How to Control for Gestational Age in Studies Involving Environmental Effects on Fetal Growth
Environ Health Perspect. doi:10.1289/ehp.11105 available via http://dx.doi.org [Online 24 June 2008]
Referencing: Perfluorinated Chemicals and Fetal Growth: A Study within the Danish National Birth Cohort
In studies on the effects of environmental factors on fetal growth, birth weight is usually corrected for gestational age. With the generalized use of ultrasound examinations in many countries, gestational age is often defined or corrected from the ultrasound measurements performed during or immediately after the first trimester of pregnancy, which are compared to a reference growth curve. As an illustration, in a cohort study investigating the association between exposure to perfluorinated chemicals and fetal growth, Fei et al. (2007) defined gestational age from ultrasound measures performed before 24 gestational weeks and, if this information was missing, from the date of the last menstrual period (LMP).
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Figure 1. Hypothetical evolution of a fetal measurement (e.g., fetal length) during pregnancy for a pregnancy exposed or unexposed to an environmental factor that can affect fetal growth from early pregnancy. The ultrasound examination leads the obstetrician to correct the date of conception (t0) for the exposed pregnancy by Δt, so this exposed pregnancy is not compared with unexposed pregnancies with the same gestational age D (solid curve) as it should, but instead with gestational age D – Dt (dashed blue curve). Consequently, the estimated difference in the gestational age–specific fetal measurement at birth between exposed and unexposed pregnancies is not the correct value β but a smaller value β´.
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The superiority of ultrasound measurements over other approaches to predict the date of delivery (Lynch and Zhang 2007) does not imply that ultrasound-based gestational age leads to an unbiased estimate of the effect of environmental factors on fetal growth. The use of ultrasound-based gestational age assumes that fetal ultrasound measurements at a given gestational week during the first trimester have very little variability. However, there is some evidence to the contrary (Bukowski et al. 2007). Part of this variability might be due to exposure to environmental pollutants. If the environmental pollutant considered can restrict fetal growth as early as the first trimester, correcting gestational age using first-trimester ultrasound measurements will erroneously shorten the gestational age of these small-for- gestational-age fetuses. This may lead to underestimating effects of environmental pollutants on birth weight or size controlled for gestational age (Figure 1), compared with studies using an accurately estimated date of conception. In practice, an accurate estimate of conception date may seldom be available outside the setting of in vitro fertilization. An alternative is reliance on LMP-based estimates, which are prone to errors due to bad recall, variability in the duration of the follicular phase of the cycle and midcycle, and early pregnancy bleeding (Lynch and Zhang 2007). Moreover, using the LMP-based estimate of gestational age would be problematic if, as already reported for specific environmental pollutants (Windham et al. 2003), the environmental factors considered could influence the duration of the menstrual cycle. Therefore, detailed studies may be needed to determine the balance between the possible biases in the estimated effect of the environmental factor entailed by the use of ultrasound-based measurements and LMP-based estimates.
This potential bias has been recognized by Savitz et al. (2002) and was alluded to by Fei et al. (2007) in their "Discussion." However, its consequences have probably not been fully acknowledged. When possible, researchers should conduct sensitivity analyses using different measures of gestational age to help quantify the potential for bias. The same approach could also be used when gestational duration is the studied outcome (Lynch and Zhang 2007).
The authors declare they have no competing financial interests.
Rémy Slama
Avenir Team "Environmental Epidemiology Applied to Fecundity and Reproduction"
INSERM U823
Grenoble, France
E-mail:
remy.slama@ujf-grenoble.fr
Babak Khoshnood
Monique Kaminski
Epidemiological Research Unit on Perinatal and Women's Health
INSERM UMR S149, IFR 69
Villejuif, France
References
Bukowski R, Smith GC, Malone FD, Ball RH, Nyberg DA, Comstock CH, et al. 2007. Fetal growth in early pregnancy and risk of delivering low birth weight infant: prospective cohort study. BMJ 334(7598):836; doi: 10.1136/bmj.39129.637917.AE [Online 13 March 2007].
Fei C, McLaughlin JK, Tarone RE, Olsen J. 2007. Perfluorinated chemicals and fetal growth: a study within the Danish National Birth Cohort. Environ Health Perspect 115: 1677–1682.
Lynch CD, Zhang J. 2007. The research implications of the selection of a gestational age estimation method. Paediatr Perinat Epidemiol 21(suppl 2):86–96.
Savitz DA, Hertz-Picciotto I, Poole C, Olshan AF. 2002. Epidemiologic measures of the course and outcome of pregnancy. Epidemiol Rev 24(2):91–101.
Windham GC, Waller K, Anderson M, Fenster L, Mendola P, Swan S. 2003. Chlorination by-products in drinking water and menstrual cycle function. Environ Health Perspect 111:935–941.
How to Control for Gestational Age: Olsen and Fei Respond
Environ Health Perspect. doi:10.1289/ehp.11105R available via http://dx.doi.org [Online 24 June 2008]
As described by Slama et al., it is not a simple matter to adjust for gestational age when analyzing birth weights. Any estimate of gestational age is prone to misclassification, whether it is based on ultrasound or last menstrual period (LMP). Ultrasound measures are based on the assumption of uniform early fetal growth or at least that the exposure under study has no impact on early fetal growth. This assumption is probably not always correct, as first demonstrated by Henriksen et al. (1995). LMP estimates are prone to large random measurement errors that may become nonrandom if the exposures under study affects menstrual bleeding patterns.
Although these problems are part of textbook knowledge (Olsen and Basso 2007), their impact appears to be limited in our experience. In our study (Fei et al. 2007), the analyses based primarily on LMP estimates provided a regression coefficient of –10.35 [95% confidential interval (CI), –20.6 to –0.15] between perfluorooctanoate and birth weight, compared with the regression coefficient of –10.63 (95% CI, –20.79 to –0.47) we presented in the article after adjustment for ultrasound-based gestational age. The reason is probably that large random errors of gestational age affect estimates much more than smaller systematic errors. Furthermore, perfluorinated chemicals may not impair early fetal growth.
Birth weight is a function of fetal growth and the duration of the pregnancy, but until better estimates become available, we must use these imprecise measures of gestational age to determine the duration of pregnancy. If the exposure under study slows early fetal growth, adjustment for gestational age based on ultrasound may underestimate an effect of the exposure on fetal growth and overestimate a risk of preterm birth. A similar bias is expected when the results are adjusted for gestational age based on LMP data if the exposure prolongs menstrual cycles.
We thank Slama et al. for reminding us that estimating gestational age is always a problem.
The authors declare they have no competing financial interests.
Jřrn Olsen
Chunyuan Fei
Department of Epidemiology
University of California, Los Angeles
Los Angeles, California
E-mail:
jo@ucla.edu
References
Fei C, McLaughlin JK, Tarone RE, Olsen J. 2007. Perfluorinated chemicals and fetal growth: a study within the Danish National Birth Cohort. Environ Health Perspect 115: 1677–1682.
Henriksen TB, Wilcox AJ, Hedegaard M, Secher NJ. 1995. Bias in studies of preterm and postterm delivery due to ultrasound assessment of gestational age. Epidemiology 6:533–537.
Olsen J, Basso O. 2005. Reproductive epidemiology. In: Handbook of Epidemiology (Ahrens W, Pigeot I, eds). Berlin:Springer, 1043–1109.
