1 Department of Anesthesiology and Environmental Research Center, Charles R. Drew University of Medicine and Science, Los Angeles, CA.
2 Center for Research in Population Health, National Institute of Public Health, Cuernavaca, Mexico.
3 Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY.
Received for publication January 10, 2002; accepted for publication August 8, 2002.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
blood; blood pressure; bone and bones; lead; pregnancy
Abbreviations: Abbreviation: CI, confidence interval.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Elevated blood pressure or hypertension presents special risks to women, especially during pregnancy. Hypertension is the most frequent complication of pregnancy, comprising 510 percent of the total (1). Although physicians distinguish among preeclampsia and eclampsia, chronic essential hypertension during pregnancy, and acute or transient hypertension, the origins of these hypertensive disorders remain unknown, and treatments are not based on correcting underlying causes (2).
All forms of hypertension during pregnancy threaten the development or life of the fetus, and some, notably eclampsia, threaten the mothers life as well. Preeclampsia is identified by an elevated blood pressure (140/90 mmHg) in the second half of pregnancy with proteinuria and, variously, reduced platelets, an elevated serum creatinine level, and headaches or other central nervous system symptoms, among others. Preeclampsia may progress to eclampsia, in which the mother suffers seizures. A necessary but not sufficient feature of preeclampsia is pregnancy hypertension. Other predictors of increased risk are higher body mass index (3), nulliparity (4), diabetes mellitus, preexisting chronic hypertension (5), and elevated blood pressure earlier in pregnancy (69).
Having a higher blood pressure within normotensive limits in the second half of pregnancy is associated with reduced birth weight (10). Lowering a womans blood pressure during pregnancy, even in cases of mild hypertension, may decrease the risk of perinatal mortality and abruptio placentae, though treatment with antihypertensive medications may also present increased risk to the fetus (11, 12).
Lead exposure is a risk factor for hypertension and elevated blood pressure in the general population. Although there are many epidemiologic studies that show a positive association between blood pressure and lead exposure (1319), inconsistencies among studies have provoked controversy regarding the effect (see Hertz-Picciotto and Croft (20) for a review). Two large-sample studies reported a small but highly significant relation between blood lead concentrations in the umbilical cord (21) and in third-trimester pregnant women (19) and maternal blood pressure during pregnancy.
Recently, small but significant associations between bone lead concentration and hypertension risk were found in an aging male sample (22) and in a middle-aged to aging female sample (23), both in the absence of a significant concurrent blood lead effect. These authors suggested that, since bone lead reflects the accumulation of years to decades of lead exposure, the increased risk of hypertension associated with a higher bone lead concentration might be the result of damage due to past lead exposure.
Gaining control over any factor that can reduce the risk of pregnancy hypertension and elevated blood pressure will improve pregnancy outcomes. The purpose of the present work was to define the relations of both maternal bone lead concentration and blood lead concentrations in the third trimester of pregnancy and postdelivery with blood pressure and risk of hypertension during and after pregnancy.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Only 1,006 of these subjects returned for the postpartum phase, a mean of 10.0 weeks (standard deviation 1.9) after delivery. All 1,006 subjects returned within 18 weeks. Subjects were between the ages of 15 and 44 years. We excluded from these analyses all subjects with documented renal disease (n = 66), cardiovascular disease (n = 22), diabetes (n = 147), or extreme postnatal obesity (a body mass index (weight (kg)/height (m)2) greater than 40) (n = 32), as well as subjects who used stimulant drugs from the amphetamine and cocaine families (n = 5) during either phase of this study. We also excluded two subjects with pre- or postdelivery blood lead concentrations greater than 5 geometric standard deviations above the geometric mean of the rest of the sample. An additional 74 subjects had missing data on one or more of the pre- or postnatal dependent or independent variables and were excluded. Some subjects met more than one exclusion criterion. Of the excluded cases, 11 had hypertension according to criteria described in the "Statistics" section below, during either the prenatal phase or the postnatal phase of the study. Of the 667 retained cases, 31 met our criteria for hypertension.
The subjects treating physicians were notified at both stages of the study if blood lead levels exceeded 10 µg/dl (0.48 µmol/liter) (the upper limit considered safe for pregnant women by the Lead Surveillance Unit of the Los Angeles County Health Department) or if measured blood pressure exceeded 140/90 mmHg.
The study protocol and all materials were reviewed and approved by the King-Drew Institutional Review Board, and all subjects signed approved informed consent forms before joining the study.
Questionnaires
Experienced bilingual interviewers administered the screening questionnaire as a structured interview at recruitment during the third trimester of pregnancy. Subjects elected to receive either the English or the Spanish version. The same interviewers similarly administered the risk questionnaire at the postdelivery session while bone lead concentration (see below) was being measured. These questionnaires allowed us to gather basic socioeconomic and demographic data and information on medical and reproductive history, history of lead exposure, and dietary habits. Risk factors assessed included work and hobby histories, use of leaded paint and ceramic ware, and consumption of pica, cigarettes, alcohol, and other drugs and medications. The questionnaires recorded detailed information on the subjects medical history, with an emphasis on past and present pregnancies, diabetes, and cardiovascular, renal, thyroid, and parathyroid diseases. The questionnaires were used in previous studies and have been described in previously published articles (19, 24, 25).
Blood lead measurements
We drew venous blood into blue-top (trace-metal-free) Vacutainers (Becton Dickinson, Franklin Lakes, New Jersey) with heparin after cleaning the venipuncture site at the end of each scheduled subject visit. We analyzed the blood samples for lead concentration using the Perkin Elmer 4100ZL Zeeman atomic absorption spectrometer (Perkin Elmer, Wellesley, Massachusetts) with a graphite furnace at the studys toxicology laboratory (Environmental Research Center, Charles R. Drew University of Medicine and Science, Los Angeles, California). We analyzed every sample in duplicate and used the mean of the two values. The studys laboratory has participated successfully in the Wisconsin State Laboratory of Hygiene proficiency testing program and the College of American Pathologys blood lead quality-assurance program for more than 6 years, with no out-of-bounds results. Data on the quality control, accuracy, and precision of the blood lead analyses have been previously published (24, 25).
The detection limit for blood lead concentration was 0.4 µg/dl (0.02 µmol/liter), since coefficients of variability for measurements below this value regularly exceeded 15 percent. All blood lead concentrations recorded below the detection limit (n = 8) were assigned the value of 0.2 µg/dl (0.01 µmol/liter).
Blood pressure measurements
We measured sitting systolic and diastolic blood pressure using a Colin Press Mate (model BP-8800; Colin Medical Instruments Corporation, San Antonio, Texas) automated cuff-inflation instrument. We calibrated the instrument every 6 months during data collection against a mercury sphygmomanometer reserved for calibration use. The accuracy of the instrument remained within ±1 mmHg of the calibration standard.
After providing informed consent and completing the screening questionnaire interview, the subject remained seated while her blood pressure was measured, 3045 minutes after being introduced to the interviewer. Postdelivery blood pressure measurements were made during bone lead measurement, also after the subject had been seated for 3045 minutes. We made the measurements with cuff size selected according to subjects upper arm diameter and with the right arm elevated to heart height. Three consecutive measurements were made at 3-minute intervals. Pearson correlations among replicate pairs of systolic and diastolic blood pressure measurements averaged 0.81 and 0.71, respectively. The mean unsigned difference among the replicate pairs averaged 4.8 mmHg for systolic measurements and 4.2 mmHg for diastolic measurements. We used the means of the three consecutive measurements in the analyses.
Bone lead measurement
We measured bone lead concentrations at the midtibia (predominantly cortical bone) and midcalcaneus (predominantly trabecular bone) with a 109Cd K-shell x-ray fluorescence system that has been described previously (2527). Briefly, photons emitted from the decay of 109Cd (88 keV) excite lead atoms within the bone matrix, causing them to emit characteristic x-rays. The amount of coherent scattering of the 88-keV 109Cd photons is proportional to the amount of bone mineral. Because the lead x-ray signal is normalized to the coherent signal, the measurement has units of micrograms of lead per gram of bone mineral (µg/g). The technique allows estimation of the error of measurement, which is an underestimate of the standard deviation of replicate measurements (28). Because of measurement error, the measured bone lead concentration may be negative, especially in cases with a low bone lead level or a thick layer of fat and skin overlying the measurement site. We measured bone lead concentration only postnatally to avoid exposing the fetus to radiation.
Statistics
We used Stata (Stata Corporation, College Station, Texas) and SPSS (SPSS, Inc., Chicago, Illinois) software to manage the data and perform descriptive and inferential statistical tests. We used t tests for independent samples and Fishers exact tests to determine possible selection bias between subjects eligible for inclusion in the data set and those not eligible. Blood lead values were natural log-transformed to normalize the variable for all statistical procedures. Bone lead data had an approximately normal distribution; that is, the distribution of bone lead values in the sample was bilaterally symmetric about the mean value, though there was overrepresentation of subjects with bone lead concentrations around the mean as compared with the tails. In other words, the distributions had significant kurtosis compared with the normal distribution. We constructed two dichotomous hypertension variables (third trimester and postpartum) from the blood pressure measurements using a systolic cutpoint of 140 mmHg and a diastolic cutpoint of
90 mmHg. Any subject with either systolic blood pressure or diastolic blood pressure above the relevant cutpoint had hypertension.
Since nearly 80 percent of the subjects were immigrants, predominantly from Latin America, and over 80 percent of the subjects were seeking medical attention for the pregnancy for the first time during the third trimester, we were unable to determine either family history of hypertension or preexisting hypertension. We used postnatal hypertension as a proxy for preexisting hypertension and added the variable to the prenatal hypertension model. Since none of the subjects with hypertension reported using alcohol, the hypertension models did not include alcohol use as a covariate. We used the dichotomous hypertension variable in a logistic regression analysis to determine odds ratios for blood lead and bone lead concentration in accounting for hypertension during and after pregnancy, after adjusting the data for body mass index, age, parity, smoking, and educational level. Hypertension after pregnancy was similarly defined.
We then removed from the database all subjects with a systolic blood pressure 140 mmHg or a diastolic blood pressure
90 mmHg during or after pregnancy. We constructed multiple regression models with blood pressure as the dependent variable to determine whether blood lead and bone lead were independently associated with variations in normal blood pressure.
The two bone lead measurements and the period-specific blood lead measurement were simultaneously entered into all models. When diagnostic tests indicated the need, robust standard errors were calculated and used in place of standard errors for calculation of confidence intervals. Partial residual plots of lead variables versus blood pressure were constructed.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Figure 1 shows box plots of bone lead measurements divided into plots of subjects with and without third-trimester and postpartum hypertension. Only calcaneus lead concentration in third-trimester hypertensive subjects appeared elevated in comparison with nonhypertensive subjects. The only systematic increase in frequency of hypertension with increasing quartile of bone lead concentration was seen with calcaneus lead in prenatal hypertensive subjects (table 2). Unadjusted odds ratios for each 10-µg/g increase in calcaneus lead level were 1.79 (95 percent confidence interval (CI): 1.21, 2.66) for third-trimester hypertension and 1.23 (95 percent CI: 0.91, 1.65) for postpartum hypertension. Unadjusted odds ratios for third-trimester and postpartum hypertension for each 10-µg/g increase in tibia lead level were 0.98 (95 percent CI: 0.21, 1.66) and 1.13 (95 percent CI: 0.81, 1.58), respectively.
|
|
|
|
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Blood pressure normally increases as the third trimester of pregnancy progresses. A spurious positive relation between calcaneus lead and gestational age at the time of prenatal blood pressure measurement could account for the observed relation between bone lead and blood pressure. Using quartiles of calcaneus lead (see table 2) and third-trimester gestational age in analysis of variance, we found a nonsignificant negative relation (F(3,664) = 1.26; p = 0.29).
Bone lead and blood pressure
Alternate analyses
Ordinary logistic regression often underestimates the probability of rare events (in the present case, 1.6 percent of the working prenatal sample), leading to biased estimates of coefficients even with sample sizes in the thousands (29). Although the odds ratio for an increase in calcaneus bone lead was significant for third-trimester hypertension, it is likely that the rarity of hypertension in the present cohort biased this estimate. We used a modified logistic regression technique (30) that corrects for this bias and calculated an alternate calcaneus bone lead odds ratio for prenatal hypertension of 1.68 (95 percent CI: 1.01, 2.78).
Use of postnatal hypertension as a proxy for preexisting hypertension may overcontrol for this factor. We constructed an alternate third-trimester hypertension model without the postnatal hypertension variable. The odds ratio for a 10-µg/g increase in calcaneus bone lead level in the alternate model was 2.09 (95 percent CI: 1.28, 3.41).
All methods of estimation suggested a significant effect of calcaneus bone lead concentration on risk of hypertension during pregnancy.
Comparison with other studies
Two published studies, one of women in late middle age (23) and the other of elderly men (31), found significant associations between trabecular bone lead concentration and risk of hypertension. Both studies used patella for the trabecular bone measurement, whereas the present study used calcaneus for the trabecular bone measurement. Increased risk of hypertension in women was found concurrently with bone lead measurement, whereas heightened hypertension risk in the men was found only several years after bone lead measurement in those who had had no hypertension at the time of measurement.
Tibia lead concentration, representing cortical bone lead, did not predict concurrent hypertension in the women or future hypertension in the elderly men. It was, however, associated with concurrent hypertension in the group of elderly men (22) cited above, as well as in a group of men occupationally exposed to lead whose ages spanned most of the adult years (32).
These studies differed from the present study in terms of the sex and age of the subjects, the range of bone lead values, the specific bone measured for the trabecular bone sample, and the blood pressure cutoff values defining hypertension, though the ages and ranges of bone lead and blood lead values among studies largely overlap. Several different explanations may account for the similarities and differences in the results of all of these studies.
Two studies, ours and that of Korrick et al. (23), found significant associations of trabecular bone lead with concurrent hypertension in women. In the latter study, the coefficient describing the effect of trabecular bone lead concentration on hypertension in premenopausal women was 19 percent of the same coefficient in postmenopausal women. Thus, hypertension in women undergoing hormonal change known to alter bone metabolism, as occurs during menopause and pregnancy, is associated with trabecular bone lead. Since even older men suffer bone loss, the association of trabecular bone lead with development of future hypertension found by Cheng et al. (31) also suggests that during periods of altered bone metabolism, particularly bone loss, increasing trabecular bone lead content may play a role in increasing risk of hypertension.
Trabecular bone lead is more easily mobilized from bone than is lead from cortical bones, since the characteristic biologic "residence time" of lead in calcaneus is calculated to range from 11 years to 29 years (95 percent CI), whereas the residence time of lead in tibia has been estimated to range from 16 years to 98 years (95 percent CI) (33). Thus, during times of high calcium stress, more lead may be mobilized from trabecular bone into the blood than from cortical bone, leading to the significant calcaneus leadblood pressure and calcaneus leadhypertension relations seen in the third trimester of pregnancy. When the calcium stress is removed and bone metabolism decreases after pregnancy, less lead is mobilized from trabecular bone, and the bone leadhypertension and bone leadblood pressure relations weaken, as seen in the present study in the postdelivery period. A recent report that bone resorption in older men especially influences release of trabecular bone lead (34) supports this idea.
The proposed bone leadblood lead pathway described above supposes that there may be a direct and immediate effect of circulating lead in blood on blood pressure. While a blood lead effect on blood pressure and/or hypertension has been noted in the work discussed in this papers introduction, only bone lead is successful in predicting blood pressure/hypertension when both bone and blood lead are tested, at least during times of altered bone metabolism.
Lead in blood is partitioned into two principal compartments, serum and erythrocyte. Lead entering the blood from endogenous or exogenous sources goes first into serum, where, within minutes, over 99 percent is sequestered in the red blood cells. Lead in serum may be readily transported to target organs and may constitute the majority of the bioavailable lead in circulation. Lead from exogenous sources, such as ingested or respired lead, enters the body in a discontinuous fashion, depending upon the exposure pattern. The rapid take-up of lead by erythrocytes suggests that elevated lead concentrations in the serum will be episodic, varying as lead is absorbed from the environment, distributed to various compartments, and eliminated from the body. Lead from an endogenous source, such as bone, may present a more constant inflow into serum than lead from exogenous sources. Constant release of lead from bone into serum may elevate the serum lead fraction continuously over extended periods of time, thus leading to greater transfer of lead from serum to target organs than occurs with the episodic intake of exogenous lead, even given equal whole-blood lead levels in the two cases. Since serum lead concentration is significantly associated with bone lead concentration (35), a direct and immediate bone lead effect on blood pressure/hypertension mediated by lead in serum is plausible. However, to our knowledge, a demonstration of greater bioavailability of serum lead over whole-blood and bone lead has not been published to date.
An alternate explanation for the associations between bone lead and blood pressure/hypertension focuses on cumulative bone lead concentration over years of lead exposure. Subjects with a higher bone lead concentration, all other factors being equal, have a history of longer or higher exposure to lead. Past higher lead exposure could have damaged organ systems involved in blood pressure control, such as kidney function (36). However, it is difficult to reconcile this view with results giving different roles to lead in cortical and trabecular bone and the role of current bone metabolic status in the bone leadblood pressure/hypertension association noted in the literature.
Blood lead and blood pressure
Previous research leads to the expectation that where there is a significant effect of lead on blood pressure, the relation is positive. In the larger cohort from which the current sample was drawn, we found that increasing prenatal blood pressure was associated with increasing prenatal blood lead concentration (19). The significant negative association between postnatal blood pressure and postnatal blood lead concentration is without precedent in the literature, though we know of no other published studies examining this relation in postpartum women.
The return of various cardiovascular parameters, such as systemic vascular resistance, end-diastolic volume, stroke volume, and cardiac volume, to prepregnancy values extends to at least 1 year postpartum (37). Altered postpartum cardiovascular function may in some way interact with circulating lead to produce the inverse postpartum blood leadblood pressure relation.
We tested a number of possible confounding factors or effect modifiers to try to determine whether changes in blood lead and body mass index from the third trimester to postpartum or third-trimester blood pressure could play a role in the inverse blood leadblood pressure relation postpartum. None of these attempts revealed a significant omitted variable or a variable whose presence or absence significantly altered the inverse blood leadblood pressure association.
Significance
The increased risk of hypertension associated with increased bone lead in pregnant women is small. However, given the prevalence of hypertension during pregnancy, the past lead exposure of a population will significantly increase the underlying rate of hypertension.
Women with low present lead exposure may have elevated bone lead levels due to past lead exposure and thus increased risk of hypertension during pregnancy. Prevention of lead exposure during a womans entire reproductive life may be required in order to reduce lead-associated health risks to the mother and fetus during pregnancy. In the context of documented histories of population lead exposure, these results also suggest that the full impact of the current low exposures to lead in the United States and much of the developed world on population health will not be felt for years, or even longer in countries just starting to implement lead reduction programs.
![]() |
ACKNOWLEDGMENTS |
---|
The opinions expressed in this article are those of the authors alone and do not necessarily reflect those of the funding agencies.
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Related articles in Am. J. Epidemiol.: