Low-to-moderate gestational alcohol use and intrauterine growth retardation, low birthweight, and preterm delivery

ELSEVIER

LowdtocModerate Gestational Retardation, Low Birthweight, LISBET S. LUNDSBERG,

PHD,

Alcohol Use and Intrauterine and Preterm Delivery

MICHAEL

B. BRACKEN,

PHD,

Growth

AND AUDREY F. SAFIYLAS,

Px-ID

PURPOSE:

Heavy drinking during pregnancy is an established risk factor for fetal alcohol syndrome and other adverse perinatal outcomes. However, there is still debate as to the effects of low-to-moderate drinking during pregnancy. ME~ODS: This prospective investigation was based on 2714 singleton live births at Yale-New Haven Hospital during 1988-1992. Alcohol drinking during pregnancy was evaluated with respect to intrauterine growth retardation (IUGR), preterm delivery, and low birthweight. RESULTS: Mild drinking, defined as > 0.10-0.25 oz of absolute alcohol per day, during the first: month of pregnancy was associated with a protective effect on IUGR (OR, 0.39; 95% confidence interval (CI), 0.20476). Overall, drinking during month 1 of pregnancy suggested a curvilinear effect on growth retardation, with consumption of > 1.00 oz of absolute alcohol per day showing increased risk. Drinking during month 7 was associated with a uniform increase in the odds of preterm delivery; the GRs were 2.88 (95% CI, 1X4-5.05) for light drinking and 2.96 (95% CI, 1.32-6.67) for mild-tomoderate alcohol consumption. CONCLUSIONS: Differences in the risk estimates for RJGR and preterm delivery may indicate etiological differences that warrant further investigation of these outcomes and critical periods of exposure. Low birthweight is not a useful neonatal outcome for this exposure because it is a heterogeneous mix of preterm delivery and IUGR. Respite the observed protective effects of mild drinking on IUGR, the increased risk of preterm delivery with alcohol use supports a policy of abstinence during pregnancy. 0 1997 Elsevier Science Inc. Ann Eternal 1997;7:498-508. KEY WORDS:

Cohort

Alcohol,

Pregnancy,

Intrauterine

Growth

Retardation,

Birthweight,

Preterm Delivery,

Study.

Early case studies and observational research demonstrated that heavy and chronic drinking presented a clear risk to the fetus, including stillbirth, perinatal death (l), congenital anomalies, and fetal alcohol syndrome (Z-6). Adverse effects on birthweight (7-lo), gestational age (8, II), intrauterine growth retardation (9,12-l 4)) spontaneous abortion (15-18), and neurobehavioral development ( 19) have been reported. For the most part, these studies have focused on heavy and excessive prenatal drinking. Inefficient excretion of ethanol by the fetus after heavy maternal drinking results in prolonged circulation of acetaldehyde, the main metabolite of alcohol, which is fetotoxic (20). Adverse effects of alcohol on fetal growth and development are likely to be dose dependent and to be related to the timing of exposure. Other studies have failed to detect an adverse association of low and moderate drinking during pregnancy with specific

From Yale University School of Medicine, Department of Epidemiology and Public Health, 60 College Street, New Haven, CT 06511. Address reprint requests to: Dr. Michael B. Bracken, Yale University School of IMedicine, Department of Epidemiolon and Public Health. 60 College Street, P.O. Box 208034, New Haven, CT 06520-8034. Received October 30, 1996; accepted May 16, 1997. 0 1997 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

neonatal outcomes (21-26). Overall, the relationships between low-to-moderate levels of alcohol exposure and birth outcomes have been inconsistent. Retrospective ascertainment of drinking during pregnancy, misclassification of exposure, failure to control for confounding, and sampling of heavy drinking populations has limited the interpretation of risk estimates for lower Ieveis of exposure. The current prospective study analyzed low to moderate levels of alcohol consumption with respect to intrauterine growth retardation (IUGR), preterm delivery, and low birthweight.

MATERIALS AND METHODS Women seeking prenatal care from 11 private practices and two health maintenance organizations in New Haven, Connecticut, during the period of April 1988 to December 1991 were approached for this study. Information on these women came from a larger study of environmental exposures and pregnancy outcome (27, 28). Of the 4493 women approached for this study, 216 were no longer pregnant at the time of the initial interview, 476 were not interviewed by the end of the 16th week of gestation, 113 had already participated in the study with a previous pregnancy, 30 were not proficient in English, 54 anticipated delivering outside 1047~2797/97/$17.00 PII S1047.2797(97~00081-1

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Selected Abbreviations and Acronyms IUGR = intrauterine growth retardation AA = absolute alcohol RR = relative risk CI = confidence interval OR = odds ratio

of Yale-New Haven Hospital, 10 reported insulin-dependent diabetes, two had medical conditions limiting study participation, and 1 subject resided outside of the study location. A total of 3591 women were eligible for the study. Of that number, 574 refused to be interviewed and 50 could not be contacted; thus 2967 women were interviewed for this study (82.6% of the eligible sample). The present analysis was restricted to 2714 singleton live births, representing the study population after exclusion of individuals with miscarriages, livebom twins or triplets, induced abortions, or stillbirths. All women were interviewed at home; the interview was conducted before the completion of 16 weeks of gestation. Baseline characteristics were evaluated up to the time of the interview; these included age, education, marital status, and race; maternal characteristics including weight, height, cigarette smoking, passive smoke exposure, alcohol drinking, caffeine exposure, exercise, and employment were also collected. Medical and pregnancy history information were evaluated, including details on pre-existing chronic diseases, history of miscarriage, spontaneous abortion, stillbirth, and parity. Each woman was interviewed postpartum in the hospital to evaluate changes in specific risk factors and exposures during the last trimester of pregnancy. Complications of labor and delivery were recorded, and medical records for both the mother and her infant were reviewed. Exposure

Assessment

lnformation on alcohol consumption was collected for specific periods during pregnancy: months 1, 2, and 3 at the initial interview and months 7, 8, and 9 at the postpartum interview. For each type ofbeverage (wine, beer, and liquor), women were asked how often they drank alcohol and how many drinks they had. An alcohol score was constructed for each month of pregnancy to evaluate the absolute alcohol (AA) content from all sources (29). The alcohol content of one drink was estimated as 15% for wine, 4% for beer, and 45% for liquor; the average volume of one standard drink was estimated as 4 oz for wine, 12 oz for beer, and 1.5 o: for liquor. For each beverage, the alcohol content was multiplied by the average volume and frequency to yield an average AA score for each month. Individual beverage scores were summed for a total alcohol exposure score. Ahwlute alcohol scores were grouped into four drinking levels: light, mild, moderate, and heavy drinking. The refer-

GESTATIONAL

Lundstq er al. ALCOHOL IJSE AND PREGNANCY 0UTX~MES

499

ent group consisted of women who abstained from alcohol. Light drinking corresponded to alcohol consumption of s 0.10 oz of AA per day; mild drinking ranged from > 0.10 oz to 0.25 oz of AA per day; moderate drinking was defined as > 0.25-1.00 oz of AA per day; and alcohol exposure of > 1.00 oz of AA per day was defined as heavy drinking. The cutoff points for drinking levels were consistent with those used in previous studies (7. 30-32). Differences in beverage type were evaluated with respect to each outcome of interest. Wine, beer, and liquor consumption were investigated as independent exposures and in combination as multiple beverage types. Outcomes

of Interest

Newborns were examined within 24 h of delivery to assess birthweight. Low birthweight was defined as < 2500 g. Standard protocols were established for umbilical cord clamping and obtaining infant weights. To assessgestational age, infants were examined within 6-24 h of delivery by a specially trained neonatal nurse. The Ballard scale of neonatal development (33) assessedgestational age with a 95% precision of 2 2 weeks. When the Ballard assessment was not available, the recorded last menstrual period was used to estimate gestational age (n = 159, or 5.7% of the study sample). Preterm delivery was defined as less than 37 weeks of completed gestational age. IUGR was measured as the lowest tenth percentile of birthweight for gestational age according to the nomogram of Babson et al. (34). This standard was appropriate for the current study sample because the two populations were similar with respect to ethnicity, socioeconomic status, residing at sea level, and access to prenatal care. Analytical

Methods

The analysis focused on exposure during two periods of pregnancy: month 1 and month 7. Alcohol exposure during month 1 provided information for the entire study population (N = 2 7 14) and may be representative of prepregnancy drinking; month 7 provided the largest possible study group (N = 2693) for assessmentof drinking in late pregnancy. For each time period, risk estimates were evaluated for IUGR, preterm delivery, and low birthweight. Crude estimates were compared to adjusted risk estimates for determination of the extent of confounding. Logistic regression in PC-SAS (Statistical Analysis System, Cary, NC) was used for multivariate analysis of each outcome. Model selection was based on backwards selection from a full model including potential confounders, independent risk factors, and the exposure of interest. Effect estimates for the final madels were generated according to model selection based on the change in the log likelihood ratio statistic compared to :I chi-squared distribution. Confounding was evaluated as a change in the parameter estimate of interest of 2 10%. For c;rlt=goriczl vari-

500

ables, a 10% change in one level was interpreted as potential confounding. Colinearity among the selected risk factors was addressed by running all final models using forward logistic regression.

RESULTS Women in the study were generally well-educated (81.5% some college education), married (92.3%), and white (90.3%); the mean age was 31 years (59.7% were 30 or over). Nulliparous women comprised less than half of the study population (44.4%), and most women (81.0%) were employed during their pregnancy. The majority of women reported no history of smoking (85.2%); a small proportion of the population who smoked stopped doing so by the seventh month of pregnancy (4.7%). Passive smoke exposure below 1 hour per week was reported by most of the population in both the first 16 weeks of pregnancy (63.6%) and in the third trimester (68.3%). Women generally exercised before their pregnancy started (71 .O%), and many continued during the first 16 weeks (56.3%); the proportion of women exercising dropped during the last trimester (44.4%). Less than half of the women reported no exposure to caffeine from coffee, tea, or soda in month 1 (44.0%), and relatively few women were exposed to > 300 mg of caffeine per day (4.8%). In month 7, fewer women were exposed to over 300 mg of caffeine per day (1.6%), while the proportion reporting no exposure remained stable (44.5%). Of the total population, 102 infants (3.8%) were classified as low birthweight and 82 (3.0%) were delivered preterm. IUGR was diagnosed in 189 subjects (7.0% of 2709); five subjects could not be classified in the Babson scale because their gestational age was < 26 weeks; those five infants are excluded in the analysis of IUGR. Trends

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Lundsberg et al. GESTATIONAL ALCOHOL USE AND PREGNANCY OUTCOMES

of Drinking

during

Pregnancy

Alcohol use during month 1 of pregnancy was reported by 49.9% of the study sample. Among the total sample, 25.9% were exposed to light levels of alcohol; 13.7% were mild drinkers, 8.3% were moderate drinkers and only 2.0% were classified as heavy drinkers. Drinking in the first trimester decreased in both absolute rates and the amount of alcohol ingested: in month 2 (N = 2710), 22.5% of the study population reported drinking and in month 3 (N = 1976), only 20.9% drank alcohol. Later in pregnancy, there was a shift in the drinking patterns: 25.0% drank in month 7 (N = 2693), 29.4% drank in month 8 (N = 2685), and 42.2% drank in month 9 (N = 2623). Although there was an increase in late pregnancy drinking, no women in month 9 drank heavily and most were light drinkers. Mean AA scores for each drinking level were lower in each period after month 1 of pregnancy.

Maternal

Characteristics

and Alcohol

Exposure

Table 1 presents the distribution of maternal characteristics and selected risk factors by level of alcohol exposure during the first month of pregnancy. Alcohol consumption was associated with higher education, parity, maternal age, and white ethnicity. Maternal smoking increased across levels of alcohol use, and a threshold effect was seen at 10 cigarettes per day. Drinking in month 1 was positively associated with caffeine exposure in month 7; separate analyses of coffee and tea consumption indicate that coffee is strongly related to alcohol intake, whereas tea is weakly related. Risk Estimates for IUGR, Preterm Delivery

Low Birthweight,

and

Table 2 shows the relative risk estimates for maternal characteristics and factors that may influence the rates of IUGR. Risk of IUGR was elevated among younger, unmarried, smoking, primiparous, and nonwhite women. Women of shorter stature and low prepregnancy weight were at greater risk for IUGR; small weight gain (< 22 lb) during pregnancy was associated with strong increased risk for IUGR. Consuming > 300 mg of caffeine daily in month 7 also appeared to increase the rate of IUGR. Although exercise decreased the risk of IUGR, employed women showed a slightly higher rate of IUGR as compared with unemployed subjects. Obstetric and medical factors related to higher rates of IUGR include bleeding during pregnancy, high blood pressure, pre-eclampsia or eclampsia, and major or minor anomalies in the neonate. Table 3 shows the crude risk estimates for IUGR, low birthweight, and preterm delivery that are associated with alcohol drinking in months 1 and 7 of pregnancy. Light drinking showed a protective effect on IUGR (RR, 0.74; 95% CI, 0.53-1.05). The effect of mild drinking in month 1 is protective and highly significant (OR, 0.37; 95% CI, 0.20-0.68). Relative risk estimates for month 7 and IUGR indicated a persistent protective effect of drinking on growth retardation, particularly at mild and moderate levels. Low birthweight appeared to be weakly associated with drinking in month 1, and light drinking in month 7 showed an increased risk for low birthweight. While month 1 drinking did not appear to be associated with preterm delivery, the risk estimates for drinking in month 7 indicated that alcohol is a significant risk factor for preterm delivery. The unadjusted RR of preterm delivery associated with light drinking in month 7 was 2.11 (95% CI, 1.26-3.54) and for mild-tomoderate drinking the RR was 2.15 (95% CI, 1.03-4.52). Smoking appeared to be the most influential confounding factor in the relationship between alcohol drinking and growth retardation. Within drinking categories, IUGR rates were highest for current smokers. There appeared to be a threshold (10 cigarettes per day) for the risk of smoking and alcohol on IUGR. The protective effect of alcohol

TABLE 1. Selected characteristics of study population by absolute alcohol (AA) categories for pregnancy month I drmkmg: Yale-New Haven Hospital, 1988-1992” Daily AA intake (02) Characteristic Study population Age (ye;trs? s 24 25-24, Q-34 2 $5 Ethnicitv Whtc Nonwhite Educaclon(yeara) d 1’ 1S--l6 2%1: Panty (I 1 2 z 3 l’reprekmancyweight (lb) c 120 12@-139 3 I4C Height (in) *” 61 62-44 2365 Smoking, month 7 Never Stop by month 7 I-9 cgarettes/d 10-I 9 cigaretres/d 3 20 cigarettes/d Caffeine. month 7 (m,g/d) NomI--l% 151.-JO@ 2%Xl Coffee month 7 (cups/d) N~uw I 32 Exercise in fiat 16 weeks (at least once a week) Yes No Exercise in third trimester (at least once a week) Yes NO Bleeding during pregnancy Yes NO High blood pressure Yes No Pre-eclanlpsialeclampsia Yes No

N

Abstinent

c 0.10

> 0.10-0.25

2714

50.1

25.9

13.7

232 864 1109 509

61.2 52.7 48.0 45.2

20.7 25.1 26.1 29.5

11.2 11.8 16.1 11.2

2450 262

47.8 72.1

24.9 17.2

14.7 5.0

501 1507 706

63.3 48.6 43.8

18.2 26.1 31.2

8.0 15.1 15.0

i206 1049 359 80

46.4 51.5 55.4 62.5

26.5 26.2 25.1 18.8

15.3 12.8 i2.0 10.0

606 1097 973

48.8 46.4 54.2

27.i 27.7 23.7

14.2 14 1 Ii.2

327 1040 1346

58.1 52.3 46.4

23.9 25.0 27.2

10.7 12.2 15.7

2302 128 139 92 42

50.3 43.8 42.5 59.8 64.3

27.2 18.8 24.5 13.0 14.3

13.7 18.0 13.7 14.1 4.8

1206 1222 242 44

52.7 47.1 51.7 54.6

28.I 25.9 16.1 20.5

11.0 16.1 15.3 13.6

1818 723 173

52.6 45.1 43.9

27.7 23.2 18.5

11.4 19.2 15.0

1528 1186

45.1 56.5

27.4 24.0

ii.7 1I.2

1195 L498

43.7 55.1

29.0 23.6

16.0 12.0

494 2196

48.4 50.4

27.9 25.6

11.9 14.2

Y7 7.3

306 2381

52.6 49.7

21.9 26.5

11.7 1i.a

3.N s.a

63 2626

57.1 49.9

15.9 26.2

4.1

7.Y 0.2 7;

13.9 6.2

502

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TABLE 1. (continued) Daily AA intake (oz) Characteristic Placental problems Yes NO Infant sex Male Female Major~minor anomaiies Yes NO

N

Abstinent

s 0.10

> 0.10-0.25

> 0.25-1.00

> 1.00

64 2623

57.8 49.9

18.8 26.1

17.2 13.6

6.3 8.4

0.0 2.1

1351 1360

50.3 50.0

25.9 26.0

13.0 14.5

8.6 7.9

2.2 1.8

386 2292

56.0 49.1

21.2 26.7

13.5 13.7

7.3 8.5

2.1 2.0

dTotal numbers may differ due to missing data.

drinking was substantial among current smokers; however, overall rates of IUGR were lower among nonsmokers. Among women who smoked up to nine cigarettes daily and abstained from alcohol, the rate of IUGR was 17.2%; drinking light-to-moderate amounts of alcohol and smoking the same amount was associated with an IUGR rate of 9.6%. However, as drinking increased above 0.25 oz of AA per day, the rate of IUGR was elevated to 29.6%. Smoking over 10 cigarettes daily showed the same pattern of risk; however, consuming moderate or heavier amounts of alcohol in month 1 and smoking led to rates of IUGR of > 31.0%. After adjustment for smoking, maternal weight, height, parity, infant sex, and medical risk factors, the adjusted OR of IUGR (Table 4) for mild drinking was 0.39 (95% CI, 0.20-0.76); light drinking carried a nonsignificant effect, with an OR of 0.85 (95% CI, 0.57-1.26). The adjusted estimates were not materially different from the crude relative risks, indicating that confounding did not explain the independent protective effect of mild drinking. In multivariate analysis alcohol exposure in month 1 appeared to be only weakly associated with low birthweight and preterm delivery. Exposure to alcohol in month 7 (Table 5) showed substantially different estimates of effect as compared with month 1, particularly for preterm delivery. After adjustment for selected factors, risk estimates for alcohol exposure and preterm delivery were increased; the OR of preterm delivery among light drinkers was 2.88 (95% CI, 1.64-5.05) and for mild-to-moderate drinkers the OR was 2.96 (95% CI, 1.32-6.67). The final model for low birthweight (Table 5) showed that light drinking was a significant risk factor (OR, 3.20; 95% CI, 1.87-5.46), and controlling for selected risk factors removed negative confounding effects. A weak protective effect appeared for mild drinking and IUGR (OR, 0.48; 95% CI, 0.18-1.23); however, light drinking in month 7 did not appear to influence IUGR. Beverage Analysis Wine was the beverage consumed most frequently among the study population (21.1% of the total sample in month

1 and 17.0% in month 7). Beer and liquor alone were consumed less frequently (6.4% and 6.0%, respectively). Drinking two or more beverages within each of the time periods was reported by some study subjects (6.2% for wine and beer drinking; 2.7% for wine, beer, and liquor drinking) within month 1. In multivariate analysis wine drinking in month I was protective for growth retardation (OR, 0.60; 95% CI, 0.37-0.98). Beer and liquor drinking alone or in combination during month 1 did not demonstrate any association with IUGR. Although drinking all beverage types in month 1 appeared to increase the risk of low birthweight, the estimate is relatively imprecise (OR, 3.26; 95% CI, 1.14-9.31). Analysis of beverage use in month 7 did not indicate that drinking any one beverage type carried a substantially higher risk than another. There did not appear to be any relation between beverage type in month 7 and IUGR. All beverage types (with the exception of a nonsignificant effect from beer) carried increased OR estimates for preterm delivery; the same pattern of risk was seen for low birthweight,

DISCUSSION Mild alcohol consumption during the first month of pregnancy was associated with a significant protective effect on IUGR (OR, 0.39; 95% CI, 0.20-0.76). Drinking across all levels of alcohol consumption during month 1 demonstrated a curvilinear pattern of risk for growth retardation. For several reasons the J-shaped curve does not appear to be an artifact. First, month 1 exposure and risk factor data were evaluated prospectively to the outcome, minimizing differential misclassification bias. If information bias existed for month 1 data, it would be nondifferential and underestimate risk estimates. Second, it does not appear that the risk was influenced by other variables or independent risk factors, which were assessedin the analysis. Third, the referent group of nondrinkers may have abstained from alcohol for specific reasons that may place them at a higher baseline risk for IUGR. Adjustment for medical risks, including chronic

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GESTATIONAL

Lundsberg et al. ALCOHOL USE AND PREGNANCY 01 !TS:OMES

503

TABLE 2. Selected characteristics of study population and association with intrauterine growth retardation (IUGR): Yale-New Haven Hospital, 1988-1992” Characteristic Age (years) s 24 25-29 30-34 3 35 Ethniciry White Nonwhite Education (years) s 12 li-If! 3 17 Parity 0 L

33 Prepregnancy weight (lb) < 120 120-139 3 140 Height (in) < 62 62-64 3 65 Smoking month 7 Never Stop by month 7 l-9 cigarettes/day 10-19 cigarettes/day 2 20 cigarettes/day Caffeine, month 7 (mg/d) None l-150 151-300 2 3Cl Coffee, month 7 (cups/d) None > 2 Exercise m tirsr 16 weeks (at least once a week) Yea No Bleedmg in pregnancy Yes No High blood pressure Yes No Pre-eclampsia/eclampsia Yes No Infant Sex Male Female Major/minor anomalies YCS NO (’ Toral numbers may differ due to missing data.

-_N

% with IUGR

RR

231 862 1107 509

10.0 6.6 4.7 6.9

1.51 Reference 1.01 1.11

2447 260

6.1 15.8

Reference 2.61

499 1504 706

7.8 7.3 5.8

1.35 1.25 Reference

1204 1067 358 80

9.1 5.3 5.3 6.3

Reference 0.58 0.59 0.69

606 1096 969

11.2 6.2 5.4

2.09 1.16 Reference

1.48, 2.Y6 0.81, 1.64

327 1038 1343

12.5 8.2 4.7

2.67 1.75 Reference

1.84, 3.84 i 27, 2.39

2299 128 137 92 42

5.9 7.0 16.8 16.3 14.3

Reference 1.19 2.84 2.76 2.41

L7.62,2.28 IN, 4.26 1.69, 4.50 1 13, 5.16

1201 1222 242 44

7.7 6.1 7.0 13.6

Reference 0.79 0.92 1.78

0.59, 1.06 C.54, 1.51 C.82, 3 84

1813 723 173

7.4 5.7 8.1

Reference 0.77 1.09

0.55, 1.08 D.65, 1.86

1525 1184

6.6 7.4

0.89 Reference

Q.68, 1.17

494 2196

9.5 6.3

1.51 Reference

1.10. 2.C8

306 2387

12.4 6.2

2.02 Reference

i .44, 2.62

63 2622

27.0 6.5

4.1Y Reference

:.72, 6.45

1348 1359

5.5 8.4

Reference 1.53

385 2289

9.6 6.5

1.49 Reference

95% Cl

--.

2 95, 2. $9 0.72, 1.41 z 74, 1.67

I 89, 3.60 0.88, 2.08 0.88, 1.77

13.42,0.79 c.37 0.94 0.29: 1.64

1.15, 2.03 1.05, 2.10 -.-.-

504

TABLE Yale-New

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3. Crude risk estimates for drinking Haven

Hospital,

in months

1 and 7: in relation

to IUGR,

Alcohol drinking, month 1 Abstinent s 0.10 oz AA/day > 0.10-0.25 or AA/day > 0.25-1.00 oz AA/day > 1.00 or AA/day Alcohol drinking, month 7 Abstinent i 0.10 or AA/day > 0.10-0.25 or AA/day > 0.25 oz AA/day

and preterm

delivery

at

I&term delivery

Low birthweight

IUGR Period of exnosure

1ow birthweight,

1988-1992

RR

95% CI

RR

95% Cl

1.00” 0.74 0.37 1.11 1.61

0.53-1.05 0.204.68 0.70-1.75 0.79-3.29

1.006 0.79 0.88 1.24 0.93

0.48-1.28 0.48-1.59 0.662.33 0.23-3.72

l.O@ 0.90 0.44 0.53

0.62-1.30 0.18-1.05 0.08-3.63

l.O@ 1.89 0.94

1.21-2.94 0.38-2.30

RR

95% Cl

l.O@ 0.83 0.91 0.89

0.49-1.42 0.48-1.75 0.42-1.87

1.00’ 2.11 2.15

1.26-3.54 1.034.52

“N = 2709. hN = 2714. ‘N = 2693.

diseases and pregnancy complications, however, did not materially change parameter estimates. It does not appear that the protective effect is due to extraneous risk factors unequally balanced among the drinking groups. The Babson criteria for growth retardation (34), using the lowest tenth percentile of birthweight for gestational age, was appropriate for this population. Selecting the third or fifth percentile of birthweight for gestational age may be too restrictive, and many cases of IUGR could be missed. Analysis of birthweight for gestational age as a continuous measure in this study reflected a similar pattern of risk among moderate or heavy drinkers and an increase in birthweight among the light and mild drinkers. Several studies reported a protective effect at low-tomoderate levels of alcohol drinking during pregnancy on the risk of small-for-gestational age births (6, 8, 14); however, all of these studies failed to control for confounding. One investigation demonstrated a protective effect from mater-

TABLE Yale-New

4. Adjusted Haven

risk estimates for drinking Hospital, 1988-1992

in month

1 in relation

nal alcohol exposure on several neonatal outcomes, including growth retardation and central nervous system deficits (35). The largest prospective study of 40,445 births (25) found a curvilinear pattern of risk similar to our results. A recent cohort study of over 10,000 births reported a significant reduction in birthweight among those women who did not drink compared to those who drank alcohol before conception (36). Protective effects seen for wine drinking are also supported by an earlier study (37). Separate analyses reported that beer reduced overall birthweight ( 12,24) and increased the risk for nonspecified adverse fetal outcomes ( 11). Increased miscarriage rates have been related to beer drinking (38), and consuming > 40 CL of wine per day was negatively associated with birthweight (12). Congeners specific to beverage type, such acetaldehyde, nitrosamines, and thiocyanate in beer and isoamyl and ethyl formates in wine (39), may affect fetal growth differentially. Variations in the risk

to IUGR,

IUGR

low birthweight,

and preterm

delivery:

Low birthweight

Alcohol use in month 1

OR

95% CI

Abstinent S 0.10 oz AA/day > 0.10-0.25 oz AA/day z 0.25-1.00 oz AA/day > 1.00 or AA/day

1.00” 0.85 0.39 1.05 1.20

0.57-1.26 0.20-0.76 0.60-1.83 0.463.08

OR 1.OOb 1.05 1.29 1.46 1.02

Preterm delivery

95% Cl

OR

95% CI

0.58-1.89 0.63-2.64 0.65-3.31 0.214.83

1.00’ 1.02 1.09 0.96 ..

0.55-1.90 0.51-2.33 0.40-2.30

dN = 2620; adjusted for smoking in month 7, ethnicity, weight, height, infant sex, parity, bleeding during pregnancy, high blood pressure, and preeclampsia/eclampsia. bN = 2602; adjusted for smoking in month 7, height, weight, ethnicity, infant sex, parity, coffee use in month 7, exercise in third trimester, employment, bleeding during pregnancy, high blood pressure, pre-eclampsia/eclampsia, anomalies, and placental problems. ’ N = 2643; adjusted for smoking in month 7, height, parity, age, caffeine use in month 7, exercise first 16 weeks, bleeding during pregnancy, high blood pressure, pre-eclampsia/eclampsia, anomalies, and placental problems.

GESTATIONAL

ALCOHOL USE AND PREGNANC?

Lundberg iXiT(

505

I’f .I/. 'i 'hlF:S

TABLE 5. Adjusted risk estimatesfor drinking in month 7 and in relation to IUGR, low birthweight, and preterm
Low blrthweight

Alcohol use in month 7

OR

95% Cl

Abstinent d 0.10 oz AA/da\i > 0.104.25 oz AA/day > 0.25 oz AA/day

1.oo” 1.12 0.48 0.91

0.73-1.69 0.18-1.23 0.12-7.10

OR 1.OOh 3.20 1.36

95% CI

-__-OR

13-5.46 0.48-3.88

1.JO .z 88 .: .Q6

l’r~wm -_---

deliver) 95% Cl 1.64-5.05 1.32-6.67

-. ’ N = 2620; adjusted for smoking in month 7, ethnicity, height, weight, infant sex, parity, bleeding during pregnancy, hqh hlo.rl pressure. and preeclampsla/eclampsia. hN = 2602; adlusted for smoking m month 7, ethnicity, infant sex, weight, height, panty, exercise m third trimester, empic~vmc!lt, bleeding dnrmg pregnancy, high blood pressure, pre-eclampsia/eclampsia, anomalies, and placental problems. ’ N = 2646; adjusted for smoking in month 7, height, bleeding during pregnancy, pre-eclampsia/eclampsia, and anomalies.

estimates for wine, beer, and liquor in the current study support separate analysis for beverage type. However, studies are often limited in examination of specific beverages, due primarily to inadequate sample size and lack of information on types of beverage consumed. Although this analysis did not investigate the effects of alcohol on spontaneous abortion, a recent analysis investigating the effects of caffeine on miscarriage found that alcohol consumption carried a weakly increased risk (28). Head circumference and birth length have been used as measures of fetal growth and development (8, 11, 38). In this data set, no relationship was observed between alcohol drinking in either month 1 or month 7 and head circumference, measured as the lowest tenth percentile. However, light drinking in month 1 had a protective effect (I’ = 0.04) on birth length, dichotomized by the tenth percentile values (40). Elevated risk estimates seen for month 7 drinking and preterm delivery are supported by several other studies of preterm delivery (12, 22, 41, 42) and gestational age (11, 21, 43). An investigation conducted in the same hospital setting as the present study (42) reported a threefold increase in preterm delivery rates among those who drank at least 14 drinks per week during the third trimester (OR, 3.0; 95% CI, 0.9-9.7). Other studies, however, failed to show any statistically significant association between alcohol use and duration of gestation (13, 23, 44, 45). Only one study reported a significant protective effect of drinking on preterm delivery (25). Clyanges in alcohol use during pregnancy were addressed by adjustment of month 7 risk estimates for alcohol drinking in month 1. After controlling for month 1, the odds of preterm delivery were elevated from crude risk estimates, indicating that early drinking carried a negative confounding effect. Light drinking in month 7 is a significant risk factor for preterm delivery after adjustment for early pregnancy drinking (OR, 2.45; 95% CI, 1.40-4.28), and mildto-moderate drinking shows a significant but less precise risk estimate (OR, 2.69; 95% CI, 1.17-6.17). In the current analysis, the increased risk of late preg-

nancy drinking on preterm delivery was not explained by selected confounding factors. Analysis of preterm labor as a potential risk factor did not explain the elevated risk of preterm delivery associated with alcohol use. Reported history of induced abortion in this study (25.6% of the study population) did not increase the risk of preterm delivery, a finding in agreement with earlier research (46). History of low birthweight, preterm delivery, or growth retardation was not examined; however, it is unlikely tbar any of these factors would materially change the risk esrimates. The Ballard score for gestational age was used ior assessing the maturity of most neonates in this study. It is unlikely that there was misclassification of gestational age greater than that seen using last menstrual period (LMF’) measurements. Evidence has suggestedthat the Ballard score does not assess gestational age differently for term or preterm in&ants (47) and that the overall assessmentof age is close to that of ultrasound measurements. Comparisons with previous studies ot preccrm delivery are limited by the focus on drinking during early pregnancy (22, 23, 44, 48). The current analyses support evaluating the relation between third-trimester alcohol exposure and preterm delivery, with evidence to show substantial differences in risk based on the period of exposure. The current study analyzed alcohol exposure for two defined periods of time during pregnancy Risk estimates for these 2 months within each outcome illustrate the importance of analyzing different windows of exposure, which is supported by earlier research (7, 8, 10, 42). The current study suggests that critical periods for alwhol exposure do exist, even at low levels of alcohol drinking. Minimal attention has been given to biological mechanisms that may be responsible for the observed feral effects of a low level of drinking. Total estrogen concentrations have shown a linear increase with alcohol intake (49, 50), which in turn may be associated with protective health effects. If alcohol does precipitate changes in total estrogen concentration, altered estrogen-to-progesterone ratios may play a role in specific neonatal outctomes “i stttdy of cardio-

506

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Lund&erg et al. GESTATIONAL ALCOHOL USE AND PREGNANCY OUTCOMES

vascular disease among a large cohort of men found a significant protective effect of moderate drinking on heart disease and overall mortality (51). Similar mechanisms may influence the etiology of perinatal events. History of alcoholism has been identified as a risk factor for poor fetal growth; abstinent alcoholics were found to have infants with lower birthweights than women with no history of alcoholism (52). This finding supports the theory of permanent reproductive damage from chronic alcohol exposure. However, there were few heavy drinkers in the current study population, and the estimates for low birthweight do not reflect an increasing pattern of risk with alcohol drinking. Nutritional imbalances, particularly zinc deficiencies (53), may operate as cofactors in the etiology of poor perinatal outcomes. However, there were few indicators of poor nutrition in this population, and it is reasonable to suggest that only heavy or chronic alcohol use would precipitate nutritional disorders. Animal models have been important in the understanding of teratogenic pathways for heavy alcohol use during pregnancy (39). Administration of alcohol or ethanol in a controlled environment, however, may not appropriately represent true risks from exposure to alcohol. Physiological differences in the metabolism of alcohol and acetaldehyde must also be taken into account. Laboratory experiments have not provided detailed information on the effects of low level and intermittent prenatal administration of alcohol in humans. Measurement and classification of alcohol exposure have been problematic in epidemiologic studies of prenatal drinking. In the current study, women who consumed alcohol drank primarily tow-to-moderate levels. However, most studies of prenatal drinking have focused on heavy drinking and its effects on birthweight. In the current study population, lower levels of drinking were common, which may be more representative of a substantial proportion of women in the general population. Averaging exposure to alcohol and creating a score that yields a daily average exposure may mask drinking patterns that influence fetal growth. Intermittent alcohol exposure, such as binge drinking, may be a particularly strong risk factor for negative birth outcomes (14,32). Binge drinking was defined as the consumption of five or more drinks on one occasion. The independenr effect of binge drinking in this study (n = 46) demonstrates the highest risk of IUGR (RR, 1.89; 95% CI, (X93-3.83) and a twofold risk for low bi~hweight (RR, 2.19; 95% CI, 0.83-5.79). Variation in units of alcohol and inconsistencies in the definition of light, moderate, and heavy alcohol use make comparisons and interpretation among studies difficult. Previous studies have measured maternal drinking in milliliters (6), centiliters (IZ), drinks (8,25), grams (I I), and ounces (14, 21). Descriptive terms applied to drinking levels also have shown great variation and tend to be subjective. It is

estimated that one drink is the equivalent of 0.5 oz of AA (20); however, constructing a validated alcohol score (29) increased the precision of our measure of exposure. Underreporting of alcohol use in pregnancy remains a significant obstacle to valid data collection (54). It is difficult to assesswhether the extent of underreporting differs by drinking level. In a low-to-moderate drinking population, it is unlikely that there would be differential reporting based on exposure classification. If alcohol exposure was reported di~erentially, we would likely see these effects in all outcomes represented for month 7 exposure. Linear increased risk estimates for preterm delivery were seen for month 7 drinking; estimates for IUGR indicate a slightly curvilinear effect, with no material increase in risk. Biomarkers of alcohol exposure are limited in their usefulness, particularly among a low-to-moderate drinking population (55). Rapid clearance of alcohol from the bloodstream makes direct measurement of blood alcohol level a poor predictor of exposure (56). Interview data remains the most feasible method to assesslow-to-moderate levels of drinking. Alcohol exposure during pregnancy represents a spectrum of effects, dependent upon factors including frequency and intensity of drinking, timing of exposure, duration of use, beverage type, and history of alcohol-related illness. Longitudinal studies are effective in determining the extent of effects from low-to-moderate maternal drinking. The protective effect of early gestational drinking on IUGR and the increased risk of late alcohol exposure on preterm delivery in this study appear to be real. These markedly different relationships of drinking with pregnancy outcomes point to the distinct etiology of preterm birth and growth retardation, which warrant separate investigation. While birthweight has historically been an end point of interest with respect to maternal drinking, the current study found no strong relation to alcohol exposure. Low birthweight is a heterogeneous mix of IUGR and early gestation and subsequently is not clinically informative in relation to maternal drinking. While the curvilinear effect of IUGR may be real, the increased risk of preterm delivery associated with late pregnancy drinking outweighs any potential benefit of alcohol on fetal growth.

This research was supported by the National Institutes of Health by grants DA05484 and HD33783. We thank the staff of the Perinatat ~pid~miolo~ Unit, the cooperating private obstetrical of&es in New Haven, Yale-New Haven Hospital, and the women who participated in this study.

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