PART IV
Additional Causes of Neonatal Mortality and Morbidity



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Improving Birth Outcomes: Meeting the Challenge in the Developing World PART IV Additional Causes of Neonatal Mortality and Morbidity

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Improving Birth Outcomes: Meeting the Challenge in the Developing World Summary of Findings: The Problem of Low Birth Weight Although reliable data on the magnitude and global distribution of low birth weight (LBW) are limited, it is estimated that approximately 16 percent of all neonates in developing countries weigh less than 2,500 grams at birth and that more than 20 million such infants are born each year. LBW may result from intrauterine growth restriction (IUGR) or preterm delivery. In developing countries, gestational age is frequently not known, which makes it difficult to distinguish between these two conditions. Nonetheless, most LBW in developing countries appears to be disproportionately due to high rates of IUGR, rather than preterm birth. Current interventions are more effective for IUGR than preterm birth. The least-developed countries have the highest rates of infant mortality and the highest rates of LBW. Since countries have been more successful in reducing infant mortality than LBW, future efforts should focus on reducing mortality in all neonates and infants regardless of their weight. Poor nutritional status is the principal cause of IUGR in developing countries. Although clinical trials have shown that increasing the food intake of pregnant women increases fetal growth, public health programs on larger populations of women have not been more than minimally effective in reducing IUGR. Malaria prophylaxis and intensive smoking cessation programs have been effective in reducing IUGR. For preterm birth, the leading causes are genitourinary infection, multiple birth, pregnancy-induced hypertension, and low prepregnancy weight. Additional risk factors include malaria and cigarette smoking. Antibiotic treatments of pregnant women appear to be effective for asymptomatic bacteriuria, are not clearly effective for bacterial vaginosis, and are not effective for trichomoniasis or chlamydia. Antihypertensive treatment has not been effictive in lowering the risks of IUGR or preterm birth. Malaria prophylaxis, intensive counseling on smoking cessation, and fish oil supplementation are effective. Where resources permit, women with documented cervical incompetence may benefit from a cerclage procedure. Two strategies for reducing neonatal and infant mortality among LBW infants that do not depend on expensive care or technology include breastfeeding and/ or use of expressed breast milk and Kangaroo mother care.

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Improving Birth Outcomes: Meeting the Challenge in the Developing World 6 The Problem of Low Birth Weight Although reliable data on the magnitude and global distribution of low birth weight (LBW, birth weight <2,500 grams) remain limited (de Onis et al., 1998a), World Health Organization estimates that more than 20 million LBW infants are born each year, affecting approximately 16 percent of all newborns in developing countries. LBW is an important risk factor for neonatal and postneonatal mortality. Moreover, LBW neonates who survive infancy are at increased risk for health, growth, and developmental problems, and those who are small for their gestational age may be predisposed to developing chronic adult disorders such as hypertension, type 2 diabetes, and heart disease. This chapter reviews the prevalence, causes, and consequences of intrauterine growth restriction (IUGR) and preterm birth in developing countries and potential interventions for preventing these two types of LBW. It should be noted that most research on IUGR and preterm birth has been conducted in developed countries and thus may have limited programmatic and policy implications for low-resource nations. This chapter therefore emphasizes the need for studies that reflect the economic, nutritional, and cultural heterogeneity among developing countries, and in particular, those that differentiate between IUGR and preterm birth. PATTERNS OF OCCURRENCE In addressing the problem of LBW, it is necessary to distinguish LBW due to restricted fetal growth (IUGR) from that due to preterm birth (deliv-

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Improving Birth Outcomes: Meeting the Challenge in the Developing World ery <37 completed weeks of gestation) (Kramer, 1987). An infant may be LBW because (s)he is either born small for gestational age (SGA), a proxy for IUGR, or is born early (preterm birth).1 The distinction depends upon the infant’s gestational age, which is not known for many LBW infants born in developing countries. To address this problem, methods have recently been developed for estimating the magnitude of IUGR and preterm delivery where conventional diagnosis is impossible. Where the prevalence of LBW is very high, it is known that most LBW infants are growth-restricted rather than preterm (Villar and Belizan, 1982; de Onis and Habicht, 1996). WHO estimates that each year, 13.7 million infants are born with LBW at term (≥37 weeks), and as many as 30 million infants are born with IUGR (many of these IUGR infants weigh more than 2,500 g and are therefore not LBW). WHO also estimates that 6.8 million infants are born both preterm and LBW; this figure underestimates the total number of preterm births occurring annually, because it excludes the large fraction of mildly preterm infants (34-36 weeks) weighing ≥2,500 g at birth. Table 6-1 summarizes data on the prevalence of LBW, IUGR, and preterm birth among countries participating in the WHO Collaborative Study of Maternal Anthropometry and Pregnancy Outcomes (World Health Organization, 1995). As seen in the table, the distribution of IUGR varies widely among developing countries. The greatest burden from this problem is borne by specific countries—those with limited resources, large populations, and high fertility rates. As many as 30-50 percent of infants born in South-Central Asia are IUGR, compared with 15-25 percent in Africa and 10-20 percent in Latin America (World Health Organization, 1995). In some developing countries, such as those on the Indian subcontinent, the majority of newborns suffer at least some degree of fetal growth restriction. Preterm birth rates vary less than IUGR rates. All of these rates should be interpreted cautiously, however, given the absence of universal birth registration and poor gestational age data in many developing countries. In areas where scales are not available to determine birth weight, other newborn anthropometric measurements can provide useful information at the individual and population levels. Studies in various settings have evaluated the use of arm, chest, and calf circumferences as surrogate measures for birth weight, and in particular for identifying LBW infants (Raman et al., 1992; World Health Organization, 1993). Currently, WHO recommends the use of chest circumference; newborns with chest circumferences 1   SGA is defined by WHO as a birth weight below the tenth percentile for gestational age based on the sex-specific reference by Williams et al. (1982). Some SGA infants are merely constitutionally small rather than truly growth-restricted. Conversely, some IUGR infants who would otherwise be constitutionally large do not meet standard criteria for SGA. Nonetheless, SGA is often used as a convenient proxy for IUGR.

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Improving Birth Outcomes: Meeting the Challenge in the Developing World TABLE 6-1 Pregnancy Outcome Among Countries Participating in WHO Collaborative Study Country LBW (% of live births) IUGR (% of live births) Preterm Birth (% of live births) Argentina 6.3 9.7 7.2 China 4.2 9.4 7.5 Colombia 16.1 17.8 15.7 Cuba 8.1 14.7 7.2 Gambia 12.1 13.5 13.5 Guatemala 12.5 25.3 15.8 India (Pune) 28.2 54.2 9.7 Indonesia 10.5 19.8 18.5 Ireland 5.6 6.9 6.2 Malawi 11.6 26.1 8.2 Myanmar 17.8 30.4 24.6 Nepal (Rural) 14.3 36.3 15.8 Sri Lanka 18.4 34.0 14.0 Thailand 9.6 17.0 21.3 United Kingdom 6.2 12.3 4.6 US/CDC (Black) 10.6 11.2 16.6 US/CDC (Hispanic) 4.8 5.8 10.2 US/CDC (White) 6.0 6.9 9.3 Vietnam 5.2 18.2 13.6   SOURCE: World Health Organization, 1995. <29 cm are designated as “highly at risk” and those with circumference ≥29 but <30 cm as “at risk” (World Health Organization, 1993). CAUSES OF IUGR AND PRETERM BIRTH The importance of a risk factor for either preterm birth or IUGR is a function of its associated relative risk, as well as the prevalence of exposure to that factor in a specific population setting (Kramer, 1987). As shown in Table 6-2, risk factors for IUGR in developing countries include low maternal prepregnancy weight or body mass index2 (BMI); low gestational weight gain; short maternal stature; pregnancy-induced hypertension; and, where prevalent, cigarette smoking and (for primiparae) malaria. Important causes of preterm delivery include genitourinary infection, multiple pregnancy, pregnancy-induced hypertension, low prepregnancy BMI, incompetent cervix, history of prior preterm birth, cigarette smoking (where prevalent), and 2   BMI is a measure of nutritional status and is calculated as (wt in kg)/(ht2 in m2).

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Improving Birth Outcomes: Meeting the Challenge in the Developing World TABLE 6-2 Determinants of IUGR and Preterm Birth in Developing Country Settings (listed in decreasing order of importance) IUGR Preterm Birth Low energy intake/gestational weight gain Low pre-pregnancy body mass index Short stature Malariaa Cigarette smokingb Primiparity Pregnancy-induced hypertension Congenital anomalies Other genetic factors Genitourinary infection Multiple birth Pregnancy-induced hypertension Low pre-pregnancy body mass index Incompetent cervix Prior preterm birth Abruptio placentae Strenuous work Cigarette smokingb aFor primiparae in malaria-endemic areas only. bAssuming a prevalence of 10-20 percent. SOURCE: Kramer and Victora, 2001. strenous physical labor (Kramer, 1987; Kramer and Victora, 2001). Although pregnancy-induced hypertension and low prepregnancy BMI are highly prevalent in developing countries, the role of genital tract infection (the leading cause of preterm birth in developed countries) remains relatively unexplored in such settings. Maternal undernutrition (characterized by low energy intake, low gestational weight gain, low prepregnancy BMI, and short stature) accounts for a large proportion of IUGR in developing countries. This is due to the high relative risk for IUGR associated with these factors, as well as their high prevalence. Mean values for these anthropometric factors are summarized in Table 6-3 for countries participating in the WHO Collaborative Study of Maternal Anthropometry and Pregnancy Outcomes (World Health Organization, 1995). Regardless of energy intake or weight gain during pregnancy, women in the lowest quartile of height have an odds ratio (OR) of 1.9 (95 percent confidence interval [CI] 1.8-2.0) of delivering an IUGR infant compared with those in the upper quartile. Similarly elevated risks are seen among those in the lowest quartile of prepregnancy BMI (OR = 1.8 [1.7-2.0]) or of weight gain (OR = 1.8 [1.5-2.2]) (World Health Organization, 1995). Adolescent girls with a low gynecological age (years after menarche) may be at particularly high risk for delivering a growth-restricted infant, possibly as a result of maternal/fetal competition for nutrients (Scholl et al., 1995), and should be considered as a high-risk subgroup in future studies. Public health professionals have reported that women in developing countries are often reluctant to increase dietary intake during pregnancy,

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Improving Birth Outcomes: Meeting the Challenge in the Developing World TABLE 6-3 Maternal Anthropometric Measures (Means) Among Countries Participating in WHO Collaborative Study Country Height (cm) Prepregnancy BMI Weight gain (kg) Argentina 157 22.4 10.8 Myanmar 151 19.8 — China 160 19.5 11.7 Colombia 155 23.3 10.1 Cuba 157 21.8 4.6 Gambia 157 19.7 6.5 Guatemala 148 20.8 7.1 India (Pune) 150 18.3 — Indonesia 149 20.2 — Ireland 158 23.7 11.0 Malawi 155 21.0 4.7 Nepal (Rural) 150 19.5 — Sri Lanka 150 18.8 — Thailand 153 20.8 8.0 UK 159 22.2 11.6 US/CDC (Black) 162 23.1 13.5 US/CDC (Hispanic) 158 23.7 12.8 US/CDC (White) 163 22.6 14.4 Vietnam 152 19.6 5.6   SOURCE: World Health Organization, 1995. and may even willfully restrict energy intake, in order to avoid delivery complications associated with a large infant (so-called “eating down”). This phenomenon has been documented in South India (Hutter, 1996), but there are few data to indicate how widespread such beliefs and practices are in developing countries, or the extent to which they can be changed through public health interventions. Clearly, more research is needed to know whether women’s reluctance to gain weight is justified and whether public health interventions can be developed that would improve fetal growth without jeopardizing maternal or fetal survival and well-being. There is no doubt that maternal dietary intake influences fetal growth and that insufficient energy intake reduces fetal size. Perhaps the most dramatic evidence for this comes from the pregnancy experiences of women during the Dutch famine of 1944-1945. When energy rations were reduced from 1700 to 700 kcal/day for women in the third trimester of pregnancy, mean birth weight decreased by more than 300 g; there was no change in the mean length of gestation (Stein et al., 1975; Susser and Stein, 1994). Few data have been published on the customary dietary intakes of pregnant women in developing countries. Available data—widely recognized as imprecise—suggest daily intakes averaging 1,500 kcal and ranging

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Improving Birth Outcomes: Meeting the Challenge in the Developing World TABLE 6-4 Reported Energy Intakes of Pregnant Women in Developing Countries Source Country Energy Intake (kcal/d) Prentice (wet season) Gambia 1,350-1,450 Oomen and Malcolm New Guinea 1,360 Gopalan India 1,400 Venkatacnalam India 1,410 Lechtig et al. Guatemala 1,500 Gebre-Medhin and Gobezie Ethiopia 1,540 Rajalakshmi Ethiopia 1,540 Mora et al. Colombia 1,620 Prentice (dry season) Gambia 1,600–1,700 Arroyave Guatemala 1,720 Maletnlema and Bavu Tanzania 1,850 Demarchi et al. Iraq 1,880 Bagchi and Bosc India 1,920 Thanangkul and Amatyakul Thailand 1,980 Mata et al. Guatemala 2,060   SOURCES: Institute of Medicine, 1992; Whitehead and Paul, 1982; Prentice, 1980. from 1,300 to 2,100 kcal/day (Table 6-4), as compared with an average of 2,000 kcal/day in industrialized countries. Whether these lower caloric intakes are inadequate is unclear, however. Women in developing countries are typically shorter and lighter than women in industrialized countries and likely perform more physical labor. Observational studies in the Gambia report negative effects on fetal growth when limited food intake and strenuous physical activity are combined (Prentice et al., 1983). An observational study from Ethiopia found that women who did not perform strenuous work (housewives with domestic help or women with sedentary jobs) gained more weight during pregnancy and had heavier infants (among those born at term) than women engaging in more physically demanding work (Tafari et al., 1980). Similarly, a Guatemalan study reported that women with three or more children at home and no household help, as well as those employed in manual work outside the home, were at significantly higher risk for delivering an IUGR infant (Launer et al., 1990). Another observational study from Zaire (Manshande et al., 1987) found a positive association between both gestational age and birth weight (among female newborns only) and a longer maternal stay in a maternity rest home; however, this result could also reflect the simple fact that women who delivered later stayed longer in the rest home. Although pregnant women in developing countries are unlikely to greatly reduce their physical activity, additional research is needed to document the work burden of women in developing countries during pregnancy (Institute of Medi-

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Improving Birth Outcomes: Meeting the Challenge in the Developing World cine, 1992). Because of the strong potential for both confounding and selection bias in observational studies of physical activity, randomized trials would be very helpful in assessing the causal impact of reductions in physical work on pregnancy outcomes in developing countries. As noted earlier, cigarette smoking is a strong risk factor for IUGR, and it is also a weaker but nonetheless important determinant of preterm birth (Kramer, 1987; Cnattingius and Haglund, 1997; Kyrklund-Blomberg and Cnattingius, 1998). Maternal smoking is an increasingly significant cause of IUGR in developing countries, rising in parallel with cigarette smoking in many areas. Table 6-5 presents the estimated prevalence of cigarette smoking among women aged 15 years or older in various regions of the world, ranging from about 26 percent of women in Eastern Europe and Central Asia to 1 percent of women in South Asia. Heavy alcohol consumption is an established risk factor for a set of dysmorphic features known as fetal alcohol syndrome, of which IUGR is one component. Because few women consume alcohol at these levels, however, the overall (population-level) public health impact on IUGR is small (Kramer, 1987). Further study of the effects of lower levels of alcohol intake on fetal growth is needed (Lundsberg et al., 1997). Malaria is a major cause of anemia and has been associated with reduced birth weight and with an elevated risk of IUGR in primiparous women, who make up 30-50 percent of pregnant women. WHO estimates that 30 million pregnancies occur each year in malaria-endemic regions of the world. In these areas, malaria constitutes a serious threat to maternal and fetal well-being. Several studies from developed countries suggest that bacterial vaginosis, and perhaps other types of genital tract infection/colonization, may initiate spontaneous preterm labor and rupture of membranes (Hillier TABLE 6-5 Prevalence of Smoking Among Women 15 Aged Years or Older by Region Region Prevalence (%) East Asia and Pacific 4 Eastern Europe and Central Asia 26 Latin America and Caribbean 21 Middle East and North Africa 5 South Asia 1 Sub-Saharan Africa 10 World 12   SOURCE: World Bank, 1999.

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Improving Birth Outcomes: Meeting the Challenge in the Developing World et al., 1995; Chaim et al., 1997). Studies from developing countries have tended to focus on the relationship between genital tract infection and fetal and/or early neonatal death (Naeye et al., 1977; Ross et al., 1982; Moyo et al., 1995; Osman et al., 1995), rather than its role in preterm birth. The maternal environment plays a far larger role in fetal growth than do genetic factors (Walton and Hammond, 1938; Brooks et al., 1995), especially in developing countries (Kramer, 1987). Congenital anomalies are strongly associated with IUGR (Khoury et al., 1988), however. Moreover, moderately high recurrence risks for IUGR within individual women (Bakketeig et al., 1986; Wolfe et al., 1987; Basso et al., 1999), intergenerational (especially mother-to-daughter) associations (Klebanoff and Yip, 1987; Klebanoff et al., 1989; Magnus et al., 1997; Klebanoff et al., 1997), concordance in twins (Clausson et al., 2000) and nontwin siblings (Johnstone and Inglis, 1974; Beaty et al., 1997), and inbreeding effects (Khoury and Cohen, 1987) all point to an important genetic contribution to fetal growth. Increased recurrence risks (Hoffman and Bakketeig, 1984; Kristensen et al., 1995; Menard et al., 1996; Mercer et al., 1999; Adams et al., 2000; Bloom et al., 2001) and intergenerational associations (Porter et al., 1997; Hennessy and Alberman, 1998) suggest that genetic factors may also play a role in preterm birth, but that role appears less important than for IUGR (Klebanoff and Yip, 1987; Klebanoff et al., 1997; Clausson et al., 2000). A short interval (<6 months) between pregnancies is often cited as a determinant of preterm birth or IUGR (Zhu et al., 1999; Shults et al., 1999), but few studies have controlled for the outcome of the previous pregnancy and the tendency of preterm birth or IUGR to repeat in subsequent pregnancies (Erickson and Bjerkedal, 1978; Klebanoff, 1999). Moreover, intervals <6 months are infrequent in developing countries where prolonged and exclusive breastfeeding are prevalent. CONSEQUENCES OF IUGR AND PRETERM BIRTH Effects on Mortality Despite the lack of reliable data on the risks of morbidity and mortality associated with IUGR and preterm delivery in developing country settings, several patterns are clear. The least-developed countries generally have the highest rates of IUGR and of infant mortality. Yet because normal-weight infants are at relatively high risk of infant death (compared with those in most developed countries), the relative risk3 (RR) associated with IUGR 3   The relative risk indicates the strength of the association between a risk factor (e.g., poor nutrition or cigarette smoking) and a health outcome (e.g., infant mortality, IUGR, or preterm birth). It is calculated by dividing the risk in the group exposed to the risk factor by the risk in the unexposed group.

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Improving Birth Outcomes: Meeting the Challenge in the Developing World (and with preterm birth) are considerably lower than in more-developed countries. Thus, for example, a 1982 study from southern Brazil reported an overall infant mortality rate of 38.1 per 1,000 live births, an IUGR rate of 9.0 percent, and a preterm birth rate of 6.3 percent. Relative risks of infant death were 4.5 for IUGR and 10.2 for preterm birth (Victora et al., 1987; Barros et al., 1992). In Bangladesh, on the other hand, a 1993-1996 study reported an infant mortality rate of 107.3 per 1,000, and IUGR and preterm birth rates of 69.2 and 17.1 percent, respectively (Arifeen, 1997). In the latter setting, the relative risks of infant death associated with IUGR and preterm birth were only 1.2 and 1.6, respectively. Industrialized countries have succeeded in reducing infant mortality without a large reduction in prevalence of LBW. Population-based data from southern Brazil (Pelotas) suggest a similar picture. Between 1982 and 1993, infant mortality fell by 50 percent (from 39 to 19 per 1,000) despite an increase in the LBW rate from 9.0 to 9.8 percent (Barros et al., 1996). Modest reductions in IUGR in developed countries appear to be attributable primarily to an increase in the size of term infants (Kessel et al., 1984; Arbuckle and Sherman, 1989; Skjaerven et al., 2000; Orskou et al., 2001; Robertson et al., 2002), which parallels increases in maternal height, prepregnancy BMI, and gestational weight gain and a reduction in maternal smoking (Kramer, 2002a,b). With the possible exception of France (Papiernik et al., 1985; Bréart et al., 1995) and Finland (Olsén et al., 1995), developed countries have not reported reductions in preterm birth. In fact, recent data from Canada (Joseph et al., 1998) and the United States (Demissie et al., 2001) show a significant increase. In Canada, part of the increase appears to be an artifactual result of the use of ultrasound (correction of earlier errors of gestational age dating based on the last menstrual period) and increased registration of births weighing <500 g. A true smaller increase in preterm birth appears to be associated with increasing obstetric intervention (induction and cesarean section), multiple gestation (secondary to treatment of infertility), and demographic changes (older maternal age, more unmarried mothers) (Joseph et al., 1998; Kramer et al., 1998; Demissie et al., 2001). Substantial reductions in neonatal and infant mortality have been achieved despite these trends in preterm birth because of improvements in the care provided to high-risk mothers and newborns, including neonatal intensive care (Richardson et al., 1998; Kalter et al., 1998; Gould et al., 2000). In some developing countries, the pattern has been similar. Brazil, for example, has witnessed continued declines in infant mortality despite a significant increase in preterm births (Silva et al., 1998; Bettiol et al., 2000). Mortality reductions associated with improved home care among both LBW and normal-birth-weight newborns in rural India are an impressive

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Improving Birth Outcomes: Meeting the Challenge in the Developing World ceeded in increasing food intake and thereby reducing the risk of IUGR. Factors other than nutrition that increase the risk of IUGR, such as pregnancy-induced hypertension, cigarette smoking, and malaria during pregnancy, can be addressed through antenatal care. As economic conditions improve in developing countries, more and better food tends to be available to pregnant women, resulting in decreased rates of IUGR. To reduce the prevalence of IUGR in low-income settings in the face of continued poverty remains a difficult challenge. REFERENCES Adair LS. 2001. Size at birth predicts age at menarche. Pediatrics 107(4):E59. Adams M, Elam-Evans L, Wilson H, Gilbertz D. 2000. Rates of and factors associated with recurrence of preterm delivery. Journal of the American Medical Association 283:1591–1596. Albertsson-Wikland K, Karlberg J. 1994. Natural growth in children born small for gestational age with and without catch-up growth. Acta Pediátrica de México 399(suppl):64–70. Alexander GR, Korenbrot CC. 1995. The role of prenatal care in preventing low birth weight. Future of Children 5:103–120. Arbuckle TE, Sherman GJ. 1989. An analysis of birth weight by gestational age in Canada. Canadian Medical Association Journal 140:157–165. Arifeen SE. 1997. Birth weight, intrauterine growth retardation and prematurity: a prospective study of infant growth and survival in the slums of Dhaka, Bangladesh. Doctor of Public Health Dissertation. Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD. Ashworth A. 1998. Effects of intrauterine growth retardation on mortality and morbidity in infants and young children. European Journal of Clinical Nutrition 52:S34–S42. Atallah AN, Hofmeyr GJ, Duley L. 2002. Calcium supplementation during pregancy for preventive hypertensive disorders and related problems (Cochrane Review). The Cochrane Library, Issue 2. Bakketeig LS, Bjerkedal T, Hoffman HJ. 1986. Small for gestational age births in successive pregnancy outcomes. Early Human Development 8:15–24. Bang AT, Bang RA, Baitule SB, Reddy MH, Deshmukh MD. 1999. Effect of home-based neonatal care and management of sepsis on neonatal mortality: field trial in rural India. Lancet 354(9194):1955–1961. Barker DJP. 1992. Fetal and Infant Origins of Adult Disease: Papers Written by the Medical Research Council Environmental Epidemiology Unit, University of Southampton. London: British Medical Journal. Barros FC, Victora CG. 1999. Increased blood pressure in adolescents who were small for gestational age at birth: a cohort study in Brazil. International Journal of Epidemiology 28:676–681. Barros FC, Huttly SR, Victora CG, Kirkwood BR, Vaughan JP. 1992. Comparison of the causes and consequences of prematurity and intrauterine growth restriction: a longitudinal study in southern Brazil. Pediatrics 90:238–244. Barros FC, Victora CG, Tomasi E, Horta BL, Menezes AMB, Cesar JA, Halpern R, Olinto MT, Post CL, Costa JD, Menezes FS, Garcia MM, Vaughan JP. 1996. Maternal and child health in Pelotas, Rio Grande do Sul, Brazil: principal conclusions from the 1982 and 1993 cohort studies [in Portuguese]. Cadernos de Saúde Pública 12(suppl 1):87-92. Available online at http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0102311X1996000500013&lng=en&nrm=iso.

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