Effect of magnitude and timing of maternal pregnancy blood lead (Pb) levels on birth outcomes

Abstract

Objective:

Associations between magnitude and timing of maternal pregnancy blood lead (Pb) levels (BLLs), birth weight, and total days of gestation were examined, as well as associations with related clinical diagnoses of low birth weight (LBW), preterm, and small-for-gestational-age (SGA) birth.

Study Design:

Among a sample of 262 mother–infant pairs studied retrospectively, one-way analysis of variance and regression statistics were used to measure the relationship between level of maternal pregnancy BLLs and birth outcomes while controlling for key maternal and newborn factors.

Results:

Women with maximum pregnancy BLLs (max-PBLLs) 10 μg/dl tended to give birth earlier and their babies were at substantially increased risk for preterm and SGA birth. By holding other explanatory factors constant, each unit increase in max-PBLL above 10 μg/dl was found to be associated with a decrease of −0.3 in total days of gestation. Compared to women with lower levels, women with max-PBLLs 10 μg/dl were at a threefold increased risk for preterm birth (adjusted OR=3.2, 95% CI 1.2–7.4) and more than a fourfold increased risk for having an SGA infant (adjusted OR=4.2, 1.3–13.9). Second trimester maximum BLLs 10 μg/dl were associated with a steep decrease in total days of gestation (a decrease of −1.0 days per each unit increase above 10 μg/dl).

Conclusions:

These data provide evidence of the adverse effects of maternal pregnancy BLLs, particularly when levels are 10 μg/dl. Prenatal Pb exposure at these levels was associated with significant decreases in total days of gestation and an increased risk of preterm and SGA birth.

Introduction

Although lead (Pb) is a well-known reproductive toxicant that readily crosses the placenta,1 questions remain about the association between prenatal Pb exposure and poor pregnancy outcomes. Of particular concern are lingering questions about how the level and timing of in utero Pb exposure might affect birth weight and length of gestation, and increase the risk of giving birth to a low birth weight (LBW), preterm, or small-for-gestational-age (SGA) infant. Characterization of these effects is important for determining appropriate clinical care for Pb-exposed women and newborns and for development of preventive public health policy, given the well-known association between poor developmental trajectories and these birth outcomes2, 3, 4 and the increased prevalence of these events among poor and other at-risk populations,5, 6 who are also known to be at increased risk for Pb exposure.7, 8, 9

Previous epidemiologic studies examining the association between prenatal Pb exposure, birth weight, length of gestation, and intrauterine growth have differed in their conclusions.10, 11, 12, 13, 14, 15, 16 Such differences might be explained in part by under- and over-control of potential confounders, choices with respect to categorical versus continuous representation of predictors and outcomes, and significant differences in the range of maternal blood lead (Pb) levels (BLLs) considered.17 Given clinical and animal studies suggesting that birth outcome may be dependent on timing of prenatal Pb exposure in addition to level of exposure,18, 19 it is also possible that differences between studies might be partly explained by between-study sample variation in timing or measurement of prenatal Pb exposure.

Here we evaluate the relationship between maternal BLLs during pregnancy and birth weight, total days of gestation, LBW, preterm, and SGA birth, among a population-based sample of 262 mother–infant pairs for whom maternal Pb testing results for whole blood drawn between day 1 of pregnancy and day of delivery were reported to state Pb surveillance agencies, which were then linked to electronic California birth records. Analyses consider several potentially confounding maternal and child factors and, where possible, indicators of timing of prenatal Pb exposure. Our hypothesis was that after appropriate control of likely confounders, we would observe a significant association between maternal BLLs during pregnancy and the birth outcomes studied. We also expected to find evidence suggesting that one or more of the observed associations was influenced by timing of prenatal Pb exposure.

Materials and methods

All mothers included in the study were identified using available surveillance data maintained by the California Childhood Lead Poisoning Prevention Branch (CLPPB) and the California Occupational Lead Poisoning Prevention Program (OLPPP). In order to identify a population-based sample of pregnant women giving birth between 1996 and 2002, who had whole blood Pb testing done between day 1 of pregnancy and day of delivery, all whole blood Pb results reported to either the CLPPB or OLPPP between 1995 and 2002 for women reported as ‘pregnant’ by a physician, public health nurse or laboratory, or who were between 14 and 45 years of age at the time of Pb testing (n=6216) were, where possible, linked to electronic birth records obtained from the California Center for Health Statistics for birth years 1996–2002. During this time, laboratories throughout the state were required to report BLLs 25 μg/dl to these state agencies and most were reporting levels 10 μg/dl. In addition, some laboratories were voluntarily reporting lower levels. Although reason for maternal test was generally not reported, given that the databases used tend to focus on occupational and childhood Pb poisoning prevention and surveillance, we suspect that the results reported were mostly from women tested due to potential Pb exposure (e.g. occupational or other environmental exposure) or because another family member was identified as having been Pb exposed.

Inclusion in the final sample required that the following: (1) the linkage of maternal Pb testing results reported to the CLPPB or OLPPP and electronic birth records be ‘highly reliable’, that is, there be a match between records on mother's first and last name (maiden or married), mother's date of birth, and residential address; (2) Pb test results be for whole blood drawn between day one of pregnancy and day of delivery (where day 1 of pregnancy was generated by subtracting total days of gestation reported in electronic birth records from infant date of birth); (3) the infant be a singleton; (4) there be no indication in the birth or in the associated CLPPB or OLPPP record(s) of maternal smoking during pregnancy; and (5) there be no indication in the birth, CLPPB, or OLPPP record(s) suggesting the presence of a non-Pb-related condition or illness known to be highly associated with any of the birth outcomes of interest (e.g. maternal diabetes, rubella). Two hundred and sixty-two mother–infant pair records met these inclusion criteria and were included in the final sample.

There were 682 BLLs received for the 262 women in the sample (ranging from 1 to 130.0 μg/dl). All maternal BLLs were reported to the California Department of Health Services by licensed laboratories that were accredited to do whole blood Pb testing. Laboratories differed in how they reported BLLs. Some BLLs were reported to the nearest whole number while others were reported to one decimal point. Also, detection limits (or the minimum level reported) ranged from 1 to 10 μg/dl. To account for such differences, for these analyses, we rounded all BLLs to the nearest whole number and, where a BLL value was reported as ‘below detection limit’ and level of detection was above 1 μg/dl (n=11), precautions were taken to ensure that our analyses were not compromised by these data points. Specifically, these values were excluded from analyses where BLL was treated as a continuous variable. Also, in instances where values were reported as being ‘below detection limit’ and the detection limit was reported as 6 to 10 μg/dl (n=3), data were excluded from categorical analyses where BLLs were categorized as 5, 6–9, 10–19, 20–39, and 40 μg/dl. These data points were included in categorical analyses where BLLs were dichotomized as <10 and 10 μg/dl.

For analyses, maximum pregnancy Pb level (max-PBLL) was considered to be the maximum BLL reported between the first day of pregnancy and day of delivery. Maximum trimester BLL was considered to be the maximum BLL reported during a specific trimester. Each woman contributed only one sample to each analysis.

Our choice to use the <10 and 10 μg/dl grouping in analyses considering max-PBLL or maximum trimester BLL as a dichotomous variable was informed by the use of the same cut point in similar investigations20 and designation of 10 μg/dl as the Pb level of concern for pregnant women by the District II and Minnesota Chapters of the American College of Obstetrics and Gynecology (ACOG).21, 22 At this time, no similar recommendations, guidelines, or pregnancy-specific levels of concern have been adopted by the national AGOG or by the Centers for Disease Control and Prevention (CDC). The CDC designates 10 μg/dl as ‘elevated’ for children and recommends guidance and follow-up at this level.23, 24

Crude (unadjusted) analyses included the comparison of the mean birth weight and the mean total days of gestation of infants born to women with differing max-PBLLs grouped as 5, 6–9, 10–19, 20–39, and 40 μg/dl. One-way analysis of variance (ANOVA) was used to compare means for the low-to-no Pb group (5 μg/dl) with each of the groups with higher Pb levels. This comparison was also done for the <10 μg/dl group compared to the 10 μg/dl group.

Crude and adjusted linear regression models were evaluated and fit to measure the relationship between max-PBLL, birth weight, and total days of gestation. Separate models were run for max-PBLLs <10 μg/dl (low max-PBLLs models) and max-PBLLs 10 μg/dl (high max-PBLLs models). Consideration of models including all max-PBLLs regardless of level (all max-PBLLs models) was contingent on findings from the low and high max-PBLLs models demonstrating a significant linear relationship in the same direction. All modeling included evaluation of the normality of the raw and residual data in order to assess the need for log transformations. A non-normal distribution of the residuals in each model was considered as a trigger for log transformation of maternal BLL data. Characteristics included as confounders in the adjusted models were maternal race (white: non-white), maternal age (<35: 35 years), prior parity (0: 1), infant sex (female: male), and insurance payment for delivery (private: public) wherein public insurance was considered a proxy for poverty. All of the factors included as confounders have consistently been shown to be associated with birth weight, length of gestation, intrauterine growth retardation (IUGR), and/or associated clinical diagnoses (LBW, preterm, or SGA birth) by other investigators.5, 25, 26, 27 In addition to inclusion of these potentially confounding factors, an a priori decision was made to include total days of gestation in the adjusted birth weight models and birth weight in the total days of gestation models in order to tease out independent associations between max-PBLLs and these birth outcomes. Because total years of maternal education was missing in 20.6% of all birth records, total years of maternal education was not included in any of the analyses.

Crude and adjusted logistic regression models were used to further evaluate the relationship between max-PBLL (grouped as 5, 6–9, 10–19, 20–39, and 40 μg/dl, or as <10 and 10 μg/dl), LBW, preterm, and SGA birth. For these analyses, LBW was defined as birth weight <2500 g, preterm birth was defined as <37 completed weeks gestation, and SGA birth was defined as birth weight for gestational age <10th percentile on population-based race- and gender-specific birth norms for singletons. We generated these norms from the same 1996 to 2002 birth records from which the study sample is drawn, which included close to 3.5 million births (n=3 336 868). Just as with linear models, the normality of the raw and residual data was evaluated in order to assess the need for log transformation of BLL data in any logistic model. Eligibility for confounder inclusion was the same as for linear models, with the exception that an a priori decision was made to include preterm birth in LBW models and LBW in preterm models. SGA models did not include race, sex, birth weight/LBW, or gestational age/preterm birth because these factors were considered in initial SGA classification.

Where sample-size allowed, additional exploratory analyses evaluating the relationship between maximum BLL by trimester and categorical and continuous birth outcomes were performed using the same methods. All analyses were completed using Statistical Analysis Software (SAS), version 8.0.28 The Institutional Review Board of the California Department of Health Services approved the protocol for this study.

Results

Sample characteristics

Listed in Appendix A (electronic publication only) are selected maternal characteristics of the study sample. Most women in the sample were Hispanic (62.2%), were less than 35 years of age (84.7%), and had one or more children (62.6%). About half of the women were receiving publicly funded health insurance (50.8%). Approximately equal numbers of male and female infants were included (49.2 and 50.8%, respectively). Although timing of blood draw tended to be restricted to a single trimester for most women in the sample, women with max-PBLLs 20 μg/dl (n=56) were more likely than those with lower max-PBLLs to have testing results reported for more than one trimester (46.4% compared to 8.0% of those with max-PBLLs from 10 to 19 μg/dl (n=25) and 2.2% of those with max-PBLLs <10 μg/dl (n=181) had test results for multiple trimesters). In general, women with max-PBLLs 20 μg/dl had multiple BLLs reported (84.0%), whereas women with lower max-PBLLs tended to have only a single BLL report (60.0% of women with max-PBLLs from 10 to 19 μg/dl and 92.7% of those with max-PBLLs <10 μg/dl had a single BLL report).

Comparisons by Max-PBLL

Table 1 compares the mean birth weight and total days of gestation of infants born to women with max-PBLLs 6 (categorized as 6–9, 10–19, 20–39, and 40 μg/dl) to those of infants born to women with max-PBLLs 5 μg/dl and compares the mean birth weight and total days of gestation of infants born to women with max-PBLLs 10 μg/dl to those of infants born to women with max-PBLLs <10 μg/dl. In general, the mean birth weight and total days of gestation of infants born to women with max-PBLLs 10 μg/dl tended to be lower than that of infants in the lower max-PBLL comparison groups.

Table 1 Relationship of maximum pregnancy blood Pb levels (max-PBLLs)a to mean birth weight and total days gestation

Results from linear regression analyses are included in Table 2. A significant linear association between total days of gestation and max-PBLL was observed in both crude and adjusted linear models considering max-PBLLs 10 μg/dl. Most notably, the max-PBLL 10 μg/dl model was found to explain 22.4% of the variance in total days of gestation. Holding all other factors constant, these findings indicated a decrease of −0.3 in total days of gestation for each 1 μg/dl increase in max-PBLL above 10 μg/dl. This relationship is illustrated in Figure 1. Examination of outliers via discordancy tests on studentized residuals >3.0 (n=2) revealed no substantial outlier effects for the adjusted model (R2=0.194, coefficient for max-PBLL when other factors held constant and outliers removed=−0.2, P<0.05). Residual diagnostics in all of the crude and adjusted linear models indicated a normal distribution and, as such, no transformation of max-PBLL data was undertaken. No such relationships were noted in any of the <10 μg/dl birth weight or total days of gestation models or in the 10 μg/dl birth weight models.

Table 2 Results from linear regression analyses measuring the relationship between maximum pregnancy blood Pb level (max-PBLL), birth weight, and total days gestationa
Figure 1
figure1

Unadjusted linear model for total days of gestation as a function of maximum pregnancy blood Pb level (max-PBLL) 10 μg/dl. R2=0.059 for unadjusted model (n=80). R2=0.224 for adjusted model including birth weight, race (white: non-white), insurance payment for delivery (private: public), parity (1: 0), maternal age (<35: 35 years), and infant sex (female:male). Coefficient for each increase in max-PBLL of 1 above 10 μg/dl controlling for other factors=−0.3, P<0.05.

Table 3 includes results from logistic regression analyses, which also point to increased risks among women with max-PBLLs 10 μg/dl. For example, after controlling for likely confounders, women with max-PBLLs 10 μg/dl were at a threefold increased risk for preterm birth and at more than a fourfold increased risk for SGA birth as compared to women with max-PBLLs <10 μg/dl.

Table 3 Frequency and percentage of women giving birth to an infant categorized as low birth weight (LBW), preterm birth, or small-for-gestational-age (SGA) by category of maximum pregnancy blood lead level (max-PBLL)

Comparisons by maximum trimester blood Pb level

Exploratory analyses of birth outcomes by maximum trimester BLL suggested similar linear relationships (or the lack thereof) between maximum trimester BLL, birth weight, and total days of gestation as our analyses by max-PBLL. Results are included in Table 4. The adjusted total days of gestation maximum second trimester BLL 10 μg/dl model was particularly telling, explaining 64.9% of the variance in total days of gestation. Holding other factors constant, this model showed that each increase of 1 above 10 μg/dl in maximum second trimester BLL was associated with a decrease of −1.0 in total days of gestation. No substantial outlier effects were observed for any trimester model.

Table 4 Results from linear regression analyses measuring the relationship between maximum trimester blood Pb level, birth weight, and total days of gestationa

Although small cell sizes restricted our ability to undertake any evaluation of the relationship between maximum maternal BLL by trimester, LBW, and SGA birth, crude analyses examining the association between maximum maternal BLL by trimester (dichotomized as <10 and 10 μg/dl) and preterm birth were computed. These findings were somewhat similar to those for max-PBLL models. Women with either a first and third trimester maximum BLL 10 μg/dl were at substantially increased risk for preterm birth compared to women with maximum first or third trimester BLLs <10 μg/dl (crude ORs 5.1 (95% CI 1.4–5.9) and 8.3 (1.9–35.7), respectively).

Discussion

These data further document the adverse effects of prenatal Pb exposure and point to important dose-dependent relationships between max-PBLL, total days of gestation, preterm, and SGA birth. Exploratory analyses by trimester of BLL test also point to potential timing-dependent relationships between prenatal Pb exposure, length of gestation, and preterm birth. Our findings of a consistent, significant relationship between max-PBLLs 10 μg/dl and problematic birth outcomes show that maternal BLLs once considered low or moderate place some mother and infant pairs at substantially increased risk. Findings of a particularly significant and substantial relationship between maximum second trimester BLL 10 μg/dl and decreased total days of gestation (−1.0 decrease in total days of gestation per unit increase above 10 μg/dl) suggest that there are some time periods during pregnancy when Pb exposure may be particularly problematic.

Similar dose-dependent relationships have been reported by other investigators utilizing maternal BLLs collected during pregnancy10, 15, 29 and by investigators using cord BLLs12 and placental Pb levels11, 30 in their analyses. Our findings of a linear association between pregnancy BLL and decreased total days of gestation are most similar to those of Deitrich et al.,29 who noted a decrease of −0.46 gestational weeks per log unit increase in max-PBLL in their prospective study of 305 mother and infant pairs in Cincinnati, OH, USA. Our results also parallel findings by Falcon et al.,30 who noted a significant correlation between decreased total days of gestation and increased placental Pb levels among a sample of 89 mother–infant pairs in Spain.

Our findings with respect to preterm birth are most similar to those of McMichael et al.,10 who reported an 11% increase in risk for preterm birth per unit increase in maternal BLL at delivery among a cohort of 831 pregnant women in Port Pirie, Australia. Our data are also similar to those of investigators who reported a significant association between umbilical cord BLL at delivery and increased risk for preterm birth.11, 12 Our findings of an association between max-PBLL and increased risk for SGA birth are somewhat paralleled by the findings by West et al.,15 who reported a significant correlation between third trimester maternal BLL and decreased newborn ponderal index score among a sample of 98 African-American mother and infant pairs in Washington, DC, USA. Our null findings with respect to an explanatory relationship between prenatal Pb exposure and birth weight, or LBW are similar to those reported by numerous other investigators.10, 12, 15

Few studies have considered timing of BLL test (as a proxy measure of timing of Pb exposure) as a potential within-sample predictor of differing patterns of risk. The few that have considered some indicator of timing13, 31 were substantially different from the present study, making comparisons difficult. Our findings of a significant relationship between second and third trimester BLLs 10 μg/dl and decreased total days of gestation are perhaps best informed by recent animal studies. Although no animal study considering timing of prenatal Pb exposure has looked specifically at the associations examined in the present study, several investigations point to the importance of considering timing of prenatal Pb exposure when evaluating associations with hormone and immune system functioning.19, 32, 33 Of note are the findings by Bunn et al.,32 who demonstrated that adult female Sprague–Dawley rats who were administered Pb acetate late in gestation (compared to those that were administered a controlled acetate compound) had elevated interleukin-10 (IL-10) and decreased IL-12 production compared with controls. Given the importance of IL-10 and IL-12 to immune system functioning,34 abnormalities in the production of these cytokines may point to persistent vulnerabilities in immune system function among those exposed to Pb late in gestation. Such vulnerabilities might be associated with impairment in the uterine environment and may represent one mechanism by which prenatal Pb exposure, especially Pb exposure in the second and third trimesters, might shorten gestation. A similar mechanism by which impairment of the hormonal environment needed to maintain pregnancy (due to prenatal Pb exposure) might be causally related to spontaneous abortion has been proposed by other investigators.20

We suspect that differences between our findings and those of some other investigators13, 31 reflect certain methodological differences between studies. It appears likely that differences with respect to source of Pb information (e.g., pregnancy BLL, cord BLL), range of Pb levels considered, timing and window of exposure, and substantial differences with respect to statistical analyses are all likely contributors to discrepant conclusions. Arguably, as was pointed out in a review of similarly focused studies conducted before 1994,17 the tendency of some investigators to ignore likely confounders and of others to over-control for possible confounders has limited progress towards consensus. Similarities between our findings and those of investigators focused on the Port Pirie cohort10, 11, 35 may be, at least, partly due to the adoption of similar restrictions where inclusion of variables in final regression models was concerned. Differences between our findings and those of some other investigators who have considered dose and timing in their analyses but have found little or no effect of prenatal Pb exposure on total days of gestation or preterm birth13, 14 may reflect over-control of confounders by these investigators. In both of these studies, researchers included a long list of possible confounders in their models.

Some specific strengths of our study include the broad range of prenatal BLLs included (1–130 μg/dl), the presence of BLL reports across trimesters (allowing for exploratory analyses by trimester of test), and consideration of a number of important and appropriate confounders in our analyses. The most notable limitations of the present study include the lack of uniformity in laboratory reporting of maternal BLLs, the tendency for most women in the sample to be tested during only one trimester, and sample-size restrictions that limited our ability to utilize more precise confounder categorizations (e.g. consideration of multiple race/ethnicity groupings rather than ‘white’ versus ‘non-white’) and also limited a more detailed exploration of categorical birth outcomes. Such limitations may have yielded some unstable results. Also, because our sample likely included a disproportionate number of women who were likely tested due to being at high risk for Pb exposure, it is possible that the observed results may have been influenced by some degree of testing bias. This possible bias along with the likelihood of more complete reporting of higher BLLs is likely reflected in the high proportion of women in the sample with one or more pregnancy BLL 10 μg/dl (30.9%). Consideration of confounders in our analyses likely accounted for such bias; nevertheless, it is important to note this possibility.

Our choice to consider the associations between outcomes by trimester of testing may have been illustrative, whereas identifying potential periods where Pb levels are elevated might have greater impact; however, the lack of multiple maternal BLLs across trimesters for each woman leaves many questions unanswered. It is possible that pattern of BLLs across trimesters may mediate observed effects. Women with decreasing BLLs over pregnancy may be at a lesser risk than women with increasing BLLs despite having similar max-PBLLs. This may also have affected findings by other investigators. These questions can only be answered utilizing a sample of pregnant women with BLLs across trimesters. Such a study could help identify factors that might encourage decreases in BLLs and/or buffer against increases in BLLs before and during pregnancy.

Despite some limitations, considered together with the findings of previous investigators,10, 11, 12, 15, 29, 30 these results show that prenatal Pb exposure is a significant risk factor for decreased total days of gestation, preterm, and SGA birth – particularly when pregnancy BLLs are 10 μg/dl. As such, where risk of Pb exposure is present (e.g., remodeling of houses built pre-1978, employment in Pb industry, use of Pb-containing materials),36 Pb testing of pregnant women and women of childbearing age might prove a useful strategy towards early identification and possible prevention of some portion of these problematic birth outcomes.

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Acknowledgements

This work was supported in part by cooperative agreement number: US7/CCU918557-03 from the Centers for Disease Control and Prevention.

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Correspondence to L L Jelliffe-Pawlowski.

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Supplementary Information accompanies the paper on Journal of Perinatology website (http://www.nature.com/jp)

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Jelliffe-Pawlowski, L., Miles, S., Courtney, J. et al. Effect of magnitude and timing of maternal pregnancy blood lead (Pb) levels on birth outcomes. J Perinatol 26, 154–162 (2006). https://doi.org/10.1038/sj.jp.7211453

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Keywords

  • birth weight
  • low birth weight
  • preterm
  • small-for-gestational-age
  • environmental health
  • heavy metals

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