Preventing Low Birthweight (1985)

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CHAPTER 2 Etiology and Risk Factors Despite important new research findings and improvements in the science of obstetr ics, our understanding of the basic causes of preterm labor and intrauterine growth retardation Is 1 imited . In the absence of adequate knowledge about etiology, a large body of information has developed about factors associated with low birthweight, often termed frisk factors, n because their an increased chance, or risk, of bearing a low b~rthweight infant. This chapter outlines data both on the etiology of prematurity and IUGR and on the risk factors associated with these outcomes of pregnancy. It also describes the process of risk assessment and analyzes several risk assessment systems. presence in an individual woman indicates Etiology As described in the previous chapter, the term low birthweight can refer to three often intertwined outcomes of pregnancy: preterm delivery, intrauterine fetal growth retardation (TUGR), and a combination of both. Although little is known about the various mechanisms that produce these conditions, several have been developed as a basis for further this section. ~ . Prematurity theoretical models research and are outlined in The mechanism for the initiation and maintenance of normal human labor is not known, but substantial progress has been made in understanding some of the important associated physiologic and biochemical events. ~ Information about the onset of preterm labor is more fragmentary and speculative. 2 Endocrine changes in the uteroplacental environment appear to be the principal factors leading to the development of uter ine contractions. 3 These endocrine changes involve hormones from both the mother and the fetus; cor tisol, estrogen, and progesterone appear to play ma jor roles . Much of this informal ion is based on stud ies o f sheep in which the process starts about 10 days before labor. 46

47 The first event in sheep Is an elevation in fetal cortisol, probably in response to fetal ACTH. This cortisol rise generates a decline in maternal progesterone due to the induction of 17 a-hydroxylase enzyme activity in the placenta, which increases the conversion of progesterone to dehydroxyprogesterone. 4 Progesterone withdrawal is associated with increased uterine muscle excitability, or responsiveness to electrical and hormonal stimuli. Dehydroxyproges- terone also is a precursor of the rise in maternal estrogen, which occurs a few days before the onset of labor. Estrogens increase rhythmic uterine contractions and also the responsiveness of the uterus to oxytocin e In sheep, estrogen elevation also causes a rise in prostagland~n (PGF2a) production hours before the onset of uterine activity. The combined changes in maternal hormones are thought to affect uterine muscle by enhancing myometrial excitability and the conduction of action potential. In contrast to sheep, the human hormonal changes appear to occur during the last 5 weeks of pregnancy, and evidence for fetal cortisol initiating the onset of labor is lacking. Amniotic fluid cortisol and maternal blood estrogen increase at 34 to 36 weeks of gestation. The former correlates with fetal pulmonary maturity and the latter may play a role by increasing prostaglandin production. Unlike in sheep, the role of progesterone in human labor is unclear .3 A decline In peripheral blood levels before labor has been suggested in at least one study, 5 although others have failed to confirm this finding. The presence of a fetal membrane progesterone binding protein, possibly facilitated by estrogen, indicates that a local withdrawal effect may occur. Several reports indicate that prostaglandins do play a role in human labor; they are synthesized from a fatty acid precursor In the chorioamnion and/or decidua at a time when estrogen levels are increasing.6 7 Last, increased levels of maternal oxytocin are not thought to contribute to initiating labor (although a threshold level may be important as a permissive factor), but may be necessary for the development of more intense contractions during the second stage of labor. Fetal oxytocin may play a role, however, as indicated by high concentrations of this hormone in umbilical cord blood. The way in which hormonal changes act to induce labor Is not clear .2 3 Animal studies demonstrate that low resistance myometria1 pathways (gap junctions) form dur ing labor and suggest that the structural and biochemical organization of myometrial muscle may be important in the development of contractions. The development of gap junctions under the influence of steroids and prostagland~ns and in relation to the estrogen/progesterone ratio is probably of major importance to the organization of the myometrium.8 The contraction of uterine muscle is significantly influenced by an increase in the concentration of free calcium on the myofibrils resulting from the action of prostaglandins, which counteracts progesterone-~nduced calcium binding In the sarcoplasm~c reticulum. Knowledge about the etiology, initiation, and maintenance of preterm labor is limited. 2 9 A The underlying pathophysiology is postulated on the basis of variations from the normal patterns of hormonal effects detected in animals and man or on the basis of -

48 inferences made about the possible untoward effects of certain clinical conditions on uteroplacental physiology. Observations suggest that infection, stress, hypertension, and other conditions may be associated with variations in the endocrine environment and metabolic state of the uterus and the cervix. These variations probably result from complex interactions involving progesterone, estrogen, oxytoc in, and other hormones; prostaglandins; calcium ions; adrenergic agents and receptors; catecholamines; and~uteroplacental blood flow. From the foregoing, it is clear that at this time it is not possible to identify a single etiology for premature birth.2 It is possible, however, to enumerate a variety of factors and clinical conditions that have been associated with the preterm onset of labor. This list includes, but is not limited to, abruptio placentae, amnionitis, congenital malformations, erythroblastosis fetalis, incompetent cervix, placenta previa, polyhydramnios, preeclampsia, premature rupture of membranes, severe maternal illness, multiple pregnancies, and urinary tract infections. In general, these are conditions in which there is an inability of the uterus to retain the fetus, interference with the course of the pregnancy, premature separation of the placenta, or a stimulus to effective uterine contractions before term. Several of these conditions are discussed later in the chapter as risk factors for preterm birth, although it is apparent that the distinction between a r isk factor and a causal mechanism is not always clear. Finally, in many cases of premature birth, no association with a pathologic factor can be identified. _ Intrauterine Growth Retardation (IUGR) Delay in the growth and development of the fetus has been associated with a variety of factors that can be grouped in terms of the locus of their impact: the placenta, the pregnant woman herself, the fetus, or some combination of these. In general, IUGR is associated with conditions that interfere with the circulation to and efficiency of the placenta, with the development or growth of the fetus, or with the general health and nutrition of the pregnant woman; however, for many growth-retarded infants no relevant pathogenic factors can be identified. Vascular and inf lammatory lesions of the placenta; placental separation and infarction; and decreases in placental weight, cellularity, and surface area may act alone or in combination to produce TUGR.~ It is postulated that such conditions result directly or indirectly in a reduction in the supply of nutrients to the fetus. 12 Multiple pregnancies (for example, twins or triplets) also may be associated with IUGR because the placenta may be unable to supply sufficient nutrients to multiple fetuses. Other placental conditions associated with IUGR include hemangioma of the placenta or umbilical cord and the parabiotic transfusion syndrome. Insufficient placental transfer of nutrients may be primarily related to abnormal transport across the placenta, to alterations in placental metabolism, or to changes in the uteroplacental circulation. 3

49 Certain conditions or diseases of pregnant women also are associated with IUGRe ~ 4 ~ 5 They are thought to directly or indirectly hamper delivery of nutrients or oxygen to the uteroplacental circulation, which results in an inability to maintain normal fetal growth and development. 6 The most frequent, recognized problem Is the presence of a maternal vascular disease, such as chronic hyper- tension or chronic renal disease. The duration and severity of the ~ . . ~ . . . ~ absorber are roughly refaced co One severity of the IUGR. Pregnancy- induced hypertension also can cause IUGR, but commonly the fetus is delivered before severe growth retardation develops. This condition, super imposed on chronic hypertension, often is associated either with IUGB or premature delivery of a fetus that has grown and developed normally up to the time of delivery. Severe forms of diabetes mellitus _ . . . ~ · . , also are frequently associated with vascular disease and IOGR. Sickle- cell disease may be associated with IUGR and placental lesions. Several conditions that lead to hypoxia in pregnant women have been associated with IUGR, including cyanotic heart or pulmonary disease and residence at high altitudes. 6 ~ 7 A variety of mechanisms have been postulated for the development of IUGR associated with cigarette smoking, alcohol and narcotic ingestion, and the administration of antimetabolites, but no definitive statement can be made concerning these etiologies. Similarly, the precise pathogenic mechanisms linking maternal malnutr ition and chronic illness during pregnancy to low birthweight (IUGR or prematurity) are unknown. Fetal factors implicated by association in the etiology of IUGR include chromosomal disorders, such as certain autosomal trisom~es; chronic fetal infections, such as congenital rubella, syphilis, and cytomegalovirus inclusion disease; certain congenital malformations and diseases; and radiation injury. ~8 Although a variety of pathogenic mechanisms have been suggested by these associations, the specific etiologies have not been established conclusively.~5 Finally, TUGR and prematurity occur together in about 30 percent of low birthweight cases. In some instances, both the prematur ity and the IUGR occur without a demonstrable association with a suspected pathogenic factor. In other cases, various combinations of the factors discussed above can be identified. Risk Factors: An Overview Recent research on the risk factors associated both with preterm delivery and TUGR has helped to identify possible causes of low b~rthwe~ght. Risk factor analysis also helps guide clinical practice and suggests possible prevention strategies at both the individual and population level. Unfortunately, the risk factor literature has many methodological and conceptual problems that make its interpretation cliff icult. For example, many studies analyze the relationship of a given risk factor to slow birthweight" rather than to the more specific outcomes of preterm delivery and intrauterine growth retardation; also, these studies commonly rely on estimates of gestational age, which often are

so approximate. Risk factors often are defined differently in different studies, and studies of small groups often do not produce information that can be applied to other populations, thereby hampering comparisons and pooling of data. More importantly, many studies examine risk factors as independent entities, although several factors may cluster in an individual and may be causally related. Finally, known confound- ing variables may not be controlled, and the cross-sectional design of many r isk factor studies makes it cliff icult to separate cause and effect. Such problems make it hard to reach conclusions about the magnitude of risk posed by single factors. Some of these limitations can be overcome by more careful statis- tical design and definition. Others are more difficult to correct. For example, many population-based studies must rely on data derived from birth certificates; in most states, these forms include only a limited number of risk factor variables relevant to low birthweight. Birth certificates in most states do not provide information on such factors as maternal height, weight, weight gain during pregnancy, or smok ing practices . A chart listing the principal risk factors for low birthweight is shown in Appendix A. Based on the studies noted in the appendix, in this chapter, and in Chapter 3, the chart records whether a given factor has been reported to increase the risk of preterm delivery or IUGR, or whether it has simply been linked to low birthweight. For some factor s, the char t also records attr ibutable and relative r isk values (defined In Chapter 11. Appendix A includes a mixture of factors for which the evidence of risk is strong and those for which the association with prematurity and/or IUGR is less clear. Because some studies have calculated relative or attributable risk values for certain factors , the committee explored the possibility of ranking the risks in order of magnitude to help set priorities for interventions and for further research. Unfortunately, the data do not permit such ordering. For some factors (including many of the infections), the committee was able to locate no risk values at all For many others, only a single value was located, and the committee judged this to be an inadequate data base from which to construct a ranking of magnitude of r isk . Another problem is that r isks imE,or ten t at an individual level are not always so for populations. It is also apparent that the estimates of risk vary significantly, probably due to def initional var. Cations and to differences in populations studied. The committee also concluded that, because of the numerous interrelation- ships among factors, it would be unwise to address them in a way that suggests each always has an independent influence on preterm delivery or IUGR. Even without an orderly ranking of risk, the committee found that the factors could be grouped in a way that helps to structure preventive interventions, which is the pr incipal focus of the repor t. In Table 2.1, which summarizes Appendix A, the risk factors are separated into demographic characteristics, medical risks that can be detected before conception, risks that can be detected during pregnancy, behavioral and environmental r isks, health care r isks, and a final category of factors whose role in low birthweight is still being def ined.

51 TABLE 2.1 Principal Risk Factors for Low Birthweight I. Demographic Risks A. Age (less than 17; over 34) B. Race (black) C. Low socioeconomic status D. Unmarried E. Low level of education II. Medical Risks Predating Pregnancy A. Parity (D or more than 4) B. Low weight for height C. Genitourinary anomalies/surgery O. Selected diseases such as diabetes, chronic hypertension E. Nonimmune status for selected infections such as rubella Poor obstetric history, including previous low birthwe~ght infant, multiple spontaneous abortions Maternal genetic factors (such as low maternal weight at own birth) III. Medical Risks in Current Pregnancy A. Multiple pregnancy B. Poor weight gain C. Short interpregnancy interval D. Hypotension E. Hypertension/preeclampsia/toxemia F. Selected infections such as symptomatic bacteriuria, rubella, and cytomegalovirus G. First or second trimester bleeding H. Placental problems such as placenta previa, abruptio placentae I. Hyperemesis J. Oligohydramnios/polyhydramnios R. Anemia/abnormal hemoglobin L. Iso~mmunization M. Fetal anomalies F. G. N. Incompetent cervix 0. Spontaneous premature rupture of membranes IV. V. Behavioral and Environmental Risks A. Smoking B. Poor nutritional status C. Alcohol and other substance abuse D. DES exposure and other toxic exposures, including occupa- tional hazards E. High altitude Health Care Risks A. Absent or inadequate prenatal care B. Iatrogenic prematurity VI. Evolving Concepts of Risk A. B. C. Stress, physical and psychosocial Uterine irritability Events triggering uterine contractions D. Cervical changes detected before onset of labor E. Selected infections such mycoplasma and Chlamydia trachomatis F. Inadequate plasma volume expansion G. Progesterone deficiency This grouping leads to the observation that many of the risk factors for low birthweight (categories I, II, and IV of the table) can be identified before pregnancy occurs; detection and possible intervention need not always wait until the prenatal per iod . Chapter 5 develops this theme more fully. The grouping also helps to highlight the importance of behavioral and environmental risks anu one neec~ tor interventions that go beyond medical care. The demographic measures can help to define target populations. The cluster of health care issues highlights the fact that not all r isks for low birthweight ~ ~ . _ -

~2 derive from characteristics of women themselves. And finally, the category of evolving concepts of risk suggests some important research areas for improved understanding of low birthweight. These themes appear throughout Part lI of this report. In the following detailed discussion of risk factors, the committee chose to focus on those that are widely distr ibuted throughout the population, amenable to prevention or treatment, or especially controversial. These include the demographic risk factors of race, age, and socioeconomic status; the medical and obstetr ic r Asks of hypertension/preeclampsia, diabetes, obstetric history (including previous induced abortion), multiple pregnancy, and infection; nutr ition; the behav ~ oral and environmental r isks of smok ing and alcohol use; and iatrogenic prematur ity. The committee also examines certain r isk factors that are more speculative in nature, including stress, uterine irritability, cervical changes, inadequate plasma volume expansion, and progesterone deficiency. Chapter 3, a review of state and national vital statistics data, provides additional information on some of the demographic factors and on the issues of pregnancy interval, obstetr ic history, and parity in relation to age. Chapter 6 explores another risk factor for low birthweight, absent or inadequate prenatal care. Demographic Risks The interrelationships among the major demographic risk factors are numerous and it is often difficult to determine the precise association between any single factor and low birthweight . Nonetheless , through careful statistical design, the independent effect of each is gradually be ing def ined . Race Table 2.2 shows the frequency of low birthweight for different racial and ethnic groups. The approximate 2:1 low birthweight ratio between black and nonblack ethnic groups has remained fairly constant for the past 20 years. When ~ ow birthweight infants are subdivided into those born at term and those born prematurely, blacks remain approximately twice as likely as whites to be in either category.~9 In one large but now dated study of approximately 50,000 pregnancies, black newborns were on average 233 grams lighter than the' r white counterparts .2 0 That black neonates are at high risk of low b~rthweight is unquestioned. The reason or reasons for this r isk are uncertain, however. Maternal age may account for part of the increased r isk. Teenage mashers are at high risk of low b~rthweight, and black mother are more likely to be teenagers than are mothers of other ethnic groups. In 1980, 26.5 percent of all black births were to teenagers. In contrast, 12.1 percent of white births and 15.3 percent of Hispani births were to teenagers. When black and white mothers of the same . s ic

53 TABLE 2.2 Percentage of Live Births Less Than 2,500 Grams Percent Less Than 2,500 Grams Percent Less Than 1,500 Grams White 5~7a 0.9a Black 12.5a 2.4a Chinese 4.9a o.6a Mexican-American S.3b o.9b American Indian 6.9c -- SOURCES: aNational Center for Health Statistics: Characteristics of Asian Births: United States, 1980. Prepared by S Taffel. Monthly Vital Statistics Report, Vol. 32, No. 10 (supplement). Public Health ~ Washington, D.C. : U.S. Government Printing Office, February 1984 . National Center for Health Statistics: Births of Hispanic Parentage, 1979. Prepared by SJ Ventura. Monthly Vital Statistics Report, Vol. 31, No. 2 (supplement). Public Health Service. Washington, D.C.: U.S. Government Printing Office, May 1982. CNational Center for Health Statistics: Factors Associated with Low Birthweight, 1976 . - ~ - ~ ~ ~ -- ~ ~ ~ - ~ ~ - ~ ~ ~ Series 21, No. 37. Prepared by S Taftel. Vital and Health Statistics, DHEW No. (PHS) 80-1915. Public Health Service. Washington, D.C.: U.S. Government Printing Office, April 1980. age are compared, however, blacks are at higher risk of low birthweight in every age group.22 The relationship of low birthweight to maternal age using 1976 data is shown in Table 2 .3; Appendix Table B.7 displays more recent and more detailed data on the same subject. Low level of maternal education is another r isk factor for low birthweight and is often used as a proxy for socioeconomic status. Table 2.4 shows the relationship between race, education, and low birthweight. In general, black mothers are less educated than white mothers. In 1980, 35 percent of black women who delivered live-born babies had completed less than 12 years of school, versus 20 percent of whites. At the other end of the educational spectrum, 16 percent of white mothers and 6 percent of black mothers were college graduates.2i Educational differences do not account for the racial differences in low birthweight, however. When matched for both age and education, blacks are still at higher risk of low birthweight.22 See also Appendix Table B.9. Black women are more likely than white women to delay initiation of prenatal care.2 ~ However, when receipt of prenatal care is held constant, black women are still at increased risk of delivering a low birthweight baby.2 3 A limitation of most studies in this area is the

54 TABLE 2.3 Maternal Age and Percentage of Infants Less Than 2,500 Grams, 1976 Maternal Age (year s) ite Black {percent) (percent) Less than 15 11.8 17 .1 15-19 8.1 14.7 20-24 6.0 12.6 25-29 . 5 .3 11.3 1 30-34 5.8 11.6 35-39 7.0 13.1 40-44 8.3 12.8 45 49 9.4 16.3 SOURCE: National Center for Health Statistics: Factors Associated with Low Birthweight, 1976. Prepared by S Taffel. Vital and Health Statistics, Series 21, No. 37. DHEW No. (PHS) 80-lgl5. Public Health Service. Washington, D.C.: U.S. Government Printing Office, April 1980. inability to adjust for the quality or content of prenatal care received. Chapter 6 takes up this issue in detail. To control for the effects of other variables that may be related to race, such as maternal stature, smoking, and others that are not included on birth certificates, one can look at special studies, such as the Collaborative Perinatal Study, which, though dated, remains an important and detailed survey of a number of important issues and processes in pregnancy. At the time of that project, fewer black than white women smoked, and among the smokers, white women smoked more than black women. When smoking status was controlled, blacks were still twice as likely as whites to have low birthweight infants. The height distributions of blacks and whites were almost identical, while blacks tended toward slightly higher prepregnant weights. At almost every combination of height and weight, and for almost every combination of weight and weight gain, black women were at hither risk of low birthweight Than white women. Furthermore, black women were at higher risk of low birthweight at all combinations of age and parity.20 Finally, it has been shown that women whose last infant was of low birthweight are at increased risk of low birthweight in the current pregnancy.24 Yet in the Collaborative Study, when women were stratified by whether or not their last child was low birthweight, blacks were still at increased risk of low birthweight during the

55 TABLE 2.4 Percentage of Single Live Births Less Than 2,500 Grams by Race and Educational Attainment of Mother White Maternal Educational Atta inment (year s ~ 1972 1977 (percent) (percent) Black 1972 1977 (percent) (percent) Less than 12 7 .29 6 .99 13 .59 13 .04 12 5.16 4.74 10.85 10.31 13-15 4.43 4 .09 9.76 9.41 16 or more 3.97 3.63 8.92 8.15 NOTE: Adjusted for maternal age and total birth order. Women under age 20 excluded. SOURCE: National Center for Health Statistics: Trends and variations in birth weight. Prepared by JC Rleinman. In Bealth, United States, 1981, pp. 7-13. DHHS No. (PHS) 82-1232. Public Health Service. D.C.: U.S. Government Printing Office, 1981. Washington, current pregnancy.2 ° In sugary, anthropometric and obstetric differences do not appear to account for the increased r isk of low birthweight seen in blacks. In trying to understand the nature of this r ask factor, it is worthwhile to examine the low birthweight incidence among Mexican- Americans, who are economically and sociodemographically similar in some respects to black Americans, yet have been reported to have a very low incidence of low b~rthweight. In 1979, 5.3 percent of Mexican- , . _ Amer ican newborns weighed less than 2 , 500 grams, compared with 5.7 percent of white babies and 12.8 percent of black babies.2 ~ This low incidence among Mexican-Amer loans is not readily explained. I t may be due in part to problems in data reporting. Selby et al. recently showed, for example, that the Spanish surname infant mortality rate may appear lower than it actually is because of uneven reporting of infant mortality in this population and that it is therefore an inaccurate indicator of Mexican-American health status.2s Similar data problems may skew reporting of low birthweight. The large difference between black and Mexican-American low b~rthweight rates also raises the possibili ty that cultural differences may play a role in pregnancy outcome. The very low incidence of childbear ing among unmarr fed Mexican-Amer ican women, unlike that among black women, and their different dietary practices and family structures support this notion. The forthcoming Hispanic HANES surrey should provide information on the physical stature and health-related behavior of Mexi-can-Amer icans and perhaps help to clarify the reasons for the low rate of low birt}1weight observed in Mexican-ATner~cans.

56 The issue of race and low birthweight is further complicated by the different birthweight-specif~c neonatal mortality rates of white and black infants that have been noted in a variety of populations. Black infants born at less than 2,500 grams have long been recognized to have better rates of survival in the neonatal period than low birthweight white infants of similar birthweights.2 6 2 7 The conclusion to be drawn from the complicated data on race, low birthweight, and race- and birthweight-specific mortality is that the reasons for the risk differential between white and black neonates are not well understood. The cumulative effects over time of poverty and social neglect, and the interaction of such factors with biological parameters, undoubtedly have played a role In these racial differences; other factors remain to be defined. Research should be pursued to obtain a better understanding of these issues. Age U. S. vital statistics data show that in 1978, 17 percent of all births were to teenagers, yet 24 percent of all low birthweight infants had a teenage mother.28 The relationship of low birthweight to age was shown in Table 2.3 The rate for both whites and blacks is highest at very young ages. It falls throughout the teenage years and reaches its lowest point between 25 and 29 years. Thereafter, the low birthweight rate rises slowly with increasing maternal age. Teenage mothers, particularly the youngest (under age 15), have many other risk factors that could be responsible for an adverse pregnancy outcome. First births are more likely than later births to be low-weight, and young mothers are more likely to be having their first birth. However, when only first births are examined' teenagers are still at higher risk than older mothers.22 Very young teenagers having higher-order births are a particularly higher isk group, probably in part because such births imply a short interval between pregnancies, which itself Is a risk factor for low birthweight. Thirty percent of second- and higher-order births to women less than 15 in 1978 were low b~rthweight. Fortunately, there were fewer than 350 such births in the United States in 1978. Young mothers are more likely to be black and of low socioeconomic status, to report late for prenatal care, and to be unmarrzed.28 They tend to be shorter and lighter than their older counterparts.29 Young teenagers, not being old enough to have completed their school- ing, are less educated than older women. These factors in combination appear to account for the higher rate of low birthwe~ght in teenage mothers. For example, in one study, 422 consecutive prim~gravidas less than 16 years old delivering at a hospital were matched by race to 422 primigrav~das aged 20 to 24 delivering at the same hospital. The adolescent mothers delivered infants that were 40 grams lighter on average than the young adult mothers, but the difference was not statistically significant. It was noted that the adolescents were more likely to be clinic patients, unmarried, and live In a census tract with low buying power. They were shorter and lighter as well. When

57 these factors were controlled, newborns of the adolescent mothers were actually slightly heavier than newborns of the older mothers, but again the difference was not significant.30 Such studies point to the conclusion that being young biologically is not an independent risk factor for low birthweight and that the increased risk probably comes from other attributes of teenage mothers-- such as low socioeconomic status, poor nuts itional status, and late receipt of prenatal care. They also illustrate the point made at the beginning of the section on risk factors--that many of the individual r isk measures are heavily intertwined and that only a few exert an independent ef feet. Socioeconomic Status Low socioeconomic status (SES) measured in several different ways (social class, income, education, or census tract) is clearly associated with an increased risk of low birthweight and preterm delivery. The literature suggests that at least some of the excess risk is due to other var tables that are also associated with both low social class and low birthweight. These include low maternal weight gain and short stature; certain obstetric complications such as hypertension and preeclampsia; possible infection; smoking; and access, source, and utilization of prenatal care. The effect of socioeconomic status is probably the sum of multiple factors, many of which may be affected by specific interventions. Populatzon-based studies of the role of SES in the pathogenesis of low birthweight are severely limited. Income and occupation data are not generally available, and maternal and paternal education are the only markers of SES present on most birth certificates. For young teenagers~and often for other groups as well, SES of the mother's parents probably would be more relevant than the mother's education. Some studies30 have used the mother's census tract of residence, which is available on birth certificates, to define SES. Most of the studies specifically addressing the role of SES have come from the United Kingdom, particularly the Perinatal Mortality Surveys of 1958 and 1970, in which social class is defined using the Registrar General's system of five social classes represented by Roman numerals I (most privileged) to V {least privileged). British studies may not be directly applicable to the United States. Social class in the United Kingdom is more rigidly defined than it is in the United States, and at the time some of these studies were carried out, the racial/ethnic mixture of the Br itish population was signif icantly different from that of the United States. More important, the absence of a U. S. . analogue of the National Health Service in Britain, which is intended to ensure relatively equal access to and quality of health care regardless of social class, limits the direct application of Br itish data in this area to the United States. Poverty has been cited by many as a major risk factor for low b~rthweight. This is supported by reports of a risk of preterm delivery 50 percent higher and a risk of term low birthweight delivery

58 95 percent higher among women in social Classes IV and V as compared with social classes I and II in data derived from the First British Perinatal Mortality Survey.3~ 32 Similarly, a case control study conducted in New Haven, Connecticut, reported a higher rate of preterm delivery among women who were of lower socioeconomic status.33 The risk diminished, but did not disappear, after adjusting for prepregnant weight, weight gain, alcohol and tobacco consumption, race, parity, and source of prenatal care. Mar ital status is a measure related to socioeconomic status and also is important in measuring risk of low birthweight. Of babies born In the United States in 1980, the low birthweight ratio for those whose mothers were unmarried was 11.6 percent, exactly twice as high as the ratio (5.8 percent) for babies with married mothers.34 Although an increased risk of low birthweight associated with being unmarried apparently exists in all subgroups of the population, the degree of that risk varies with age, race, and other factors. Chapter 3 explores such variations. The significance of marital status as a risk factor is underscored by the dual facts that the proportion of births occurring to unmarried women has been increasing for both white and black women for several decades and that the proportion of out-of-wedlock births to teenagers is also increasing. Investigators recently have engaged in studies attempting to understand how socioeconomic status, as determined by various measures, affects the risk of low birthweight, i.e., is the relationship a direct one or mediated by other variables known to be associated with both low socioeconomic class and low birthweight? For example, the 1970 British Mortality Survey found that mothers of Social Class I had babies that were on average 161 grams heavier than did mothers of Social Class V. Smoking was inversely correlated with class--upper-class women were less likely to smoke. Among nonsmokers, the weight difference between Social Class I and V was only 90 grams. Thirty-seven percent of the social class difference in birthweight was attributed to smoking.35 Women of low SES also were shorter than those of high SES in this study. Lower-SES mothers also were more likely to be relatively young or old, and they registered for prenatal care later than did higher-SES women. Another aspect of low socioeconomic status that may help to explain its relationship to low birthweight is derived from two separate bodies of data: the information that various classes of genital tract infections are associated with low birthweight and the possibility that these organisms may be more prevalent in low SES women. The subject of genital tract infection is discussed In more detail later in this chapter . Medical and Obstetr ic disks A large number of medical and obstetric factors have been linked to low birthweight, as noted on Table 2.1. Some can be detected before

59 pregnancy, including chronic illness in the mother and a history of obstetric problems; others, such as preeclampsia, arise only during pregnancy. This section focuses on a subset of these ma jor medical and obstetr ic r isks: hyper tens ion/preeclamps ia; d iabetes; obstetric history, including the role of previous induced abortion; multiple pregnancy; and infection. Hypertension/Preeclampsia Hypertension is the disease most often associated with fetal growth In a retardation and also can be associated with preterm delivery. study by Low and Galbraith, 27 percent of IUGR with an identifiable cause could be attributed to severe preeclampsia, chronic hypertensive vascular disease, or chronic renal disease. Infants with IUGR were born to 30 percent of patients with a diagnosis of chronic hypertension and 46 percent of patients with severe preeclampsia. 3 6 Low birthweight is strongly linked to maternal blood pressure elevation. Growth retardation of the fetus occurs with hypertension, and preterm delivery may occur (because of abruptio placentae, for examples or be undertaken to terminate the pregnancy when maternal preeclampsia or chronic hypertension are present. In a study of 2,997 normal patients registering early (before the sixteenth week) for prenatal care, Breart et al. examined the relationship between IUGR (defined as a birthweight less than fifth percentile for a given gestational age) and a variety of maternal factors. They reported risk factors for IUGR as mother's age, number of previous pregnancies, birth of a previous low birthweight infant, smoking, and elevation in diastolic blood pressure. IUGR occurred in only 3 percent of births when the diastolic blood pressure was less than 9G-mm Hg, 6 percent when it reached 90-mm Hg during pregnancy, and 16 percent when it was 110-~mn Hg or more. In their determination of the number of infants with IUGR attr ibutable to hyper tens ion, Brear t et al . used the hypothesis that, in the absence of hypertension, the observed rate would be 3.2 percent. According to this hypothes is 9 44 of 141 growth-retarded infants, 31 percent, were attr ibutable to hypertension. 3 7 Using data from the Collaborative Perinatal Study, Friedman reported on perinatal mortality rates for various levels of systolic and diastolic blood pressure, with and without proteinuria. Mortality rates were higher with elevations in blood pressure and further increased when both elevated blood pressure and proteinuria were present. 3 ~ Lin et al. reported on fetal outcome among 157 hypertensive patients whose underlying disease had been established by renal biopsy. The perinatal mortality rate was very high, 134 per 1,000. Three-quarters of the deaths were st' llb~rths; 22 percent of the infants were small for gestational age; and 40 percent were born before term. The highest perinatal mortality was among women with preeclampsia.39 The fetal growth retardation associated with maternal hypertension is currently attributed to uterine ischemia.40 _ .

60 Diabetes Maternal diabetes mellitus, most often thought of in relation to babies that are large for gestational age, is also associated with an increased risk of both preterm delivery and intrauterine growth retardation. Although these risks have decreased in recent years due to improved management of diabetes, clinicians car ing for diabetic women still consider the illness a serious threat to fetal well-be~ng . In the past, diabetes-related premature births often resulted from physician interventions to avoid unexpected intrauterine deaths. In some cases, the early delivery was appropriate; in others, errors were made in judging fetal maturity. With improved techniques to assess fetal well-being, gestational age, and pulmonary maturity, the number of unnecessary early deliveries associated with maternal diabetes has decreased.4~ Also in the past, women with insulin-dependent diabetes often suffered from polyhydr~mnios, probably related to poor control of maternal diabetes. Polyhydramnios contributed to premature labor, which also resulted in the delivery of low birthweight infants. Such polyhydramnios is unusual today; however, Roversi recently observed an increased risk of spontaneous preterm delivery in pregnant patients with diabetes and associated this with poor diabetic control even In the absence of hydramnios. 4 2 Roversi's findings have not been confirmed by other authors. Premature delivery may be necessary for pregnant women with insulin-dependent diabetes complicated by diabetic vasculopathy. In such cases, preterm delivery may be indicated because of worsening maternal retinopathy, nephropathy, or hypertension. These infants are often both premature and growth retarded. IUGR has been observed in pregnancies complicated by insulin- dependent diabetes mellitus. AS noted above, hypertension and maternal vasculopathy, particularly nephropathy, increase the risks of growth retardation and premature delivery. In a recent series by Kitzmiller, 8.8 percent of women with nephropathy were delivered before 34 weeks as compared to 4.3 percent of other women with diabetes mellitus. The incidence of growth retardation in women with diabetic nephropathy was almost 21 percent, a figure 10 t Ames higher than that for other patients with diabetes mellitus.4 3 Increasing evidence indicates that poor control of maternal diabetes during the early weeks of pregnancy may contribute to both poor fetal growth and congenital anomalies. Molsted-Pedersen, studying women with insulin-dependent diabetes, demonstrated the phenomenon of early growth delay, in which the crown-rump length of the fetus measured in the first trimester by ultrasound lags behind normal development.4 4 Such cases are typically found in mothers with poor diabetic control. The fetuses remain small throughout pregnancy, never achieving the weight seen in infants without early growth delay. Furthermore, these fetuses more often have congenital malformations.~5 Fuhrmann has shown that excellent control of maternal diabetes before and during the early weeks of pregnancy will prevent the development of malformations.4 6 The effects of such control on the phenomenon of early growth delay have not been explored.

61 At present, gestational diabetes or carbohydrate intolerance of pregnancy has not been associated with an increased risk of preterm labor in the absence of other contributing factors. Several investigators have observed that hypoglycemia measured by means of glucose tolerance testing may be related to intrauterine growth retardation. 7 Whether this hypoglycemia signals a decrease in the nutrients available to the fetus requires further research. Obstetric History The history of a woman's previous pregnancies is of prime importance in the prediction of a subsequent low birthweight infant. Based on a detailed study of the weights and gestational ages of all -births in Norway from 1967 through 1973, Bakketeig concluded that a premature first birth is the best predictor of a preterm second birth, and that growth retardation of a first birth is the most powerful predictor of growth retardation during a second pregnancy. The risk of the birth of a subsequent low birthweight infant is 2 to 5 times higher than average for mothers who have had a previous low birthweight delivery and increases with the number of prior low-weight births.24 Previous fetal and neonatal deaths also are strongly associated with preterm low birthweight; again, the risk increases as the number of previous poor fetal outcomes goes up. A history of abruptio placentae or isoimmunization is associated with increased risk of premature delivery; the large namer of preterm bir ths among previously isoimmunized women may be due in part to medically necessary early cesarean sections or inductions of labor.4 ~ 4 9 Although previous pregnancy history is the most reliable predictor of low birthweight in a current pregnancy, this information obviously is not availabi e for women who are having their f irst baby. Almost 43 percent of all U.S. births in 1980 were to primiparous women, and 87 percent of births to girls under 18 years of age were first births.50 Previous Induced Abortion The large number of legal induced abortions--about 1, 500, 000 occur annually in the United States--makes it important to assess the potential effect of induced abortion on preterm delivery and IUGR in subsequent pregnancies. Hogue et al. have completed two major reviews of studies regarding the effects of induced abortion on subsequent reproduction and the impact of particular abortion techniques on subsequent pregnancy outcomes. s 2 Most of the studies reviewed by Hog ue and her colleagues had important methodological problems, including poor control of confounding variables and conceptual difficulties in defining appropriate comparison groups. Conclusions from these review articles include the following: · The r isk of midtr imester spontaneous abortion, low birthweight, or preterm delivery ~ n a pregnancy following one that Is terminated by vacuum aspiration abortion in the first trimester (the most frequently

62 performed abortion procedure in the United States) is no greater than the risk of adverse outcome expected for a first pregnancy. _ . , _ . . . . . . . . . . ~ · Increased rlSK at 00th low olrtnwelgnt and preterm Delivery following a first trimester abortion by dilatation and curettage (D and C) under general anesthesia, as distinct from vacuum aspiration, has been reported in some countries, but not in others. Failure to adjust for confounding factors may be responsible for these discrepancies; also, abortion is illegal yet frequently performed In some of these countries, which may affect the data. · Thir teen epidemiologic studies of pregnancy outcome following more than one induced abortion have failed to disclose a clear pattern. Studies that showed multiple abortions to have adverse effects on rates of ectopic pregnancy, spontaneous abortion, preterm delivery, and low birthweight are offset by investigations that found no increase in the incidence of ectopic pregnancy, spontaneous abortion, preterm delivery, or low birthweight. The studies that demonstrated positive, significant associations between multiple induced abortions and these reproductive problems have generally focused on D and C procedures, especially those requiring relatively wide dilatation of the cervix. Studies of vacuum aspiration have involved too few women to allow for a definitive conclusion about whether that procedure also may have adverse effects when performed more than once. The world literature is too scanty to allow assessment of the effects of the D and E (dilatation and evacuation} procedure (a midtrimester abortion technique), although some concern exists that cervical dilatation of more than 12 mm (required in most D and E procedures) may lead to problems of cervical incompetence. An additional conclusion that is reasonable to draw from the two review articles of Hogue et al. is that research is needed to investigate further the relationship of induced abortion to subsequent pregnancy outcome. The fact that some studies have suggested an increased risk of preterm delivery associated with induced abortion in some c i rcumstances , coupled w, th the large number of such procedures in the United States annually, under score the importance of this research topic. Multiple Pregnancy Multiple pregnancies (such as twins or triplets) are associated both with shorter gestation and low birthweight infants. The National Center for Health Statistics reports that, in 1976, plural births were about 9 times as likely to be of low birthweight as single births.22 The overall incidence of low birthweight in 1976 was 54.3 percent for infants In plural deliveries, compared with 6.3 percent for infants in single deliveries. At full term, infants in plural deliveries were 11 times more likely to be of low birthweight than singleton deliveries. Additionally, plural deliveries are associated with more frequent low Apgar scores, breech position, and maternal complications of labor. Perinatal and neonatal mortality is greatly increased in twin pregnancies and morbidity is high among survivors.

63 Infections A variety of infections have been associated with both preterm delivery and intrauterine growth retardation. For some infectious agents , a causal role in low birthweight can be asserted; for others, the situation is less clear. This section highlights selected infections in both categor ies . Interest in the consequences of infections for both mother and fetus is heightened by the fact that many are amenable to therapy or prevention. Intrauter ine Infection of the Fetus Congenital rubella syndrome in the newborn, resulting from maternal rubella virus infection, is most often thought of in terms of the congenital anomalies that typify the condition. Growth retardation is another cardinal sign of the syndrome. Before introduction of the rubella vaccine, the incidence of fetal infection in the United States was 4 to 30 cases per 1,000 live births.5 3 Today, the major reservoir of infection has been decreased significantly by compulsory vaccination of infants and young children, and the number of congenitally infected neonates has been reduced dramatically. Nevertheless, fetal infection with rubella will continue to be seen in the United States until the cohort of women immunized in childhood predominates among women in the childbearing years. Cytomegalovirus infection, like rubella, also causes fetal growth retardation. Infection with cytomegalovirus is very common in women in the childbearing years: the incidence is 40 to 150 infected mothers per 1,000 pregnancies and 5 to 25 infected fetuses per 1 , 000 1 ive births.53 A prototype vaccine for cytomegalovirus has been developed and has resulted in slight protection in susceptible, nonpregnant volunteer s . Genitourinary Infection of the Mother Infections of the genitour inary tract also are relevant to low birthweight . Bacter fur ia is present in 3 to 8 percent of pregnant women and varies with parity; the incidence is higher in women of parity greater than three.54 Untreated or inadequately treated symptomatic urinary tract infections, which may include pyelonephritis, are known to have adverse effects on both mother and fetus, including low birthweight. Among the 55,697 pregnancies followed in the Collaborative Perinatal Study, 1,906 (3.4 percent) had symptomatic ur inary tract infections . s s The effect on the fetus of untreated asymptomatic genitour inary tract infections during pregnancy is controversial. Studies by Kass and Elder et al. in the 1960s identified a relationship between asynaptomatic maternal bacteriur ~ a and low birthweight.5 6 5 7 The results of other investigations have not consistently demonstrated this relationship. The importance of asymptomatic urinary tract infection may be the subsequent increased incidence of acute pyelonephritis, which, as noted above, is closely associated with low birthweight. In a series reviewed by Runin, 13 to 40 percent of pregnant women with asymptomatic bacteriuria who were left untreated developed overt signs

64 of urinary tract infection . Most of these symptomatic episodes were acute pyelonephritis.58 For women with asymptomatic bacteriuria who do not go on to develop acute pyelonephritis, data are not consistent as to whether treatment has a significant positive effect on birthweight or gestational age at birth.54 Asymptomatic pregnant women should be screened routinely for bacter~uria, because symptomatic urinary tract infections can be prevented in most patients by treatment of asymptomatic infections. Many tests for bacteriuria have been developed, including various chemical tests and direct cultures. Direct culture is most reliable and is available in an inexpensive and easy-t~use form, the di p slide. This technique utilizes a glass slide coated on both sides with an agar medium. The slide is dipped into the specimen of urine and incubated at room temperature, which is adequate for gram-negative bacteria, the most common cause of bacteriuria. Patients with known infections can be given dip slides and taught to culture their ur ine at home.59 Mycoplasma infection is another possible cause of low birthweight. Braun et al. found that women who were colonized in the genital tract by mycoplasma had more low birthwe~ght infants than women who were not cot canted. Multivar late analysis of the data indicated that the relationship of genital mycoplasmas to birthwe~ght was independent of other variables, such as age, race, parity, and maternal weight.60 Kass et al. reported that mycoplasma-infected pregnant women treated with a 6-week course of erythromycin in the third trimester showed a markedly reduced incidence of low birthweight.6~ These findings are consistent with results from other studies suggesting that infection due to mycoplasma or other organisms susceptible to erthromycin may play a role i n fetal development and birthweight. Additional research is needed to conf irm such f indings and explore their signif icance . Chlamyd~a trachomatis is present in the genital tracts of between 2 and 30 percent of pregnant women. In one recent study, isolation of C. trachomatis from the cervix did not predict low birthweight, prematurity, or premature rupture of the membranes. Increased risk of low birthwe~ght and premature rupture of the membranes did occur, however, among women with immunoglobulin antibody to C. trachomatis.62 Ascending primary infection due to chlamydia or mycoplasma may cause inflammation of the placenta resulting In poor diffusion of nutrients to the fetus or premature rupture of the membranes. Interest in. the association between certain pathogens and low birthweight also centers on their possible role in triggering preterm labor. Bejar et al. recently postulated that many genital bacteria, including gram-negative enteric organisms and anaerobic bacter ia, may provide a stimulus capable of prematurely initiating the biochemical sequence that leads to labor.6 3 To determine the importance of such genital infections in the outcome of pregnancy, future studies must comprehensively define the cervical and vaginal flora, and identify local and systemic immune responses.

65 These research findings, suggesting the important though complicated role of selected infections in low birthweight, led the National Institutes of Health to sponsor a research planning workshop in 1981 on maternal genitourinary infections and the outcome of pregnancy.s4 This workshop was the stimulus for the initiation of a multicenter study of the role of genitourinary infections in the etiology of low birthweight. Women colonized with specific organisms will be invited to participate in a randomized, double-blind trial of one or more antimicrobial agents or placebos from 24-26 weeks until 38 weeks of pregnancy. All women screened will be followed to determine pregnancy outcome. This study, now under way, will help to determine which organisms are associated with prematurity and IUGR, among other outcome measures, and whether antimicrobial treatment could reduce the associated incidence of low birthweight Nutrition This section focuses on a series of nutrition-related factors that have been associated with low birthweight. Some material pertains to the interval before pregnancy, some to the prenatal period. Four types of research have been used to examine the effect of nutrition during pregnancy on birth outcomes: animal studies; human war famine studies; nutritional intake/fetal outcome correlational studies; and experimental nutrition intervention studies. They all point to a common conclusion: good nutrition has a positive influence on birthweight, but the magnitude of the effect is unclear. Controlled studies of extreme nutritional deprivation of research animals has shown that consistent restriction of diet during pregnancy (such as reducing dietary intake by 50 percent) results in a marked (25 to 30 percent) decrease in litter birthweight; 6 4 6 5 however, the birthweight reduction is always less than the magnitude of the dietary reduction. Metabolic, tissue, and cellular deficits also have been found with dietary restrictions.6 6 6 ~ Restrictions of diet during the final stage of pregnancy are associated with the largest birthweight deficits.68 Findings from these animal models cannot, however, be translated directly into human terms. Fetal development consumes a much larger proportion of material resources for small primates than for humans;69 hence, small primate vulnerability to nutritional restrictions is greater. Human famines caused by war are an unfortunate analogue of the animal laboratory nutrition reduction studies and have been examined to shed light on the impact of dietary restrictions on human birth outcomes. Studies of the effects of famine on pregnancy outcome during World War II in Leningrad70 and Holland indicate that extreme, sustained nutritional deprivation can compromise pregnancy outcome and increase the incidence of low birthweight. For example, studies from Leningrad--which experienced extreme food restrictions from September 1941 to February 1942--show marked fetal impact, including a 500-gram reduction in average birthweight, a 50 percent low birthweight rate, a 41.2 percent prematurity rate, and a 32.3 percent overall infant

66 mortality rate. It should be noted, however, that the famine model of absolute deprivation may have only limited applicability to the problem of low birthweight in other settings characterized more by dietary imbalances and/or chronic caloric deprivation. Studies of nutritional intake/fetal outcome examine the correlation between maternal nutritional intake during pregnancy (using either a direct estimate or an indirect estimate based on maternal weight gain) and the birthweight of the offspring. Nutritional intake, estimated directly from dietary surveys, has proved to be inconsistently related to birth outcomes.72~75 The methodological limitations of dietary recall studies have hindered this line of research. Many cross- cultural studies show that women from poorer social classes have infants of smaller birthweight than more affluent women. While socioeconomic status factors other than poor nutrition may play a role in this relationship, restricted diets may be a key component. Poor weight gain during gestation has been widely correlated with decreased fetal weight. Data from the Collaborative Perinatal Study clearly document that increased maternal weight gain is related to larger b~rthweight, decreased low birthweight rates, and decreased neonatal mortality.20 76 Low birthweight occurred 4 times more frequently among women who gained less than 14 pounds than among those who gained 30 to 35 pounds. Consistent with such data are those of Taffel and Keppel, who recently explored the relationship between a mother 's weight gain during pregnancy and the occurrence of low birthweight by analyzing data from the 1980 National Fatality and Fetal Mortality Surveys. 7 7 They found that many groups of women known to have an increased risk of delivering a low birthweight infant also were more likely to have inadequate weight gains. For example, they found that black mothers were twice as likely as white mothers to gain less than 16 pounds during pregnancy. Mothers 3S years of age or older and teenage girls were less likely to gain at least 16 pounds, as were unmarried women, poorly educated women, and women of lower socioeconomic status. For mare led women only, the investigators also exams ned the relationship between smoking and weight gain, and found that the weight gain of nonsmokers averaged 1.3 pounds more than that of others smoking at least 11 cigarettes daily. With regard to pregnancy outcome and weight gain, the authors concluded in their analysis of births to white mothers only that, rafter controlling for mother 's prepregnant weight, age, education, per Sod of gestation, live birth order, and infant's sex, mothers who gained less than 21 pounds were still 2.3 times as likely to bear low birthweight infants as mothers who gained at least 21 pounds . Except for per iod of gestation, no other factor has this strong an impact on birthweight. Thus, it is apparent that weight gain is one of the most impor tent correlates of bir thweight" (pp. 3-4 ~ . Edger imental nuts ition supplementation studies, another source of data on nutrition and low birthweight, developed from efforts to test or clinically apply the hypothes is that increased nutr itional intake dur ing pregnancy improves bir th outcome. These studies are operationally and methodologically problematic and vary widely in quality; none is without critics. Considered together, however, they

67 indicate that supplementation can have small but positive benefits. For example, Stein et al. conclude that prenatal dietary supplements can lead to a modest {40 to 60 grams) r Use in birthweight; that a balanced calorie/protein intervention produces more positive benefits than protein-only interventions (which may be harmful, depending on the precise nature of the supplement); and that the optimal time for nutritional intervention remains to be clarified. Several of the supplementation studies specifically showed reductions in the incidence of low birthweight.~ While the results are generally positive, these studies are sobering because they indicate that extensive nutritional interventions may have only a marginal impact on pregnancy outcome. ThiS conclusion may reflect more on difficulties in assessing supplementation than on the relationship between nutr ition and pregnancy. Complicating the study of the impact of maternal nutrition on low birthweight risk is the fact that, while both nutritional status before pregnancy and nutritional intake during pregnancy influence birth- weight, they are not independent. Prepregnancy weight and weight gain during pregnancy are negatively correlated.7 9 ~ ° Substantial prepregnancy weight can compensate for low pregnancy weight gain, and vice versa. 82 A combined deficit appears to be the most detrimental.8 3 The existence of these two compensating maternal nutrition systems--prior nutr itional storage and nutritional intake--is clearly protective for the developing fetus ; it helps guarantee that adequate nutrition will be available. However, it makes analysis of the impact of nutrition on pregnancy outcome difficult. Maternal dietary inputs or absences during pregnancy do not translate directly into fetal growth or its retardation. The relationship and trade-offs between these two maternal nutrition systems remain to be fully explored. In sum, the magnitude of nutritional effects on low birthweight is not easily assessed because nutritional status is cliff icult to isolate from other socioeconomic characteristics and because of the complicated relationship between prepregnant weight and weight gain dur ing pregnancy. While researchers have found positive correlations between b~rthweight and nutr itional status, there is wide variability in the degree of these associations. A reasonable conclusion is that poor nutr itional status before pregnancy and inadequate nuts Optional consumption dur ding pregnancy appear to have a negative impact on fetal weight gain, thereby increasing the risk of low birthweight. Behavioral and Environmental Risks This section describes two factors that can contribute to low b ir thwe ight, smok ing tobacco and dr ink ing alcohol . Smoking Smok ing is one of the most impor tent preventable determinants of low birthweight in the United States.84 In 1979, the Surgeon General

68 of the United States warned clearly of the risks to infants of mothers who smoke cigarettes: "Smoking slows fetal growth, doubles the chance of low birthweight and increases the risk of stillbirth. Recent studies suggest that smoking may be a significant contributing factor in 20 to 40 percent of low weight infants born in the United States and Canada. n ~ 5 In so stating, the Surgeon General was summarizing a body of literature on smoking and pregnancy that is by now extensive. In 1957, Simpson first reported that infants of women who smoked dur ing gestation were of significantly lower weight than the infants of comparable nonsmokers.8 6 Since that time, more than 50 studies have been published, involving more than half a million births from a broad spectrum of ethnic groups and nationalities, documenting the adverse effect of maternal smoking on birthweight. ~ 7 After surveying many of these studies, Stein et al. concluded ". . . Smoking during pregnancy is associated with a reduction in birthwe~ght of offspring in the range of 150-250 grams. The relation of number of cigarettes smoked to varying decrements in birthweight is less well def ined. Yet smok ing, def fined grossly by presence or absence, or somewhat more f inely in terms of half-packs, has maintained a relatively constant relationship to birthweight over a per Sod of at least 20 years. This constancy has persisted in spite of the reported reduction in the average tar arid nicotine yields of the cigarettes marketed. Thus, for reasons that are not yet fully understood, cigarette smoking retards intrauter ine growth and it decreases mean gestation by about 1 to 2 days.... The association between cigarette smoking and intrauterine growth, over time, through the social classes, over age groups, ethnic groups, and geographic locations remains f irm and stable. This consistency brings a weight and certainty to the public health message for reproduction as it does for cancer of the lung. For epidemiologists, consistency is one of the most powerful or iter ia for judging cause. In cancer of the lung, the processes are also poorly understood, but the label on the cigarette pack is correct. The label should also read that cigarette smok ing could be harmful to the fetus" (p. 1154 ~ . ~ ~ The r isk of smoking for low birthweight is of heightened concern because of the prevalence of smok ing among pregnant women . Although exact rates of smoking dur ing pregnancy are not known, a 1980 Surgeon General's report estimated that 20 to 30 percent of pregnant women in the United States smoke. ~ 9 Such estimates are consistent with f igures on smoking rates for U. S . women of childbear ing age. In 1980, about a third of women of childbear ing age (17 to 39 years of age) smoked.90 Although smoking is less prevalent among teenagers than among older individuals, it is troublesome to note that teenage girls are more likely to smoke than teenage boys; In 1979, 26 percent of girls 17 to 18 years old smoked, compared to 19 percent of boys in the sane age group.89

69 Alcohol The data on maternal alcohol consumption and its association with low birthweight are not as uniform as for smoking. It is reasonably certain that pregnant women who drink heavily are at risk of delivering a baby with fetal alcohol syndrome--characterized by IUGR and a variety of congenital abnormalities.9~ With regard to moderate or even light alcohol use, however, the data are less clear. Stein et al. recently reviewed a large body of studies on the role of alcohol use in IUGR and concluded that it is "unlikely that regular drinking of fewer than 2 dr inks daily either before or dur ing pregnancy is an important determinant of intrauterine growth retardation" (p. 1156~.~8 In contrast, two other recent studies suggest that moderate use of alcohol during pregnancy can compromise birthweight. Mills et al. reported on a prospective study of more than 30,000 pregnancies in women who were part of a health maintenance organization; the study demonstrated a significant increase in the risk of IUGR associated with drinking one to two drinks per day even after adjusting for other important risk factors, such as maternal age, race, education, marital status, maternal weight for height, smoking, parity, prior reproductive history, hypertension, and preeclamps~a.9 2 An unpublished report by Graves et al., based on an analysis of the data from the 1980 National Natality and Fetal Mortality Surveys, also demonstrated a significant increase in the rate of low birthweight in married women drinking one or more drinks per day during pregnancy. Again, the researchers controlled for many other variables known to be associated with the rate of low birthweight, including maternal age and race, family income, maternal prepregnant weight and weight gain, maternal and paternal weight-to-height ratios, and maternal smoking.93 Because moderate alcohol use during pregnancy may pose added risks to fetal development, common sense suggests avoiding both heavy and moderate alcohol use in pregnancy. Consistent with this cautionary stance, in 1981 the Surgeon General advised pregnant women not to drink alcoholic beverages. Iatrogen~c Risks Iatrogenic prematurity refers to the birth of a physiologically immature and/or low-weight infant who is delivered prematurely as a result of medical intervention. Justifiable iatrogenic prematurity may result from cesarean sections performed before term to avoid even more serious consequences for the mother or the infant. Some cases of iatrogenic prematur ity are accidental, however , resulting either from mistiming of induced labor or nonemergency cesarean section, or from unintentional induction of labor during an oxytocin challenge test or some other procedure. Accidental iatrogenic prematur ity is probably most frequently associated with an overestimation of gestational age by physicians responsible for scheduling repeat cesarean sections. Three studies conducted in the early and mid-1970s found that from 4 to 8 percent of infants admitted to neonatal intensive care units in

70 three different cities had been born prematurely as a result of labor inductions and electively timed cesarean sections.9 4 - 9 6 In one of these studies, 12 percent of infants admitted to a neonatal intensive care unit over a 6-month period with respiratory distress syndrome (RDS}, which is often associated with premature birth, were born after elective interventzon.9 4 In another study, a full third of cases of RDS in infants seen in a neonatal intensive care nursery, also over a 6-month per Mod, were judged to be the result of inappropriate obstetric intervention.97 It is difficult to estimate the extent of the problem in more recent years, however. In 1981, Bowers et al. described 71 cases of newborn RDS following repeat cesarean sections. Although 29 (41 percent) were judged to be at term on the basis of both physical examination and b~rthweight, at least one critical element of prenatal gestational-age documentation (the date at which unamplified fetal heart tones were first heard) was missing in all 71 cases. Other important pieces of data that were often missing included documentation of the date of quickening, evidence of a positive pregnancy test, and a record of uter fine size at the first prenatal visit. In 37 percent of the cases, the recorded uterine fundal height measurement was inconsistent with the date of the last menstrual period, but the inconsistency was ignored. Although ultrasound was used to measure the fetal head in 32 cases, the resulting information was not used correctly in 20 cases.98 Such findings are unfortunate, given that it is increasingly possible to prevent a large portion of Pathogenic prematurity by combining accurate prenatal assessment of gestational age with prenatal fetal maturity testing. Taffle et al. describe a study of 252 consecutive, elective, repeat cesarean sections performed at a Naval medical center, in which no cases of iatrogenic prematurity occurred. The authors attribute these results to an obstetric care setting in which the scheduling of repeat sections was controlled by rigid adherence to a clearly defined process of assessing fetal age and maturity.99 Iatrogenic prematurity also could be reduced by decreasing the persistently high rate of both reseat and urimarv _ _ , ~ cesarean sections. Quilligan estimates that the total number of such operations could be reduced by more than ha~f.~°° Evolving Concepts of Risk This section explores several risk factors more speculative in nature than those described earlier. They are currently being studied in a variety of settings and may over time evolve into important predictors of low birthweight. These factors are stress; uterine irritability and the notion of "triggering factors.; certain cervical changes; inadequate plasma volume expansion; and progesterone deficiency.

71 Stress The relationship between socioeconomic status and low birthweight suggests that a woman's response to and interaction with her environment may have an impact on pregnancy outcome. This concept has led to a variety of studies on the potential effects of certain environmental characteristics. It may be, for example, that payer ty is a risk factor for low birthweight partially because of the high levels of stress associated with being poor; the same might be true for the risk factor of being unmarried. Currently, two types of factors are receiving considerable attention: physical stress and fatigue, particularly as related to work during pregnancy; and psychological distress resulting from maternal attitudes toward the pregnancy or from external stressors in the environment. Physical Stress Numerous studies have examined the risks for both preterm delivery and lUGR posed by physical stress, especially in the work place. The literature in this area is hard to interpret for many reasons. Problems of definition are common, issues of physical and psychosocial stress are often intertwined, and the quality of the study methods varies. Moreover, the studies imply that employment may be more physically stressful than being unemployed--a questionable perspective for some employed pregnant women with young children at home. Studies on employment and pregnancy outcome are further limited by the many differences between working women as a group and unemployed women. The Cardiff Birth Survey clearly documents that women who decide to keep working during pregnancy differ in age and health status from those who do not.~°~ Naeye et al. analyzed data on 7,722 births from the Collaborative Perinatal Study (the data for which were collected between 1959 and 1966) to determine effects of maternal work status during pregnancy. They found that although gestations were not shortened, the newborns of women who worked in the third trimester weighed an average of 150 to 400 grams less than the newborns of nonemployed mothers. The growth retardation was greatest among infants whose mothers' jobs required standing much of the time and increased as the mothers worked further into the third trimester. Low prepregnancy weight, poor weight gain during pregnancy, and hypertension were also associated with lower birthweights.~ 02 A similar association between prematurity and some occupational categories was noted by Mamelle et al.~03 In contrast, the Card~ff Birth Survey found virtually no ill-effects associated with employment. In fact, a significantly higher proportion of births were growth retarded in the unemployed groups than in the employed groups, even after controlling for adverse medical and obstetric history.~°~ In general, the work-related studies and a major study of overall physical stress by Papiernik et al.~04 indicate that there is probably some association between low birthweight, manifested as both IUGR and prematurity, and activities that require long periods of standing or other substantial amounts of physical stress. It cannot be concluded, however, that maternal employment as such increases the risk of low birthweight.

72 Psvcholoa i cal Stress Historically, concern about the effect of psychological stress emerged in the context of studies exploring the normal emotional changes that occur as a woman faces the many changes occasioned by pregnancy and motherhood.~°S More recently, researchers have addressed the effect of maternal stress on pregnancy outcome. The results have been mixed. In some studies, the proportion of women with evidence of adverse psychological states has been found to be higher among women who had deliver ies considered "abnormal" by their obstetricians ° 6 - ~ ~ 3; this effect appeared to depend partly on Me timing of the stress in relation to delivery ~ 2 and on the presence of psychosocial supports. ~ ~ 3 In other studies, however, no association has been found between increased stress and adverse pregnancy outcome; for example, no differences in outcome were noted between women refused abortions and comparison groups.~4~~6 Many studies have noted a relationship between stress and conditions that increase the r isk of IUGR and preterm labor, such as toxemia, but data supporting a specific relationship between maternal psychological distress and low bir thweight are not strong. Other adverse outcomes have been associated with maternal psychosocial distress, including per inatal death and congenital anomalies, fetal distress, ~ ~ ~ neonatal motor iounatur ity, ~ ° 7 and depressed Apgar scores (this particular association was not found by another groups. However, only one study has linked psychosocial stress with premature labor; researchers found higher stressful event scores among women in preterm labor as compared to those in labor at term. ~ ~ 7 In summary, numerous studies suggest a link between maternal psychological stress and adverse pregnancy outcome generally, but the impact of stress on low birthweight specifically needs further investigation . Manv studies suf fer from a ser ions methodoloa ical flaw--the stress is ascertained after the event (the study by NUckolls et ally 3 iS an important exception). Such retrospective studies introduce the potential of recall bias, which could increase the reporting of stress and stressful events among mothers with adverse outcomes. The studies are also difficult to interpret in the aggregate because concepts and definitions of stress vary significantly. Sample sizes, too, are often very small, which makes it difficult to isolate the specific outcome of low birthweight; all poor outcomes are usually combined into a s ingle measure . Also, the studies usually fail to control for smok ing behavior, a major correlate of low b~rthweight . , ~ . . . Uter ine Irr Stability The precise role that uterine irritability plays in the paths physiology of preterm labor is not well understood. The contractile state of the uterus is modified by various physiologic and endocrine states. This subject was recently reviewed by Hobel.~4 The nature' history or the evolution of uter ine activity and its sensitivity to oxytocin has been studied by Calderyo-Barcia.~20 Before 30 weeks, the uterus shows minimal spontaneous uterine activity. Between 30

73 weeks and term, however, the uterus exhibits more spontaneous activity and is more sensitive to oxytocin. The notion that uterine activity might be a risk factor for preterm labor was first suggested by Wood et al. in 1965.~2~ In 1981, Suranyi and Szomolya published evidence suggesting that contractil ity in the subclinical phase of preterm labor could be a reliable method for predicting the onset of preterm labor . ~ 2 2 Recently Tamby Raja et al . studied the diurnal rhythm of uter ine activity in normal, lower isk pregnancies and found, as noted above, minimal activity before 30 weeks. ~ 2 3 Between 30 and 36 weeks, however, women had mild spontaneous uter ine contract ~ ons, pr imar fly in the morning and afternoon from 7 A.M. until 5 P.M. During the remainder of the 24-hour cycle, the uterus was quiet at this gestational stage. Between 36 weeks and term, mild uter ine contractions began to be detected from 6 P.M. to midnight as well, although from midnight until 6 A.M. the uterus remained quiet as it was at earlier gestational stages. By contrast, patients at high risk for preterm labor were found to have uterine activity throughout the 24-hour cycle in this latter par t of pregnancy. Such studies suggest that excessive uter ine activity may be a component of the events leading up to true preterm labor. Assessing the extent of uter ine activity could be a part of the surveillance of patients at r isk for preterm labor . Closely related to assessing uterine activity is the possibility that certain events can "trigger" uterine contractions, which in turn can lead to preterm labor. For example, all of the prematurity prevention programs described in Appendix C include patient education for higher isk women concerning the concept of tr igger ing factors, self-detection of uter ine contractions, and the advisability of avoiding events or situations that appear to stimulate such contractions. Program personnel describe wide variation in the types of events that women report as stimulating uterine contractions--sexual activity, climbing several flights of stairs, lifting heavy loads, and others . Sexual intercourse also has been discussed as a risk factor for preterm labor because of the pass ibil ity that coitus can be a means of transfers ing pathogenic bacter ia to the ur inary tract or to the cervical opening and thus to the amniotic membranes . A1SO, suggested that absorbed seminal prostaglandins may initiate contractions. Research in all these areas is inconclusive, Cerv ical Changes ~ t has been uter fine however . ~ 2 4 Several studies have suggested that cervical assessment may be another means to detect heightened risk for preterm labor. For example, part of Papiernik's and Creasy's approach to identifying women at risk of preterm delivery, described in Appendix C, involves serial pelvic exams to evaluate the cervix--pr imar fly its shortness and state of dilatation. ~ ° 4 ~ s ~ The station of the presenting part and thinness of the lower uterine segment also may be important. A, ~ ,

74 The value of cervical assessment in later pregnancy may lie in ability to identify changes that occur several days, and sometimes its even weeks before preterm labor. These changes may be early signs of risk and, if identified, could lead to interventions designed to prevent further changes within the cervix. A second reason for identifying early changes is that once the cervix opens, the uterine environment is exposed to ascending pathogenic bacteria and the risk of infection increases. There may, however, be a potential risk In the repeated pelvic exams required to monitor cervical changes. A recent prospective study by Lenihan of patients at term showed a significant relationship between weekly pelvic exams and premature rupture of the membranes.) 2 5 At present, no data exist on the risks of frequent pelvic exams in patients prior to term. The technique of the pelvic exam may be important, an issue not described in the Lenihan study. Another potential problem associated with cervical assessment is that the identification of a short cervix, either by ultrasound or by pelvic exam, increases the likelihood of the physician initiating some form of intervention, including cervical cerclage, which itself carries risks. Recently, concern has been expressed about the marked increase in the use of cervical cerclage in some developed countries. This concern has led to the initiation of prospective randomized trials in both France and Great Britain.~26 These studies, when complete, should identify the types of patients, other than those with classical incompetent cervix, who might benefit from this more aggressive form of therapy. Inadequate Plasma Volume Expansion Plasma volume increases at least 30 percent during pregnancy.~27 Most of this increase occurs before 24 weeks gestation. Because plasma volume increases more than red blood cell volume between the twenty- fourth and thirty-fourth weeks, normal pregnant women generally have lowered hematocr its. Failure to expand blood volume has been associated with an increased risk of pregnancy-induced hypertension, IUGR, and preterm labor. Goodlin et al. found significantly lower maternal plasma volumes in all three of the above disorders.] 2 8 They also showed that therapy for preterm labor--betamimetics, bedrest, hydration, and plasma volume expansion with 5 percent albumin--increased plasma volume at least 15 percent. Prospective randomized trials are needed to determine whether plasma volume expansion prevents preterm labor in women with low plasma volumes. Progesterone Deficiency Progesterone, a key hormone for the maintenance of pregnancy, preserves uterine quiescence. It helps to stabilize the physiologic properties of both the muscle cell wallow and fetal membranes, and prevents the release of arachidonic acid, a precursor of prosta-

75 glandins. ~ 3 0 A few studies have suggested that progesterone deficiency and decreasing progesterone levels are associated with pretermit 3 ~ - ~ 3 3 and term labor ,s respectively; this possible association remains controversial, however. In 1977, Cousins et al. reported significantly lower maternal serum progesterone levels in patients in preterm labor when compared to normal controls.~33 At about the same time, Csapo and Herezeg also reported significantly lower progesterone concentrations in patients with preterm labor. 3 ~ These investigators reported that maternal progesterone concentrations increased in patients successfully treated with isoxsupr ine hydrochlor ice, a labor-suppressing agent . Neither group, however, measured progesterone before preterm labor to determine whether the low progesterone levels were a consequence of preterm labor or a factor predictive of preterm labor. There are limited data to suggest that low progesterone levels precede preterm labor.~32 134 Studies to show the efficacy of progestational agents In the prevention of preterm labor are limited. ~ 3 2 ~ 3 5 - ~ 3 ? Potential r isks to the fetus associated with the use of progestational agents have led the FDA to recommend that there is no justif ication for using proges~ogens in threatened abortion or as a pregnancy test in the f irst 4 months of pregnancy. ~ 3 ~ The r isks of these agents after 20 weeks Is unknown. Risk Assessment In an effort to use r isk factor data to help structure prenatal care for pregnant women, researchers have developed a variety of techniques to measure risk status--that is, to distinguish women at high risk of preterm.labor or IUGR from women at low risk. The following section discusses the evolving science of risk assessment and includes a critical review of several risk assessment instruments. Risk management techniques originated in 1962 with the development of "risk registers" In England; however, until 1969, little appeared in the obstetric literature. A detailed review of the literature since that time indicates that much of the work to date has been directed toward predicting perinatal and neonatal mortality.) 3 9 - ~ 4 ~ Relatively less work has been devoted to predicting low birthweight. Papiernik was the fir st to report on a method developed solely for identifying the patient at risk for preterm labor. 4 2 ~ 4 3 Other European work has focused on the development of a screening system and program to prevent low birthweight related to both prematurity and IDGR.~ 4 4 In the United States, these approaches have been modified and augmented In an effor t to improve their predictive power . Several researchers have attempted to incorporate biochemical, ultrasound, and other diagnostic information into more sophisticated mathematical models. 4 5 - ~ 4 ~ Others have tr fed to simplify the content of the r isk instruments while retaining their predictive value. ~ 4 9 iso However, both the difficulty of such an undertaking, especially for distingu~sh- ing women at r isk for intrauter ine growth retardation, and the need for further improvement continue to receive attention. ~ s ~ ~ ~ s 3

76 Screening for Obstetric Risk The design of a risk assessment instrument begins with decisions about what outcome is to be predicted and which factors are to be reviewed to predict risk. In obstetrics, the factors generally constitute a subset of the risk factors listed in Table 2.1, selected on the basis of the literature or the experience of the designer. The factors are given numerical weights and grouped in some fashion to provide a score. This score is used to assess the probability that an individual woman is at risk of, for example, a preterm delivery. The basis of selection of the r isk factors, the determination of a numerical weight for each factor, and the cut-off point indicating "high risk. are relatively controversial.~5 4 - ~ 5 7 Moreover, the scores are statements of probability and cannot be viewed as definitive predictors for a specific woman. A1SO, the instruments achieve standardization in the characterization of risk at the expense of an appreciation of the dynamic nature of the individual course. Nonethe- less, these instruments have been shown to be useful clinical tools. Understanding the use of risk assessment instruments requires an appreciation of certain screening principles. First, accuracy in the prediction of risk is defined In terms of sensitivity (the ability of the instrument to identify those with adverse outcomes such as low birthweight) and specificity (the ability to detect those without adverse outcomes) (Table 2.51. These are called true pos itives ~ a) and true negatives (d), respectively. Those who score in the high-risk range but do not have an adverse outcome are labelled false positives {b); those scar ing in the lower isk range but exper fencing adverse outcomes are called false negatives (c) . For any instrument, the sensitivity and specificity can be changed by selecting a different cut-off point to designate ~high-risk,. but this always involves a trade-off. Selecting a lower score (i.e., fewer risk factors) will increase the sensitivity, but more false positives also will be identified (i.e., fewer will be identified as true negatives). The converse occurs when a higher cut-off point is selected, i.e., an increase in specificity (true negatives) but a decrease in sensitivity (true positives). A high sensitivity (i.e., a high rate of detecting those with adverse outcomes) appears desirable until the implications of large numbers of false positives are appreciated. These implications are best conveyed by an examination of the proportion of those predicted at high risk who eventually experience the adverse outcome, the predictive value positive (Paid. A low PV+ indicates that many more women are predicted to be at high risk than actually have adverse outcomes. This overd~agnosis will affect the cost of services, because women classified as high risk will receive special (and often more expensive) care, but do not develop the problems being predicted by the risk assessment. In addition, women misclassified as high risk may exper fence complications of unnecessary diagnostic and therapeutic procedures. The risk of overdiagnos~s is dependent on the prevalence of the adverse outcome in the population. For a risk assessment

77 TABLE 2.5 Validity Measures of Screening Tests Adver se Outcomea Risk Status Present Absent Total H igh Risk (a) (b) (Ahab) Low Risk (c) (d) (cad) Total ( a+c ) tb+d) ( a~b+c+d) Sensitiv ity = a/a+c Specif ic ity = d/b+db Predictive Value + (of high r isk) Predictive Value - (of low risk) = a/albC = d/c+dC "Preterm labor or intrauter ine growth. properties of instrument, not dependent on nature of population. CDepends on prevalence of outcome in population. instrument of a given sensitivity and specificity, the lower the prevalence of the adverse outcome in the population, the more likely it is that a woman classified as high risk will be a false positive. Instruments designed to predict low birthweight and preterm birth are summarized in Table 2.6. To illustrate the points above, the sensitivity and specificity of these instruments and their PV+ in different populations are summarized in Table 2.7. The sensitivity values extend over a wide range, but the major ity correctly identify as high ~ isk approximately 65 percent or more of those with eventual adverse outcomes The c~nci~i~i-`r is higher be_ ~~;~~~^~ ~~~~ than IS more by ~ A, ~ _2 _~ ~& _~= Ivy 111~ ~~~L VU— W=lil~ll for pr imiparous women, probably because pr for obstetr ic exper fence such a strong predictor of subsequent obstetr ic r isk . In general, than half of women with low birthweight infants will be identified these instruments. This also means, however, clinicians must continue to expect the occurrence of low-weight births among women determined to be at low r isk of such an outcome. Even using some of the better risk-assessment systems, several women who are judged to be h igh r isk but eventually turn out not to be so will receive special care for every truly high-risk woman identified with a risk assessment instrument. Although this may seen undesirable, the alternative must be considered. As shown in the Table 2.7, the proportion with low birthweight or preterm labor in the populations studied ranges from 2 to 8 percent. To reduce the risk of adverse outcome without some form of risk assessment would require special services for all.

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82 Strengths and Limitations Well-constructed risk assessment instruments have the potential to reduce the misdiagnosis of both IUGR and preterm labor and are useful adjuncts to clinical judgment in evaluating the risk of low birthweight.~45 In addition, they offer the possibility of grouping risk factors by their modifiability or preventability, thereby suggesting potential interventions. The effects of such an approach have been explored by at least two investigators. 4 0 ~ ~ 4 Finally, risk assessment systems encourage more appropriate referrals for care and more reasonable expenditures of resources for the management of preterm birth.~34 use less The limitations also must be recognized. First, because the performance of a risk assessment instrument is to some extent dependent on the prevalence of adverse outcome In a population, it Is unlikely to produce the same results in every setting. Second, the instrument cannot be used in a rote manner as a substitute for high-quality professional care. Errors in classif icat~on occur, so some degree of continued monitoring of low-risk women is required, as well as attention to the more generic needs of all pregnant women for support and education to make pregnancy a positive experience and to enhance their ability to care for ~ new child. Improving Risk Assessment Fur ther ref inement of our knowledge about the etiology, natural history, and epidemiology of low birthweight, and about associated risk factors, will contr ibute to improvements In the science of risk assessment. Information is needed to permit a clearer delineation of which outcomes to predict, which factors to monitor, and which weights to assign to individual factors. Other ways to strengthen the impact of r isk assessment include establishing more uniform outcome definitions to allow comparisons among risk assessment instruments; testing various risk assessment methods in the same population; testing risk assessment instruments on populations other than those contributing to their development (Papiern~k has shown a clear drop in the correlation of risk value and outcome between the group from which a risk assessment instrument was developed and a test grouping; and designing systems to permit some degree of individualization of the risk score, if such systems are not too complicated to use. Finally, users of risk assessment instruments should receive more explanation of the utility and expectations of risk scores and of the probabilities they represent. Conclusions The risk factor literature suggests several conclusions. A variety of factors are clearly and consistently linked to low birthweight and can be used to help define high-risk groups and to target resources for

83 intervention. Important ones listed at the beginning of the chapter include several sociodemographic factors; various medical and obstetric risks; certain behavioral, environmental, and occupational factors; and selected risks based in health care practices. It Is also apparent that risks for low birthweight are widely distributed throughout the population and that a substantial amount of low birthweight will continue to occur outside of groups defined as high risk. This fact highlights the need for greater understanding of r isk and etiology; it should not be used to minimize the value of using existing r isk information for targeting interventions. Risk factor data also suggest another conclusion. Many of the established risk factors are amenable to prevention or therapy, and of these, many can be recognized before pregnancy occurs. Smoking Is perhaps the best example. Other examples include poor nutr itional status, certain chronic illnesses, and susceptibility to infections such as rubella. Even demographic risk factors such as age can be managed before conception, for instance, by avoiding pregnancy at extremes of the reproductive age span; and the risks posed by high parity and brief interval between pregnancies can be decreased through family planning. Another major conclusion that emerges from the literature on the to answer very long list of questions. Our understanding of the basic causes of preterm labor and IUGR is seriously inadequate. A 1983 workshop sponsored by the National Institute of Child Health and Human Developments 6 ~ outlined promising research areas pertinent to IUGR, and a recent review article by Huezar and Naftolint touches on a etiology of low birthweight is that more research is needed number of topics that should be studied to provide a better under- standing of the normal onset of labor and of the pathogenesis and process of preterm labor. In the absence of more complete information about basic causal mechanisms, efforts to prevent low birthweight will remain ~ zmited. Factors whose role in low birthweight are uncertain need additional analys is . Stress, for example, may be a s ignif icant r isk factor for both IU=R and preterm labor, but more research is needed to understand the nature and magnitude of this risk. Other possibilities that merit study include, for example, the role of selected genitour inary infections in low birthweight, the natural history of uterine activity throughout pregnancy (to determine the value of uterine activity assessment as an index in evaluating the risk of preterm labor), and related topics mentioned in the section on evolving concepts of risk. Well-established risk factors also require more attention. For some factors, such as race, research is needed to understand why the risk exerts its effect. For others, such as alcohol, the magnitude of risk at various levels of consumption needs to be better defined. For both known and less-certain r isk factors, efforts should be made to distinguish risks for very low birthweight (1,500 grams or less) from risks for moderately low birthweight (1,500 to 2,500 grams) at various gestational ages. As Chapter 3 suggests, the incidence trends and sequelae of these two classes of low birthweight differ. Relating individual r isk factors to more ref. ined measures of low birthweight should provide clues to both cause and prevention.

84 The committee's review of r isk assessment systems and instruments suggests that they are helpful in distinguishing between h ~ gh- and low-risk women. The significant incidence of low birthweight deliveries in low-risk individuals and groups suggests, however, that additional research is needed to improve the predictive capabil ity of these systems. It also indicates that clinicians must be alert to the possibility of low birthweight even in pregnant women judged to be at low r isk of such an outcome. Refer ences 1. Husaar G and Naftolin F: The myometrium and uterine cervix in normal and preterm labor . N . Engl . J . Med . 311: 571-581, 1984 . 2 . Bar den TP: Premature labor. In Neonatal-Perinatal Medicine, edited by AA Fanaroff and RJ Martins, pp. 139-144. St. Louis: The C.V. Mosby Co., 1983. 3. Speroff L, Glass RH, and Rase NG, eds.: Clinical Gynecologic Endocrinology and Infertility, 3rd Edition, pp. 316-322. Baltimore/London: Williams and Wilkins, 1983. 4. Liggins GC: Premature delivery of foetal lambs infused with ghicocorticoids. J. Endocr inol. 45: 515-523, 1969 . 5. Turnbull AC, Flint APE, Jeremy JY, Patten PT, verse MJNC, and Anderson ABM: Significant fall in progesterone and rise in estradiol levels in human peripheral plasma before onset of labour . Lancet I :101-104, 1974 . 6. Nosy ~ and Liggins GC: Role of prostaglandins, prostacyclin and thromboxanes in the physiologic control of the uterus and in per tur ition. Seminar Perinatol. 4:45-66, 1980. 7. Challis JRG and Mitchell F: Hormonal control of preterm and term partur itzon. Seminar Perinatol. S: 192-202, 1981. 8. Car sten ME: Calcium accumulation by human uterine microsomal preparations: Effects of progesterone and ocytocin. Am. J. Obstet. Gynecol. 133:598-601, 1979. 9. Tamby Raja RL, Anderson ABM, and Turnbull AC: Endocrine changes in premature labor. Br. Med. J. 4:67-71, 1974. 10. Cr easy RR and Liggins GC: Actiology and management of preterm labour. In Recent Advances in Obstetrics and Gynecology edited by J Stallworthy and GG Bourne, pp. 21-45. Edinburg: Churchill L ivingstone, 1979 . 11. Shanklin DR: Influence of placental lesions on newborn infants. Pediatr. Clin. North Am. 17.25-42, 1970. 12. Gruenwald P: Chronic fetal distress and placental insufficiency. Biol. Neonat. 5: 215-265, 1963. 13. Scott RE and Usher R: Fetal malnutr ition: Its incidence, causes and effects. Am. J. Obstet. Gynecol. 94:951-963, 1966. 14. Hobel CJ: Prevention of preterm delivery. In Fetal Physiology and Medicine, edited by RW Beard and PW Nathaniels, pp. 757-779. New York: Marcel Dekker, 1984. 15. Rliegman R and Rins K: Intrauterine growth retardation: Determinants of aberrant fetal growth. In Neonatal-Per inatal

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