Intrauterine infections are thought to be responsible for up to 50% of extreme preterm births of less than 28 weeks of gestation, where both neonatal mortality and morbidity are high, and are refractory to conventional tocolytic therapy. In addition, extrauterine or systemic infections may play an important role in preterm birth. Observational studies show an association between maternal urinary tract infections, bacterial vaginosis, periodontal disease and both preterm birth and low birth weight.16 There is a great deal of heterogeneity between studies regarding the association between these infections and preterm birth; ascertainment bias, with under-reporting in LMICs, makes it difficult to assess the overall contribution of infection to preterm birth. However, the proportion of affected women is likely higher in LMICs, emphasizing the need for country-specific investigation into the associations among infection and preterm birth.
In addition, malaria and syphilis are important contributors to a wide range of adverse pregnancy outcomes in LMICs. Malaria may affect fetal growth and gestation through maternal anemia and placental infection. Placental infection has been associated with low birth weight and preterm delivery. While there is limited evidence regarding the effect of malaria interventions for affecting the rate of preterm birth, evidence does support the use of 2 interventions to improve related adverse pregnancy outcomes: insecticide-treated nets (ITNs) or intermittent presumptive treatment (IPTp). In a systemic review, women in their first or second pregnancies receiving IPTp during pregnancy experienced reduced anemia, parasitemia, placental malaria, perinatal deaths and low birth weight (6 trials, relative risk [RR] 0.57%, 95% confidence interval [CI] = 0.46-0.72).20 No effect on preterm births was observed in the only trial assessing this outcome. A review of 5 randomized clinical trials of ITNs during pregnancy showed a 23% reduction in low birth weight in the African trials.21 Unfortunately, no effect was demonstrated on reducing preterm births in a trial conducted in Kenya.22
Syphilis, caused by Treponema pallidum, is an important cause of both stillbirth and preterm birth. Primary and secondary syphilis in pregnancy leads to fetal infection in virtually all cases, with approximately 30% to 50% of pregnancies resulting in stillbirth or death shortly after delivery. Observational studies have also demonstrated an association between syphilis and preterm birth. In United Republic of Tanzania, women with high-titer active syphilis had a 6-fold greater risk of preterm birth compared with seronegative women.23 It is estimated that syphilis accounts for one-fourth of the preterm births in this population. A study from Malawi reported similar findings.24 Penicillin is known to effectively reduce the risk of congenital syphilis but there are no intervention studies showing an effect of syphilis screening and treatment on preterm birth.
Decidual Hemorrhage/Thrombosis
Decidual hemorrhage may cause either late or early preterm birth. Vascular lesions of the placenta are commonly associated with preterm birth and PPROM. Vascular lesions of the placenta have been reported in 34% of women with preterm delivery, 35% of women with PPROM, and in 12% of term uncomplicated deliveries.25 The proposed mechanism linking vascular lesions to preterm birth is related to uteroplacental ischemia and thrombin is thought to play a central role.
Stress
Stress results in preterm activation of the maternal or fetal hypothalamic-pituitary-adrenal axis and is increasingly recognized as an important cause of late preterm birth. Stress may be simply defined as any challenge, whether physical or psychological that threatens or is perceived to threaten homeostasis of the patient. The authors of several studies have found 50% and 100% increases in preterm birthrates associated with maternal stress, usually defined as a composite of life events, anxiety, depression, or perceived stress.26 The authors of in vitro and in vivo studies have demonstrated a correlation between hypothalamic corticotropin release, maternal stress and an association to the timing of birth.16
Uterine Overdistension or Cervical Insufficiency
Uterine overdistension plays a key role in the onset of preterm labor associated with multiple gestations, polyhydramnios, and macrosomia. Multiple gestation, frequently attributable to assisted reproduction technologies, including ovulation induction and in vitro fertilization, is one of the most important causes of late preterm birth in HICs. Cervical insufficiency has traditionally been associated with second-trimester pregnancy losses, but recent evidence suggests that cervical disorders are associated with a wide variety of adverse pregnancy outcomes, including early preterm birth. Cervical insufficiency may be caused by congenital disorders, in utero diethylstilbestrol exposure, loss of cervical tissue after a surgical procedure, traumatic damage, and infection. Cervical length of less than 25 mm measured by transvaginal ultrasonography is correlated with risk of preterm birth,27 but this predictive screening test is not widely available in LMICs. Unfortunately, the mechanisms whereby uterine overdistension and cervical insufficiency lead to preterm labor are incompletely understood, and international studies relevant to LMICs are lacking.
Environmental Factors
Various environmental exposures have been linked to poor pregnancy outcomes. Maternal serum and umbilical cord blood levels of pesticides, such as dichlorodiphenyl trichloroethane are associated in some, but not all, studies with preterm delivery. Other organophosphate pesticide metabolites are associated with preterm birth at increasing exposure levels in the later part of pregnancy. Air pollution (particulate matter, carbon monoxide, lead, ozone, nitrogen dioxide, and sulfur dioxide) is associated with a variety of poor birth outcomes, including preterm birth. Although there is an association between indoor air pollution and low birth weight, further studies are needed regarding the association with preterm birth. Daily energy needs are often met by burning solid fuels, and women cooking in poorly ventilated homes are disproportionately exposed to air pollution.
The harmful effects of smoking during pregnancy are well established and it has been causally associated with preterm delivery and stillbirth. More than 80% of all smokers now reside in LMICs.28 Recent prevalence studies of smoking during pregnancy show wide variability, with rates greater than 25% in South America, 8% in urban Africa, and 18% in the Pacific Islands.29 Although the mechanisms that increase the risk of preterm birth are not clear, it is known that both nicotine and carbon monoxide are potent vasoconstrictors, produce placental damage, and decrease the uteroplacental blood flow. Research regarding maternal exposure to second-hand smoke and studies in LMICs is needed.
Specific Interventions
A recent review has highlighted the evidence for interventions directed toward the mother to prevent preterm birth with special reference to LMICs.29 Approximately 2000 intervention studies were evaluated, and only 2 specific interventions were found to be effective in preventing preterm birth: smoking cessation and progesterone therapy for women at high risk of preterm birth. A recent Cochrane review demonstrated smoking cessation during pregnancy reduced preterm birth (RR = 0.86%, 95% CI = 0.74-0.98) and low birth weight (RR = 0.83%, 95% CI = 0.73-0.95) by approximately 20%.30
In addition, a meta-analysis of 6 randomized trials, 5 of which were in HICs in which the authors compared the use of progesterone with placebo in high-risk women showed a reduction of preterm births in the intervention group (RR = 0.65%, 95% CI = 0.54-0.79).31 However, we estimate that even with widespread adoption of these interventions (progesterone and smoking cessation), the overall impact in reducing global preterm birthrates would be <3% to 4% (M. Gravett and C. Rubens, unpublished data, 2010). Although annually this would result in approximately 500,000 fewer preterm births, this estimate highlights the need for continued research into efficacious interventions to prevent preterm birth.
In HICs cervical cerclage is frequently used for the treatment of cervical insufficiency associated with previous spontaneous preterm births. In 4 randomized controlled trails of cervical cerclage for high-risk women, there was no difference in the occurrence of preterm births between intervention and control women (RR = 1.04%, 95% CI = 0.99-1.10).32 However, in a recent multicenter randomized trial of women with a prior spontaneous preterm birth less than 34 weeks and cervical length less than 25 mm, cerclage was found to reduce previable birth, perinatal mortality, and decrease recurrent preterm birth in women with especially short cervices (<15 mm).33 This suggests cerclage, in selected clinical settings, may be appropriate but the overall impact on reduction of preterm birthrates is likely to be small and feasibility in LMICs limited.
Observational studies demonstrate a relationship between increased rates of preterm birth and short birth spacing, decreased folate levels, and indoor air pollution. However, interventional studies have either not been performed or have not demonstrated a statistically significant decrease in preterm birth with directed therapy.
With limited capability to prevent preterm birth, attention has been given to interventions to improve the health and survival of preterm neonates, as recently reviewed by Barros et al29 these interventions include both intrapartum interventions given to women in preterm labor or with PPROM and postnatal interventions to improve neonatal survival and reduce morbidity. An extensive review of these interventions is beyond the scope of this paper. Briefly, 11 interventions that are applicable to LMICs were demonstrated to improve survival of preterm newborns, including 3 intrapartum interventions (maternal prophylactic corticosteroids, latency antibiotics following PPROM, and delayed cord clamping) and 8 postnatal interventions (vitamin K supplementation, case management of neonatal sepsis, room air for resuscitation, kangaroo mother care, early breastfeeding, thermal care, surfactant therapy, and application of continued distending airway pressure for respiratory distress syndrome).
Among intrapartum interventions, maternal corticosteroid administration for patients in preterm labor or with PPROM at less than 34 weeks of gestation to reduce respiratory distress syndrome has shown the greatest benefit. A recent Cochrane review demonstrated a 34% reduction (RR = 0.66%, 95% CI = 0.59-0.73) in respiratory distress syndrome among neonates given antenatal corticosteroids.34 Further, additional benefits of antenatal corticosteroids were observed, including reductions of 46% (RR = 0.54%, 95% CI = 0.43-0.69) in cerebral hemorrhage and 31% (RR = 0.69%, 95% CI = 0.58-0.81) in neonatal mortality. Several of the studies included in the meta-analysis were from LMICs, indicating the translational feasibility of this intervention. Antibiotic treatment after PPROM at less than 32-34 weeks of gestation has also been demonstrated to prolong latency from rupture of membranes to delivery, and reduce neonatal infections and oxygen therapy but has not been demonstrated to prevent preterm birth or reduce risks of low birth weight.35
Although the aforementioned postnatal interventions have been shown individually to improve preterm survival, most have been bundled into effective community-based intervention packages.[36], [37] and [38] These intervention packages, usually, including education of community health workers or skilled birth attendants, birth kits to improve hygienic delivery, and thermal care, have consistently led to a 30% to 70% reduction in neonatal mortality. One recent analysis found that adoption of antenatal and postnatal intervention packages at a 90% coverage level could save 1.04-1.88 million newborn lives in South Asia and sub-Saharan Africa.39 However, most neonates included in community-based intervention programs are born near term. It is likely these interventions would be efficacious in late preterm neonates, born at 34 to 36 weeks of gestation, who constitute most preterm births, however, data are lacking.
Conclusions
The etiologies of preterm birth are known to be complex and multifactorial and require further research. Smoking cessation, progesterone treatment, and cervical cerclage have shown some success as preventative interventions and should be encouraged when appropriate. The adoption of these demonstrably efficacious interventions may prevent up to 500,000 preterm births annually. However, their application on a global scale is limited. The acceptability of scaling up these interventions will be challenged by how any particular country society can deal with chronic sequelae of prematurity. Currently, even in those settings where access or availability of these interventions is not an issue in LMIC, decisions to provide or withhold available interventions may be determined by whether a child will have a chronic or disabling condition, family resources, and its impact on the child's life or the family's well being.40 Although it is clear preterm birth is complex and has a significant effect on global neonatal mortalities and chronic morbidities, continued efforts to understand the etiologies of preterm birth to develop more effective interventions that are affordable, especially preventive modalities for LMICs and in HICs, are urgently needed. Because less than 4% of the preterm births would be eliminated if all interventions (smoking cessation, progesterone for high risk women, and cervical cerclage; M. Gravett and C. Rubens, unpublished observation, 2010) even if delivered and effectively used universally at scale, a balanced approach to implementing life-saving interventions with high coverage in LMICs with a strong research and development effort to develop prevention strategies is required. An integrated, coordinated effort to address the unmet, significant research and development needs is required to identify causes and prevention strategies.41
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 Address reprint requests to Michael G. Gravett, MD, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Box 356460, Seattle, WA 98195-6460
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