Patterns of Prenatal Alcohol Use That Predict Infant Growth and Development

Data for this analysis are from a prospective cohort study of pregnant women in western Ukraine conducted as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) (www.cifasd.org), supported by the National Institute on Alcohol Abuse and Alcoholism. This randomized clinical trial of micronutrient supplementation has been described elsewhere in detail.^24,25 Briefly, all pregnant women who presented to 1 of 2 centralized prenatal care facilities in the Ukraine, the Rivne Regional Medical Diagnostic Center and the Khmelnytsky Perinatal Center, between April 2008 and August 2012 were eligible for screening about their alcohol consumption around conception and the most-recent month of pregnancy. Women who reported binge episodes of 4 to 5 alcoholic drinks per occasion at least weekly, at least 5 episodes of 3 to 4 drinks, or at least 10 episodes of 1 to 2 drinks in the month around conception and/or in the most-recent month of pregnancy were recruited. After the identification of a participant who was exposed, the woman who was the next minimally exposed or unexposed (<2 drinks per occasion, ≤2 drinks per week in the month around conception, and no alcohol in the most-recent month of pregnancy) was recruited for participation. Women were interviewed about demographics, behaviors, and pregnancy characteristics by using standard questionnaires on enrollment and again at ∼32 weeks’ gestation. After birth, information on growth was collected from medical records. Mothers of live-born infants were invited back twice postpartum (∼6 and 12 months of age), at which time neurodevelopmental assessments were conducted with the infants.

This analysis was approved by the institutional review board at the University of California, San Diego.

After enrollment, women who reported ever being drinkers in their lifetimes completed a timeline follow-back assessment of day-by-day alcohol consumption by type, quantity, and frequency in a typical week around conception and in the most-recent 2 weeks of pregnancy.²⁶ The quantity and frequency of alcohol consumption in response to these questions were summarized as the average number of drinks per day over the period for which each mother was reporting as a reflection of the overall quantity of alcohol consumed. This information was then converted into absolute ounces of alcohol (ozAA) per day. One standard drink is equivalent to 0.5 ozAA. At a follow-up pregnancy visit at ∼32 weeks’ gestation, women were asked if their alcohol consumption had changed since the enrollment visit, and if they answered yes, they were again asked to recall alcohol consumption for the previous 7 days commensurate with the enrollment visit procedures.

For each participant, a 40-week gestational exposure profile was created from the following information. The average ozAA per day reported at conception was assumed to have continued until the point of self-reported pregnancy recognition (mean: 5.6 weeks’ gestation). At the week of pregnancy recognition, exposure was assumed to have changed to the average ozAA per day reported at the enrollment visit. This amount was carried forward until the gestational week of the follow-up pregnancy visit, at which consumption was updated and assumed to have changed or continued unchanged from enrollment until 40 weeks’ gestation. To identify similar clusters of individual PAE trajectories, we employed the R statistical software package “kml.”^27,28 Additional information on k-means longitudinal (kml) data is found in the Supplemental Information.

Infant weight, length, and head circumference at birth were abstracted from medical records and converted to sex- and gestational age–specific percentiles based on US Centers for Disease Control and Prevention growth charts.²⁹ Neurodevelopment was evaluated at 6 and 12 months of age with the Bayley Scales for Infant Development, Second Edition.³⁰ Testing was administered by 1 of 2 Ukrainian psychologists who were blinded to each mother’s alcohol exposure group. Participants who missed the 6-month assessment (n = 120) were still eligible to complete the 12-month assessment.

We focused our analyses on the Mental Developmental Index (MDI) and Psychomotor Development Index (PDI), both of which were standardized to a scale with a mean of 100 and an SD of 15. The MDI is used to assess early cognitive and language development through measures of knowledge, problem solving, and memory. The PDI is used to evaluate body control, the manipulation of large muscles, and fine manipulation skills. All scores were age standardized and age corrected for births before 37 weeks’ gestation (n = 22).

Maternal age, gestational age at enrollment, gestational age at pregnancy recognition, cohabitation status (married, single, divorced, or separated), maternal prenatal or multivitamin use (randomly assigned to a multivitamin supplement for the trial and/or self-report of vitamin use in pregnancy at the time of enrollment), and maternal smoking status (never, quit before pregnancy, quit at recognition of pregnancy, or continued) were captured from the maternal enrollment interview. Socioeconomic status (SES) was calculated by using Hollingshead³¹ scores based on maternal report of maternal and paternal occupation and education.

Descriptive characteristics (frequencies and means) were stratified by trajectory groups. To test the association between trajectory group and maternal characteristics, we performed an analysis of variance for continuous variables and χ² with Fisher’s exact tests (when necessary) for categorical variables.

Generalized linear models were constructed to estimate β coefficients for trajectory group and growth outcomes (weight, length, and head circumference) and neurodevelopment (MDI and PDI) at 6 and 12 months of age. All models were adjusted for vitamin use in pregnancy, Hollingshead SES, maternal age at enrollment, maternal smoking status, and gestational age at enrollment.

To account for 25% to 27% loss to follow-up on the 6- and 12-month neurodevelopmental examinations, respectively, we repeated the neurodevelopment models with the inclusion of stabilized inverse probability of censoring weights (IPCWs).³² Loss to follow-up at 6 and 12 months of age was associated with lower SES (P = .003) and lower educational achievement (P = .001) and was marginally associated with younger maternal age (P = .16). Also, although alcohol trajectory group was not statistically significant (P = .32), 39% of infants born to women in the C trajectory group (low-to-moderate PAE sustained across gestation) and 27% in the D trajectory group (moderate-to-high PAE with reduction early in gestation) did not complete the 6-month neurodevelopmental assessment versus 23% in the A trajectory group (minimal to no PAE throughout gestation). Thus, SES, maternal education, maternal age, and trajectory group were included in the denominator of the stabilized weights.

We enrolled 776 women into the study at a mean gestational age of 18.2 weeks. Of these, 483 (62.2%) completed the second pregnancy interview at a mean gestational age of 31.9 weeks, in which alcohol consumption over the previous 2 weeks was again collected. Eight participants who did not report pregnancy recognition (necessary for trajectory creation) were excluded, as were 2 twin sets, resulting in 471 women in the final analytic sample. Women who completed both pregnancy visits were more likely to have higher SES, have attended college, and have realized they were pregnant ∼1 week earlier in gestation (mean: 5.6 weeks) and were less likely to have had a preterm delivery than women who only completed 1 pregnancy visit. The groups did not differ on smoking behaviors, vitamin use, cohabitation status, age, or amount of alcohol consumption reported at the enrollment visit.

A 5-trajectory solution was selected on the basis of quality criterion and clinical relevance (Fig 1). Trajectories were best described as minimal to no PAE throughout gestation (trajectory A), low-to-moderate PAE with discontinuation early in gestation (trajectory B), low-to-moderate PAE sustained across gestation (trajectory C), moderate-to-high PAE with reduction early in gestation (trajectory D), and high PAE sustained across gestation (trajectory E). Of note, although trajectory C started at a lower exposure in the first trimester relative to trajectory D (0.42 vs 0.62 ozAA per day), the members in trajectory C maintained a higher dose through the second trimester (0.33 vs 0.27 ozAA per day), resulting in a higher mean consumption over gestation (0.31 vs 0.26 ozAA per day; Table 1).

As anticipated on the basis of the study design, 230 women (48.8%) reported no alcohol consumption from the time of conception through the second pregnancy interview. The majority of women in the sample were married or cohabitating with a partner, had medium-to-high SES, used a prenatal or multivitamin in pregnancy, and were an average of 26.0 years of age at enrollment. Overall, the prevalence of preterm birth (<37 weeks’ gestation) in the sample was low (4.6%). When these factors were analyzed by trajectory group, women in trajectories C and E (sustained-use trajectories) reported later recognition of pregnancy, were less likely to have a college degree, and were less likely to use prenatal and/or multivitamins than those in the other trajectories (Table 2).

In multivariable models adjusted for vitamin use in pregnancy, Hollingshead SES, maternal age at enrollment, maternal smoking status, and gestational age at enrollment (Fig 2), only trajectory E (sustained high use) was associated with a reduced birth weight percentile (−16.5; 95% confidence interval [CI] −28.2 to −4.9) and length percentile (−12.6; 95% CI −22.6 to −2.5) compared with trajectory A (minimal or no use). There were no statistically significant effects observed between PAE trajectories and head circumference.

Greater alcohol use in pregnancy was associated with lower neurodevelopmental scores (Fig 3). Trajectory E (highest sustained use) was associated with deficits in MDI and PDI scores at both 6 and 12 months of age relative to trajectory A (minimal or no use). Moderate-to-high use with reduction (trajectory D) was associated with reduced MDI scores at 6 and 12 months of age, and low-to-moderate sustained use (trajectory C) was associated with reduced performance on the PDI at 6 months of age and the MDI at 12 months of age. PAE characterized by trajectory B (low-to-moderate discontinued use) was not associated with any neurodevelopmental deficits. IPCWs did not meaningfully change any estimates or conclusions; thus, results adjusted with IPCWs are presented.

Group-based trajectory methods allow for the retention of quantity, frequency, and timing of PAE in the exposure categorization. Using LCA, we identified 5 distinct trajectories of alcohol consumption in pregnancy: a minimal or no use group, 2 groups with low-to-moderate or moderate-to-high consumption with reduction early in pregnancy, and 2 groups with low-to-moderate or high consumption with sustained use. As anticipated, the trajectory with the highest sustained use was associated with reduced weight and length at birth and deficits in neurodevelopmental domains at both 6 and 12 months of age, replicating decades of research.^2,3,13,33 

Interestingly, on most neurodevelopmental outcomes, trajectory C (low-to-moderate sustained use) had larger deficits compared with trajectory D (early moderate-to-high consumption), although CIs overlapped widely, and not all findings were statistically significant. These differences, although modest and not statistically significant, persisted through the 12-month follow-up period. This same pattern was also observed with birth weight and length percentiles, although again with overlapping CIs that crossed the null. These observations reveal that for certain infant adverse outcomes, prolonged exposure to alcohol through gestational weeks 10 to 20, even at modest amounts, may be more detrimental than brief periods of higher consumption limited to earlier in pregnancy. Researchers in previous studies have reported a dose-response pattern between PAE and neurodevelopmental outcomes, although low-to-moderate levels of consumption tend to have more variation and be more difficult to interpret.³³ Although our findings are generally in concurrence, the nuance between sustained low-to-moderate exposure and discontinued moderate-to-high exposure are intriguing and reinforce the notion that intervention, even after the first trimester, should be strongly encouraged.^9,34,35 

This methodology of exposure assessment is not without precedent. In a recent analysis of 11 692 pregnancies in the Safe Passage Study, Dukes et al²⁰ performed Proc Traj to describe alcohol (drinks per drinking day) and tobacco exposure measured up to 4 times in pregnancy. Proc Traj is another LCA methodology that is available in SAS (SAS Institute, Inc, Cary, NC)³⁶; yet unlike kml, this methodology allows for formal checks of the validity of partitioning trajectory groups. Their sample included participants from the Northern Plains of the United States and South Africa. Remarkably, despite the differences in sample characteristics and size, both studies revealed 5 trajectories that were used to best describe PAE with the same general patterns of consumption: 2 with high or low continuous use, 2 with high or moderate use with early pregnancy discontinuation, and a group with no use. Similar to our sample of pregnant women in the Ukraine, participants from the Safe Passage Study who continued drinking were less likely to have completed higher education and were more likely to have enrolled later in pregnancy. In a second study of 6597 women recruited in Australia between 1981 and 1983, the investigators performed LCA on drinking measured at 4 time points: prepregnancy, early pregnancy, late pregnancy, and 6 months postpartum.²³ Exposure was defined at each time point as the product of the frequency and quantity of alcohol consumption. Three trajectories were identified: high consumption (with reduction in early pregnancy), light consumption (<0.5 glass per day), and abstainers. Mothers who were unmarried and multiparous were more likely to be in the high-use category.²³ 

To our knowledge, our study is the first in which researchers report on LCA for PAE and associated growth and neurodevelopmental outcomes in offspring. The relatively homogenous sample of women, recruited 1:1 for alcohol exposure, allowed for a broad and heterogeneous distribution of alcohol consumption in a relatively small sample. The 2 structured interviews on alcohol exposure in pregnancy and the clinician-assessed growth and neurodevelopmental outcomes are additional strengths of the study. This study has several limitations. PAE is not deterministic; some children who are exposed to low doses of alcohol are affected, whereas others who are exposed to high or sustained doses are not.⁹ Physiologic, genetic, and epigenetic factors, such as placental functioning, maternal IQ, illicit and licit substances, and nutritional and sociodemographic factors may all contribute to outcomes. Many of these covariates were not collected or vary over the course of a pregnancy, which could result in residual confounding. Additionally, we relied on maternal recall of alcohol exposure, which if differentially reported by trajectory group could result in biased estimates. Similarly, women with only 1 pregnancy visit were excluded from analysis and differed on select baseline characteristics. This could limit the generalizability of results in those strata. Also, in LCA, there is subjectivity in the number of trajectories selected. Although we used the quality criterion available in kml, strata size and clinical relevance were also considered. Although we were reassured that the same basic trajectories were found in the Safe Passage Study when using LCA with formal group partitioning criteria, we recognize that both samples consist of high-risk populations, which is likely the reason for the difference in trajectory shapes in the Australian sample. As a result, other samples will probably not have the same patterns of use, and the generalizability of these consumption patterns may be limited. Finally, infant screening measures are relatively insensitive to mild-to-moderate developmental deficits due to the participants’ young age; thus, future developmental testing is appropriate.²⁵ Future work with the methodology will include an exploration of associations between trajectory groups and cardinal and noncardinal physical features as well as the repetition of these analyses with preschool and school-aged growth and neurodevelopmental evaluations to determine if these observations in infancy are enduring.

Classifying PAE by using group-based trajectory methods allows for a more nuanced approach for describing complex exposure patterns. Using this method, with our findings, we confirmed that high, sustained PAE across gestation confers the highest risk for adverse infant outcomes but demonstrated that even low-to-moderate PAE continued across gestation is associated with certain deficits. This strongly reinforces the important message that no matter the initial amount of consumption, cessation increases the chances for improved offspring outcomes. Trajectory methods of classifying the dose, timing, and duration of PAE may be more informative than other methods when predicting the effects of PAE on infant outcomes. With our findings, we support the continued use of the methodology to further delineate risk by different patterns of consumption. This approach can be used to help clinicians counsel pregnant women on the risk of alcohol use even at moderate-to-low levels. Furthermore, it can be used to help identify high-risk infants for targeted early intervention.

CI

confidence interval

CIFASD

Collaborative Initiative on Fetal Alcohol Spectrum Disorders

FASD

fetal alcohol spectrum disorder

IPCW

inverse probability of censoring weight

kml

k-means longitudinal

LCA

longitudinal cluster analysis

MDI

Mental Developmental Index

ozAA

absolute ounces of alcohol

PAE

prenatal alcohol exposure

PDI

Psychomotor Development Index

SES

socioeconomic status

All or part of this work was done in conjunction with the CIFASD, which is funded by grants from the National Institute on Alcohol Abuse and Alcoholism. Additional information about CIFASD can be found at www.cifasd.org. We acknowledge the contribution of Omni-Net, Ukraine, and the participating families and staff in Rivne and Khmelnytskyi, Ukraine.