An analysis of the effects of prenatal alcohol exposure on growth A teratologic model.код для вставкиСкачать
American Journal of Medical Genetics Part C (Semin. Med. Genet.) 127C:28 –34 (2004) A R T I C L E An Analysis of the Effects of Prenatal Alcohol Exposure on Growth: A Teratologic Model NANCY L. DAY* AND GALE A. RICHARDSON The association between prenatal exposure to alcohol and growth is linear, and effects have been measured at levels of exposure that are considerably below one drink per day. Thus, with respect to growth deficits, there is no safe level of drinking during pregnancy. Alcohol exposure during gestation causes growth deficits among the offspring at birth and during infancy. At older ages, however, growth deficits are reported in some, though not all, studies. Exposed offspring who grow up in more privileged environments are apparently able to make up their growth deficits, while those raised in less optimal circumstances do not. This means that there is an interaction between the environment in which a child is raised and the expression of the effects of prenatal alcohol exposure. The long-term implications of growth deficits are not yet well understood. ß 2004 Wiley-Liss, Inc. KEY WORDS: prenatal; alcohol; growth; teratology INTRODUCTION We present findings from the Maternal Health Practices and Child Development (MHPCD) Project. This study assessed the relation between prenatal alcohol exposure at each trimester and growth at seven time points: birth, 8 and 18 months, and 3, 6, 10, and 14 years of age. We discuss these findings and those of other researchers using a theoretical model of teratogenesis. the relationship between alcohol exposure and growth as an outcome: 1. Effects are a function of the dose. 2. Effects are a function of the developmental stage of the organism at the time of the exposure. Time, with respect to prenatal alcohol exposure, has two components: the stage of pregnancy when the exposure occurs and the duration of exposure. 3. Outcomes are a function of both the toxic exposure and the environment. THEORETICAL MODEL The teratologic model is a biologically derived model [Vorhees, 1989]. The following hypotheses relate directly to Nancy L. Day is Professor of Psychiatry and Epidemiology at Western Psychiatric Institute and Clinic, Maternal Health Practices and Child Development Project, Pittsburgh, Pennsylvania. Gale A. Richardson is Associate Professor of Psychiatry and Epidemiology at Western Psychiatric Institute and Clinic, Maternal Health Practices and Child Development Project, Pittsburgh, Pennsylvania. *Correspondence to: Nancy L. Day, Western Psychiatric Institute and Clinic, Maternal Health Practices and Child Development Project, 3811 O’Hara St., Pittsburgh, PA 15213-2593. E-mail: email@example.com DOI 10.1002/ajmg.c.30013 ß 2004 Wiley-Liss, Inc. The last hypothesis must be addressed in detail in human populations where, by contrast to laboratory experiments, preand postnatal environments are more complex and factors in the environment that affect development cannot be controlled. A vulnerability model [Horowitz, 1987] best fits the model that we are proposing for alcohol-exposed offspring. In her model, Horowitz defines axes, representing the continua of biological characteristics and of environmental factors. Each ranges from optimal to detrimental, and the intersection of these axes determines the outcome. A vulnerable child, exposed to the same stress as a less vulnerable child, will do less well. The obverse is also true; given the same level of biological vulnerability, children exposed to a more negative environment will do less well than those exposed to a more positive environment. Thus, children who have been exposed prenatally to alcohol will be more vulnerable by virtue of that exposure; in the face of environmental stressors, they will be less able to adapt and more likely to have problems. METHODOLOGICAL ISSUES There are several important methodological issues related to the teratologic model that must be addressed. Dose-Response The teratologic model assumes that the relationship between exposure and response is a dose-response curve. Thus, theoretically, there are effects at every exposure dose. This is in contradistinction to the detectable level of effects, which is dependent on the sample size and resultant power of the statistical analyses. However, it is important to separate the scientific fact of a doseresponse curve from the practical aspects of counseling; the effects at some levels of exposure may be clinically insignificant. In contrast to most teratogens, there have been reports from both the animal ARTICLE [Schenker et al., 1990] and the human [Sampson et al., 1989] literature that the relationship between alcohol exposure during pregnancy and outcome may depend on the pattern of drinking. This has been interpreted as evidence of a threshold effect. However, although the association between binge drinking and outcome may be stronger than the relationship between other patterns of drinking and outcome, this does not, by itself, prove that it is a threshold effect. Women who binge drink are likely to be heavier drinkers between binges, and in the absence of assessing the contribution of the pattern of continuous exposure, the effects cannot be attributed to the binge drinking pattern. It is possible to evaluate statistically whether the relationship between prenatal alcohol exposure and outcome is a dose-response or a threshold relationship. With the availability of appropriate techniques such as nonparametric smoothing, nonlinear curve fitting, and cumulative sum methods, future research needs to address this issue more fully. Time of Exposure during Pregnancy Two aspects must be considered in assessing the patterns of exposure during pregnancy: the stage of the pregnancy when exposure occurs and the duration of exposure. Fetal development is a sequential, staged process. There are differences in the patterns of growth among length, weight, and head circumference. The peak velocity of growth in length occurs early in pregnancy, while growth of weight and head circumference peak in velocity later in pregnancy [Kliegman and Hulman, 1987]. The outcomes of offspring exposed throughout pregnancy will differ from the outcomes of offspring exposed only during early pregnancy or at a discrete point in pregnancy. Moreover, the The outcomes of offspring exposed throughout pregnancy will differ from the outcomes AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) of offspring exposed only during early pregnancy or at a discrete point in pregnancy. effects will vary depending on the outcome. Because of this, it is important to assess the pattern of drinking during pregnancy, looking separately at the time points of pregnancy. This requires drinking measures that are, at the very least, trimester specific. In addition, the characteristics of the women who drink heavily early in pregnancy differ significantly from those of the women who continue to drink through the third trimester [Peindl et al., 1996]: it is important to include these variables in the analyses. The MHPCD Study The women in this study were recruited from a prenatal clinic. Women were selected if they were in the fourth month of pregnancy and 18 years of age or older. Interviewing was done in a private setting in the clinic. The refusal rate at recruitment was 15%. A total of 1,360 women were screened at the initial interview and a study sample was selected on the basis of first-trimester alcohol use [Day and Robles, 1989]. All women who had an average use of three or more drinks per week and a random sample of one-third of the women who drank alcohol less often or not at all were selected. A parallel cohort was selected to study the effects of marijuana use during pregnancy. All women who used marijuana during the first trimester at the rate of two or more joints per month and a random sample of women who used less than this amount were selected. The two cohorts were combined for the analyses presented in this chapter. The women in the MHPCD study were selected from a prenatal clinic, not from a substance use treatment center. Their substance use during pregnancy was, in general, light to moderate, although subjects who represented the entire spectrum of use were included in the sample. The women were healthy and of lower socioeconomic status. 29 Forty-eight percent of the women were Caucasian; the remainder were African American, reflecting the distribution of the clinic population. At first trimester, 60% of the women had completed high school, their mean age was 23 years (range ¼ 18–42), and their average family income was $450 per month. A majority (67%) of the women were not married and 32% were primigravidas. At each phase of the protocol, the maternal interview consisted of a core data set and additional questions appropriate to the age of the child. The interview included an assessment of the mothers’ use of alcohol, tobacco, marijuana, and other drugs, including other illicit drugs and prescribed and over-thecounter medications. At each follow-up phase, the environment of the child was carefully assessed across multiple domains. The children’s weight, height, head circumference, and palpebral fissure width were measured at each phase. At birth, 763 live, singleton offspring were examined from the initial combined cohort of 829 pregnancies. Attrition resulted from 18 fetal or perinatal deaths, eight were refusals, 16 subjects who were missed, 21 who moved away from the city, one infant who was placed for adoption, and two sets of twins. On average, the offspring weighed 3,198 g (range ¼ 1,040–4,990) at birth; 10.2% were low birth weight (<2,500 g), 8.5% were premature (<37 weeks gestation), and 13.6% were small for gestational age (<10th percentile for growth). Substance use was assessed for each trimester of pregnancy at fixed time points during pregnancy. Alcohol and marijuana use were determined for each month of the first trimester. For second and third trimesters, assessment was over the entire trimester. Usual, maximum, and minimum quantity and frequency were determined for beer, wine, liquor, and wine and beer coolers [Day and Robles, 1989]. Tobacco use and illicit drugs other than marijuana were measured for each trimester. In all of our analyses, we controlled for the effects of other substances used during the prenatal period, including tobacco, marijuana, and other illicit 30 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) drugs during each trimester. Additionally, all analyses controlled for the current environment of the child and for current maternal alcohol, tobacco, marijuana, and other illicit drug use. Prenatal alcohol and marijuana exposures were used as continuous variables, expressed as average daily volume (ADV) and average daily joints (ADJs). Tobacco was measured in cigarettes per day. For all analyses, illicit drugs were grouped together and were used as a dichotomous variable. RESULTS AND DISCUSSION The Effects of Prenatal Exposure to Alcohol on Offspring Growth In the MHPCD study, alcohol consumption in the first and/or second month of pregnancy predicted an increased risk of having a low birth weight baby (<2,500 g) [Day et al., 1989]. Alcohol consumption in the first and/or second month of pregnancy predicted an increased risk of having a low birth weight baby (<2,500 g). Drinking during early pregnancy was also associated with an increased risk of giving birth to an infant below the 10th percentile for length or head circumference. There was a significant linear relationship between second-trimester alcohol use and birth weight. These results are similar to many of the reports from longitudinal studies of drinking practices. In the Seattle Longitudinal Prospective Study, approximately 500 predominantly white middle-class women were interviewed regarding their alcohol use during the month prior to pregnancy recognition and the fifth prenatal month. Alcohol use in the fifth prenatal month was associated with reduced birth weight, length, and head circumference Alcohol use in the fifth prenatal month was associated with reduced birth weight, length, and head circumference. [Streissguth et al., 1981]. Smith et al.  enrolled three groups of lowsocioeconomic-status single black women in the Atlanta area (N ¼ 149) who 1) did not drink during pregnancy, 2) quit drinking in the second trimester, or 3) drank throughout pregnancy. Duration of alcohol use during pregnancy significantly predicted birth weight, length, and head circumference, as did the dose of alcohol exposure. In addition, there was an interaction between dose and duration; women who drank heavily and continuously throughout pregnancy had the smallest infants. Fried and O’Connell  enrolled a sample of 667 predominantly white middle-class women. There was a significant reduction in birth weight and length among offspring of women who drank more than two drinks per day, averaged across pregnancy, compared with the remainder of the sample. Jacobson et al. [1994a] studied a sample of 417 pregnant black inner-city women. Exposure to alcohol, averaged across pregnancy, was associated with decreased birth weight, length, and head circumference, although only among offspring of women over the age of 30. The infants of women who drank an average of more than four drinks per day were the most affected. By contrast, Ernhart et al.  found no relation between prenatal alcohol exposure, averaged across pregnancy, and birth size, after controlling for confounding variables. Russell and Skinner  assessed 531 women recruited from private and public prenatal care. There were no effects of alcohol use prior to pregnancy recognition on birth weight, length, or head circumference of the offspring. ARTICLE In the MHPCD study, the relations between prenatal alcohol exposure and growth deficits were more evident at eight months of age than they had been at birth. Weight, length, and head circumference were each significantly and inversely correlated with secondand third-trimester alcohol exposure after significant factors in the current environment were controlled [Day et al., 1990]. Difficulty of feeding was significantly associated with alcohol exposure during the first trimester, although not with current maternal alcohol use. This pattern of growth deficits persisted at 18 months of age. Each of This pattern of growth deficits persisted at 18 months of age. the growth parameters was significantly affected by prenatal exposure to alcohol during the second and third trimesters of pregnancy and by drinking continuously throughout pregnancy [Day et al., 1991a]. Decreased skinfold thickness, a measure of fat deposition, was predicted by first-trimester alcohol exposure. Jacobson et al. [1994b] also found effects of prenatal exposure on weight and length at 6.5 months, although the effects were only detectable at the level of four or more drinks per day. At 13 months in this latter study, prenatal alcohol exposure was associated with decreased height, but only among offspring of mothers over age 30. At 18 months, we also assessed the effects of two measures of drinking: one was ADV, an averaged measure of consumption, and the other, frequent heavy drinking (FHD), was a measure of binge drinking or the frequency of consuming five or more drinks on one occasion. Although both patterns were significant predictors of growth deficits, when ADV was controlled, FHD did not contribute further explanation [Day et al., 1991a]. Therefore, binge drinking was not by itself a significant predictor of growth deficits. This is consonant with the theoretical model ARTICLE that predicts that continuous rather than episodic exposure should predict growth deficits since episodic exposure can allow repair between episodes. By contrast, the Seattle study found no association between drinking in the fifth month of pregnancy and growth at eight months, although there was a significant effect of drinking in the month prior to pregnancy recognition on weight and length [Barr et al., 1984]. Two studies of predominantly white middle-class women did not find effects of prenatal alcohol exposure on infant size at 12 months [O’Connor et al., 1986] or at 12 and 24 months [Fried and O’Connell, 1987] of age. At three years of age in the MHPCD study, a change in exposure from zero to one drink per day during the second and third trimesters predicted weight reductions of 2.9 and 2.2 pounds, respectively [Day et al., 1991b]. Alcohol exposure during both the first and third trimesters had significant negative effects on height at three years, and exposure during trimesters two and three significantly predicted reduced head circumference. Skinfold thickness was significantly associated with firsttrimester alcohol exposure. A longitudinal analysis of the data through three years demonstrated that the effects of gestational alcohol exposure differed across this time interval: from birth through eight months, the alcohol-exposed children grew at a rate that was slower than that of the nonexposed offspring [Geva et al., 1993]. Subsequent to that, the change in weight had the same slope as that of the unexposed children, but there was no catch-up growth and they remained consistently smaller. Length and head circumference did not have differential growth patterns across time among the exposed offspring and the rate of growth of these measures was parallel to that of the nonexposed offspring. Length and head circumference remained consistently smaller and the offspring did not make up their growth deficit. At our six-year follow-up, offspring weight was predicted by alcohol exposure during the first, second, and third trimesters. The effect AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) At our six-year follow-up, offspring weight was predicted by alcohol exposure during the first, second, and third trimesters. sizes were 2.0, 1.6, and 2.6 pounds, respectively, for a change from zero to one drink per day [Day et al., 1994]. Height, head circumference, and palpebral fissure width were also significantly reduced by exposure to alcohol during gestation. In addition, at six years, the child’s appetite was significantly predicted by alcohol exposure in the first trimester. This was consistent with earlier findings of an association between feeding difficulty at eight months and first-trimester alcohol exposure [Day et al., 1990]. Both findings are consistent with the fact that the appetite and satiety centers in the brain develop at this time [Moore and Persaud, 1993]. However, after controlling for reduced appetite, the effect of prenatal alcohol exposure was still significant. Thus, poor appetite did not explain the growth deficits. In the more advantaged cohort studied in Seattle, there were no significant associations between growth and prenatal alcohol exposure at age seven [Streissguth, 1992]. Other studies that found alcohol-associated growth deficits at birth have also not found growth deficits at follow-up [O’Connor et al., 1986; Fried and O’Connell, 1987]. A study of 8,556 pregnancies in Australia also did not find a relation between light and moderate alcohol use during pregnancy and head circumference or weight at birth or at five years of age [O’Callaghan et al., 2003]. Two studies have reported that head circumference measured at school age was affected by prenatal alcohol exposure. In Atlanta, at offspring ages ranging from five to eight years [Coles et al., 1991], children who were exposed to alcohol throughout pregnancy had smaller head circumferences. There was no 31 association with either weight or height. In another study, at six years, head circumference was negatively associated with alcohol use in the year prior to pregnancy [Russell et al., 1991]; there was no effect of prenatal alcohol exposure on weight or height. In the MHPCD cohort, at age 10 years, prenatal alcohol exposure predicted a 4-pound decrease in child weight for a change in first-trimester alcohol exposure from zero to an ADV of one drink. Comparable statistics for the second and third trimesters were 7 and 7.1 pounds, respectively [Day et al., 1999]. Alcohol exposure also significantly predicted reduced height among the offspring, smaller head circumference, and reduced skinfold thickness. Each of these findings remained significant after controlling for other variables that predicted prenatal exposure and growth. One variable was of particular interest. Women who drank during pregnancy were more likely to use illicit drugs and to drink subsequent to the pregnancy: these variables were always controlled in the analyses. At 10 years, children whose mothers were current polysubstance users (defined as two or more drinks per day of alcohol and any illicit drug) weighed, on average, 89.9 pounds compared to 92.2 pounds among the children whose mothers did not currently use multiple substances. The significant effects of prenatal alcohol use persisted after controlling for the current substance use. Earlier reports on people with FAS indicated that the effects of prenatal alcohol exposure on size were ameliorated as the children went through puberty [Streissguth et al., 1991]. However, this was not the case in the MHPCD cohort. At age 14, growth continued to be significantly predicted by prenatal alcohol exposure. First- and At age 14, growth continued to be significantly predicted by prenatal alcohol exposure. 32 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE quality of the household environment, maternal substance use, presence of a male in the household, maternal social support, and psychological status were significant predictors of the children’s size. The effects of prenatal exposure were independent of the effects of the current environmental factors, and when we modeled interactions between the current environmental factors and prenatal alcohol exposure, none of the interactions was significant. CONCLUSIONS Figure 1. gestation. Weight at 14 years of age by trimester of alcohol exposure during second-trimester alcohol exposures predicted significantly reduced weight in the offspring at age 14 (Fig. 1). Third trimester followed the same pattern, but was not significant because there were smaller numbers of women drinking at this phase. Prenatal alcohol use also predicted height (Fig. 2) and head circumference (Fig. 3). Second trimester predicted significantly decreased skinfold thickness with increasing alcohol exposure [Day et al., 2002]. These growth deficits at age 14, as with the earlier findings, had a dose-response relation to exposure during gestation and were detectable at exposures considerably below one drink per day. After controlling for other significant covari- Figure 2. gestation. ates, including stage of pubertal development, exposure to other substances during gestation, and measures of the current environment, these results remained significant. At 14 years, we also assessed the effects of different patterns of exposure, i.e., whether ADVor binge drinking better predicted the growth effects. At this phase, as at earlier phases, we found that the effect of prenatal alcohol exposure on growth was not solely explained by binge drinking. Indeed, there was a significant association between ADV and growth in the absence of binge use. At each follow-up point, social and environmental factors such as the number of people living in the household, Height at 14 years of age by trimester of alcohol exposure during Several overarching conclusions are worth noting. Exposure to alcohol during gestation causes growth deficits in the offspring at birth and in early infancy in most studies. Second, at older ages, the findings diverge: while growth deficits persist throughout childhood in low-income populations such as the MHPCD cohort, such deficits are generally not detectable at follow-up in more advantaged populations. Thus, there is an interaction between the environment and prenatal exposure, and as predicted by the vulnerability model, it is the combination of the child’s biological vulnerability, which was created by the prenatal exposure, and the environment that leads to longterm growth deficits. The effects of alcohol exposure during pregnancy have been shown in the MHPCD study to be dose-response and cannot be explained solely by episodic heavy (binge) drinking. Similar findings have been reported by two other studies [Streissguth et al., 1981; Smith et al., 1986]. Our findings that the relationship between prenatal alcohol exposure and growth is modeled best as a doseresponse have important implications for prevention, counseling, and intervention. Optimizing the environment in which the vulnerable children are raised may offset some of the negative effects of prenatal alcohol exposure on growth. In addition, a dose-response relation between prenatal alcohol use and outcome implies that women should be advised not to drink during pregnancy. Why is the relation between alcohol and growth important? The first answer ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) Figure 3. Head circumference at 14 years of age by trimester of alcohol exposure during gestation. is that although the actual growth difference is quite small and would not be detectable except in a large study, the fact that it exists and indeed persists over time means that it is a permanent marker of alcohol exposure during gestation. Further, it is important that the relation between prenatal alcohol exposure and effects is linear and that effects can be detected at quite small amounts. This means that there is no safe level of drinking during pregnancy. Further, it is important that the relation between prenatal alcohol exposure and effects is linear and that effects can be detected at quite small amounts. This means that there is no safe level of drinking during pregnancy. It is not clear, however, what the long-term biological significance of a growth deficit might be. We know that large deficits in size signal genetic, endocrine, nutritional, environmental, or metabolic problems. Some children who are born small for gestational age experience a period of rapid growth in the first year, allowing them to catch up with their peers; others do not, and still others become short relative to their peers in the first two years of life. Children in these two latter groups, some of whom were likely to have been alcohol exposed, were more likely to remain small through adulthood [Luo et al., 1998]. 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