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Improving Birth Outcomes: Meeting the Challenge in the Developing World Summary of Findings: Reducing Neonatal Mortality and Morbidity in Developing Countries An estimated 4 million neonates (aged up to 28 days) die each year. These deaths account for about 40 percent of under-5 mortality and two-thirds of infant (aged up to 12 months) mortality. Ninety-eight percent of neonatal deaths occur in developing countries. The true burden of neonatal mortality in developing countries is unknown because many deaths occur in the home and are not reported. Limited epidemiological research indicates the main causes of neonatal deaths are infections, birth asphyxia, birth injuries, complications of preterm birth, and birth defects. Because complications of childbirth too frequently cause neonatal death, skilled assistance is recommended for all deliveries along with access to the appropriate level of neonatal care when needed. Preconceptional and antenatal care provide an opportunity to reduce risk factors for neonatal mortality and morbidity. These include detection and treatment of maternal infections; immunization of women of reproductive age against tetanus; and counseling on risks to a healthy pregnancy and birth preparedness, emphasizing the importance of a clean and safe delivery assisted by a skilled birth attendant. Clean and safe newborn care should prevent and manage neonatal infections and other illnesses that can otherwise become life threatening. Caregivers must be able to recognize signs of illness, and when they appear, promptly seek appropriate medical assistance.
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Improving Birth Outcomes: Meeting the Challenge in the Developing World 3 Reducing Neonatal Mortality and Morbidity The greatest risk of childhood death occurs during the neonatal period, which extends from birth through the first month of life. About 60 percent of all deaths to children under age 5 and nearly two-thirds of infant deaths (birth to 12 months) occur during the neonatal period (Rutstein, 2000). About two-thirds of all neonatal deaths occur during the first week of life. Current estimates place the annual neonatal death toll at 4 million (Save the Children, 2001). Approximately 98 percent of neonatal deaths occur in the developing world (World Health Organization, 1996b). The highest annual neonatal rates are in South Asia, where an estimated 51 deaths occur for every 1,000 live births. Each year in South Asia alone, 2 million children die within a month of their birth. By comparison, the rates per 1,000 live births are 42 in Africa, 25 in Latin America, and fewer than 10 in Europe and North America (World Health Organization, 1996b). The burden of neonatal morbidity in developing countries is unknown; however, a recent study of neonatal morbidity in rural India revealed that nearly half of the 763 infants observed developed high-risk morbidities (those with a case fatality greater than 10 percent), and nearly three-quarters suffered low-risk morbidities, some in addition to high-risk conditions (Bang et al., 2001). CAUSES OF NEONATAL MORBIDITY AND MORTALITY Most neonatal deaths occur at home, following unsupervised deliveries; thus little accurate information is available as to their causes (Stoll,
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Improving Birth Outcomes: Meeting the Challenge in the Developing World FIGURE 3-1 Global estimates of the direct causes of neonatal mortality. SOURCE: WHO Mother-Baby Package, 1994. 1997). Limited epidemiological research indicates that the principal direct causes of neonatal death are infectious diseases, birth asphyxia, birth injuries, and the sequelae of preterm birth and birth defects (Figure 3-1). During the early neonatal period (0-7 days), the major causes of death are asphyxia, infection, complications of prematurity, and birth defects; infections cause most late neonatal deaths (8-28 days) (Lawn et al., 2001). This chapter addresses neonatal infections, birth asphyxia, birth injury, hypothermia, and hyperbilirubinemia. Strategies to reduce mortality and morbidity associated with low birth weight are discussed in Chapter 6; those associated with birth defects, in Chapter 7; and those associated with perinatal transmission of HIV, in Chapter 8. Infectious Diseases Infections are the major cause of mortality and morbidity in infants under 3 months of age in developing countries (Stoll, 1997). As noted in Chapter 1, more than 20 percent of children born in developing countries acquire an infection during the neonatal period, leading to an estimated 30 to 40 percent of all neonatal deaths (Stoll, 1997; Stoll, 2000). Most of these deaths are caused by acute respiratory infections, bacterial sepsis and/or
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Improving Birth Outcomes: Meeting the Challenge in the Developing World TABLE 3-1 Estimated Global Burden of Disease Due to Major Neonatal Infections Infection Estimated No. of Cases Estimated Case Fatality Rate* Estimated No. of Deaths Sepsis 750,000 40% 300,000 Meningitis 126,000 40% 50,400 Tetanus** 355,000 70% 248,000 Acute respiratory infections 2,650,000 30% 800,000 Diarrhea 25,000,000 0.6% 150,000 HIV 550,000 na na Total 29,431,000 — 1,548,400 na = Data unavailable: Most HIV-related deaths occur after the neonatal period. * Fatality rates may be much higher in developing countries. ** Updated data from World Health Organization, 1999a. SOURCE: Stoll, 2000 (data from 1995). meningitis, neonatal tetanus, and diarrhea (Table 3-1). Maternal infections, including sexually transmitted diseases (STDs) such as HIV (the topic of Chapter 8) and syphilis, can be transmitted to the fetus or newborn in utero, through contact during labor and delivery, and in some cases, through breastfeeding. Sepsis In many countries, bacterial sepsis accounts for a substantial burden of disease and has a 40% case fatality rate (Stoll, 2000). Early-onset neonatal sepsis (48-72 hours) usually results from organisms acquired from the maternal genital tract during birth and often is associated with maternal complications; late-onset neonatal sepsis (7-28 days) is more likely to be caused by organisms acquired from the environment (Korbage de Araujo et al., 1999; Martius et al., 1999; Moreno et al., 1994; Kuruvilla et al., 1998; Schuchat et al., 2000; Stoll et al., 2002a,b). Estimates of the incidence of neonatal sepsis are based largely on cases that reach the hospital, which undoubtedly underestimates the incidence in the community. In pooled data from hospital-based case series, the incidence was 6 cases per 1000 live births (Stoll, 2000); other studies suggest that rates may be even higher (Kuruvilla et al., 1998; Asindi et al., 1999). Among patients enrolled in the WHO Young Infants Study—a study of infants under 3 months of age with serious infections conducted at four sites (Ethiopia, the Gambia, Papua New Guinea, and the Philippines)—30 percent of infants with a positive blood culture died (WHO Young
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Improving Birth Outcomes: Meeting the Challenge in the Developing World Infants Study Group, 1999a). In 47 hospital-based studies, case fatality rates were as high as 69 percent (Stoll, 2000). Left untreated, bloodstream infections can spread to the meninges, resulting in meningitis. Estimates of neonatal meningitis incidence range from 0.3 to 2.8 per 1,000 live births (average 1/1000 live births), and reported case fatality rates range from 13 to 59 percent (Stoll, 2000). Omphalitis (umbilical infection) continues to be a problem in developing countries (Cushing, 1985). Births in the home, nonsterile cutting of the cord, and unhygienic cord care after birth all increase the risk of omphalitis. Because localized umbilical infection is not prevented and may be inadequately treated in developing-country settings, it may be associated with the subsequent development of necrotizing fasciitis and/or neonatal sepsis (Faridi et al., 1993; Weber et al., 2001). Moreover, omphalitis in patients with neonatal tetanus (discussed below) is associated with an increased risk of bacterial sepsis (Egri-Okwaji, 1998). Because the majority of developing-country studies that present data on the bacterial etiology of neonatal sepsis and meningitis are hospital-based, they may not reflect what is happening at the community level. While group B streptococcus (GBS) remains an important cause of early neonatal sepsis in industrialized countries (Schuchat, 1998), it appears to be a much less important pathogen in developing countries (WHO Young Infants Study Group, 1999a; Stoll, 2000). The most frequent organisms reported from case series in developing countries are gram-negative organisms (especially Escherichia coli and Klebsiella) and Staphylococcus aureus (Stoll, 2000; Mulholland, 1998). The organisms responsible for neonatal sepsis and meningitis are similar, change over time, and vary by geographic region. Therefore, prospective microbiological surveillance is key for prevention and appropriate treatment of these diseases. The emergence of antibiotic-resistant pathogens is a particularly alarming problem in developing countries. Hospital-based studies of the bacterial etiology of neonatal sepsis and reports of nosocomial outbreaks from a variety of countries demonstrate that the problem of antibiotic resistance is of global concern (Banerjee et al., 1993; Reish et al., 1993; Haddad et al., 1993; Bhutta, 1996; Ako-Nai et al., 1999; Musoke, 1997; Musoke and Revathi, 2000). The widespread availability of antibiotics and their indiscriminate and inappropriate use contribute to this problem, along with poor infection-control practices in hospitals. Surveillance capacity and the transfer of surveillance information must be developed to determine both the global and local impact of resistant microorganisms and to identify interventions that can address this threat (Williams, 2001). Strategies are needed to reduce the risk of infection, as well as to encourage the judicious prescription and appropriate use of antibiotics in the community and in hospital (Levy, 2001; Boyce, 2001;
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Improving Birth Outcomes: Meeting the Challenge in the Developing World Perchère, 2001; Bell, 2001; de Man et al., 2000). Some epidemiologists caution, however, that the prudent use of antibiotics is unlikely to reverse resistance trends and that the true clinical impact of antibiotic resistance has not yet been measured (Phillips, 2001). Acute respiratory infections Pneumonia and other acute respiratory infections (ARIs) account for up to a quarter (Pan American Health Organization, 1999) or perhaps more of all mortality in children under 5, but it is difficult to determine the incidence of neonatal ARI in developing countries because many sick neonates are not referred for medical care. The risk of death due to ARI is highest in young neonates and decreases with age (Garenne et al., 1992). Most ARI deaths are due to pneumonia, which annually kills more than 3 million children under the age of 5 in developing countries (Garenne et al., 1992). Like sepsis, neonatal pneumonia may have an early onset if acquired from the maternal genital tract or a late onset due to infection from the hospital or home environment. Bacterial pneumonia is the most common; streptococcus pneumoniae is the most frequent cause. Low birth weight is associated with higher mortality (Misra et al., 1991). The risk of pneumonia increases in infants who are of low birth weight and/or malnourished, and in those who are not breastfed (Victora et al., 1999). In preterm neonates of low birth weight, respiratory distress syndrome, due to surfactant deficiency, is a major risk for early death (Mlay and Manji, 2000). Information on the prevalence of this disorder in developing countries is especially difficult to obtain because most infants of very low birth weight (those weighing less than 1500 grams, who are at greatest risk) die soon after birth. In these cases, causes of death other than prematurity are poorly recognized (Bhutta et al., 1999). Tuberculosis A leading infectious disease, tuberculosis (TB) kills more than 2 million people worldwide each year, including 250,000 children, despite the availability of cost-effective prevention and treatment (United Nations Children’s Fund, 2000). The vast majority of these deaths occur in developing countries; approximately 70 percent of all TB cases occur in Asia (United Nations Children’s Fund, 2000). TB is a particular risk in areas where HIV is prevalent, as approximately 40 percent of people whose immune systems have been weakened by HIV develop TB (United Nations Children’s Fund, 2000; Thillagavathie, 2000). The reportedly higher TB prevalence in men than in women appears to be an artifact of gender differences in notification rates (Thorson and Diwan, 2001).
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Improving Birth Outcomes: Meeting the Challenge in the Developing World In pregnant women, TB has been shown to increase the risk of fetal loss, preterm delivery, and low birth weight (Starke, 1997; Jana et al., 1994). Although rare, transplacental congenital infection may occur (Connelly Smith, 2002; Starke, 1997); infection with HIV increases a woman’s risk for placental or genital TB. The most common route of mother-to-child transmission is postnatal from an untreated infected mother to her newborn. Infected newborns are at high risk for severe disseminated TB and death (Starke, 1997; Adhikari et al., 1997). Diarrheal disease Several community-based studies suggest that diarrhea is responsible for approximately 3 percent of all neonatal deaths (Stoll, 2000). Diarrheal episodes tend to occur with greatest frequency among children aged 6 months to 2 years; in many developing countries, initial episodes frequently occur in the first 6 months of life (Bern et al., 1992; Snyder and Merson, 1982; Jacobson, 1999). Some factors common to developing countries—home delivery; relative segregation of newborn infants for a period of time after birth; and the high prevalence of early, exclusive breastfeeding—protect against neonatal diarrhea. Among hospitalized newborns in developing countries, nosocomial diarrhea is an important problem (Aye et al., 1991; Yankauer, 1991; Tessema, 1994). Rotavirus Rotavirus is an important cause of diarrhea among infants and children worldwide, occurring most commonly in those aged 3 months to 2 years. However, several studies from developing countries report rotavirus infections in newborns (Haffejee, 1995; Parashar et al., 1998b; Cicirello et al., 1994; Espinoza et al., 1997; Gomwalk et al., 1990). Tetanus Worldwide, about a quarter-million infants die from tetanus each year (Table 3-1). Risk factors for neonatal tetanus occur in the antenatal, perinatal, and neonatal periods: failure to immunize the mother against tetanus; unhygienic delivery and cutting of the umbilical cord at birth; and unsterile handling of the cord in the early days of life. Cultural practices prevalent in specific areas, such as the application of ghee (Pakistan and India) and other unclean substances to the cord after birth increase risk (Traverso et al., 1991). Diagnosis of neonatal tetanus is relatively straightforward: the newborn can suck at birth and for the first few days of life, then loses this ability between 3 and 10 days of age, then develops spasms, stiffness,
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Improving Birth Outcomes: Meeting the Challenge in the Developing World convulsions, and death. For decades, community surveys have determined the burden of disease and mortality rates for tetanus (Galazka and Stroh, 1986). Routine national surveillance, however, may still underestimate the true occurrence of the disease (Singh et al., 1997). In some of the least-developed countries, neonatal tetanus remains a major cause of neonatal death, particularly among infants delivered at home and without skilled assistance (Gasse, 1995; Gupta and Keyl, 1998; Gurkan et al., 1999; Davies-Adetugbo et al., 1998). Between 1990 and 2000, deaths caused by neonatal tetanus declined by half through a combination of maternal immunization and clean delivery practices (United Nations Children’s Fund, 2002). Substantial reductions in neonatal mortality due to tetanus occurred in China, Indonesia, Bangladesh, India, and Pakistan. Nevertheless, approximately 250,000 neonates died of tetanus during 1997; the majority of these deaths occurred in Africa and Southeast Asia, with nearly 20 percent in India (World Health Organization, 1999a). Sexually transmitted diseases More than 333 million cases of the four major curable STDs—syphilis, gonorrhea, chlamydia, and trichomoniasis—were estimated to occur in 1995, the vast majority in developing countries (Gerbase et al., 1998). Collectively, STDs rank among the leading causes of morbidity worldwide, a burden borne disproportionately by women of reproductive age. STDs among pregnant women often receive delayed treatment or none at all, largely because they are asymptomatic or unrecognized (Sturm et al., 1998). Most STDs are readily transmitted from mother to child during pregnancy and/or childbirth (Moodley and Sturm, 2000). The extent of neonatal infections with these agents in developing countries is difficult to estimate. Adverse pregnancy outcomes associated with STDs range from miscarriage and preterm birth (see Chapter 7) to congenital infections to maternal, fetal, and neonatal mortality (Carroli et al., 2001a; Moodley and Sturm, 2000). Neonatal HIV is discussed in detail in Chapter 8. Among women worldwide, there are approximately 7 million new cases of syphilis each year (Gerbase et al., 1998). Rates of congenital syphilis parallel those of syphilis in women of reproductive age. Many developing-country studies have found seroprevalence rates of syphilis among pregnant women of 5 to 15 percent, or up to two orders of magnitude higher than typical rates in developed countries (Carroli et al., 2001a); in South Africa, rates of infection in pregnant women have been reported to range from 6 to 19 percent (Rotchford et al., 2000). Untreated syphilis during pregnancy increases the risk of late fetal death, low birth weight, preterm birth, and severe neonatal disease (Lumbiganon et al., 2002). Data from a demonstra-
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Improving Birth Outcomes: Meeting the Challenge in the Developing World tion project in Zambia determined that syphilis was the most significant cause of adverse pregnancy outcome among women attending antenatal clinics (Hira et al., 1990); a more recent prospective study of congenital syphilis in a Papua New Guinea hospital found that the infection was responsible for 6 percent of admissions and 22 percent of all neonatal deaths (Frank and Duke, 2000). Syphilis is transmitted from an infected mother to the fetus largely via transplacental infection, and rarely via contact with an infectious genital lesion during delivery. Active infection with syphilis in pregnant women is estimated to result in fetal or infant death or disability for 50 to 80 percent of affected pregnancies (Gloyd et al., 2001). The majority of infants born to mothers with untreated syphilis are asymptomatic at birth, but if left untreated may develop clinical manifestations of disease months to years after birth (Dorfman and Glaser, 1990; Sanchez et al., 1991). Symptoms of early congenital syphilis include intrauterine growth restriction, anemia, thrombocytopenia, jaundice, and hepatosplenomegaly (Stoll et al., 1993). The most devastating complications of untreated or late congenital syphilis are neurological manifestations that include mental retardation, hydrocephalus, cranial nerve palsies, and seizures (Stoll, 1994). With adequate treatment of infected mothers, syphilis is a preventable cause of neonatal morbidity and mortality. Neonates delivered vaginally to mothers with untreated gonorrhea are at great risk of developing gonococcal conjunctivitis, which, if left untreated, can lead to blindness. Rarely, neonates develop disseminated gonococcal infection (Desenclos et al., 1992; Rawstron et al., 1993). Similarly, chlamydia infections occur in approximately two-thirds of infants born by vaginal delivery to infected mothers (Moodley and Sturm, 2000). Chlamydia can cause conjunctivitis and/or pneumonia, which may not be evident until the infant is several weeks old. Neonatal infection with herpes simplex usually occurs during delivery, via an infected birth canal or an ascending infection following the rupture of membranes to women with primary genital herpes at the time of delivery (Prober et al., 1988; Brown et al., 1996; Brown et al., 1987). The infection can spread to the central nervous system and beyond, and has both a high mortality rate and a high likelihood of neurodevelopmental sequelae among survivors (Tookey and Peckham, 1996; Brkic and Jovanovic, 1998; Jacobs, 1998; Whitley et al., 1991). Maternal urinary tract infections Infections of the urinary tract, particularly asymptomatic bacteriuria, occur in an estimated 4 to 7 percent of all women (Carroli et al., 2001a; Dempsey et al., 1992;). Unless the infection is treated with antibiotics, an
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Improving Birth Outcomes: Meeting the Challenge in the Developing World estimated 20 to 40 percent of pregnant women with asymptomatic bacteriuria will develop pyelonephronitis (Smaill, 2003); of those who do, 20 to 50 percent will experience preterm deliveries (Carroli et al., 2001a). Antibiotic treatment is associated with reductions in preterm delivery and low birth weight (Smaill, 2003). Malaria Malaria in pregnancy has serious health consequences for both mother and newborn. Because it causes significant maternal morbidity, its prevention and treatment are discussed in Chapter 2. The primary malaria-associated risk for neonates is reduced birth weight, which is discussed in Chapter 6. In highly endemic settings, malaria has been estimated to account for 13 percent of low birth weight (LBW) due to intrauterine growth restriction (IUGR) (Steketee et al., 1996). Noninfectious Conditions Perinatal asphyxia Of the estimated 4 to 7 million neonates born each year worldwide that require some form of resuscitation immediately after birth, approximately 1 million die and another million suffer serious sequelae (Saugstad et al., 1998). Epidemiological data provide only rough estimates of the global burden of perinatal asphyxia, in part because of the imprecision of diagnosis. Numerous definitions of perinatal asphyxia, all of which correspond to the failure to initiate and sustain normal breathing, have been used in studies from developing countries. These include apnea or gasping with a slow heart rate (<80) at birth, absent or poor respiratory effort at 1 minute, gasping at 1 minute, low Apgar scores (variously defined), and the need for assisted ventilation for more than 1 minute (Paul et al., 1997; Chandra et al., 1997; Daga et al., 1990; Saugstad et al., 1998; Kinoti, 1993). In addition, data on perinatal asphyxia are largely hospital-based and therefore may either underestimate or overestimate the true magnitude of the problem, as seen in many studies (Paul et al., 1997; Chandra et al., 1997; Daga et al., 1990; Kinoti, 1993; Chaturvedi and Shah, 1991; Boo and Lye, 1991; Nathoo et al., 1990; Ellis et al., 2000). The incidence of perinatal asphyxia is thought to be higher in developing than developed countries because of the higher prevalence of risk factors for the disorder, as well as the lack of appropriate interventions (Deorari et al., 2000). Mortality is greater among preterm than term infants, and decreases with increasing birth weight. However, asphyxia also has an important effect on mortality among normal-weight term in-
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Improving Birth Outcomes: Meeting the Challenge in the Developing World fants, who otherwise have a good chance for survival (Paul et al., 1997). The contribution of perinatal asphyxia to long-term neurodevelopmental disability in developing countries is unclear (Ellis et al., 1999). Conditions that increase the risk of asphyxia include antepartum hemorrhage, prolonged labor and/or prolonged rupture of membranes, drugs given to the mother that may depress respiration (e.g., magnesium sulfate, narcotics), cord accidents, vaginal breech deliveries, multiple gestation, pregnancy-induced hypertension, congenital anomalies, and IUGR with placental dysfunction (Chandra et al., 1997; Daga et al., 1990; Chaturvedi and Shah, 1991; Boo and Lye, 1991; Nathoo et al., 1990). In most resource-poor countries, where the vast majority of births take place at home, asphyxia is difficult to anticipate. The passage of meconium in the amniotic fluid and an abnormal fetal heart rate (bradycardia or persistent tachycardia) are the only simple ways to predict asphyxia prior to delivery in most developing countries; only about half of all cases can be detected this way (Chaturvedi and Shah, 1991). Birth injury Birth injury is a nonspecific term that includes potentially preventable and unavoidable injuries—mechanical or hypoxic-ischemic—suffered by the neonate during labor and delivery. Specific injuries include intracranial hemorrhage; blunt trauma to the liver, spleen, or other internal organs; injury to the spinal cord or peripheral nerves (the most devastating is cord transection; the most common is brachial plexus injury); and fractures to the clavicles or extremities. Although WHO has estimated that birth injuries are responsible for 11 percent of neonatal deaths worldwide (World Health Organization, 1996c), the incidence of specific injuries in most developing countries is unknown. Birth injuries can result in transient neonatal problems, long-term morbidity, and death. Predisposing factors include macrosomia, cephalopelvic disproportion, dystocia, prolonged or obstructed labor, breech presentation, and prematurity. Although injury may occur despite skilled care at delivery, some injuries result from inadequate medical knowledge or suboptimal care during labor and delivery and are therefore potentially preventable. A specific diagnosis is preferable to the use of the nonspecific term “birth injury,” especially when considering prevention strategies. Hypothermia Hypothermia, defined as a body temperature below 36.5°C, is frequent in newborns, especially those of low birth weight. Several studies have shown that without adequate care, many newborns will experience severe
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