Birthweight differences between USA and China and their relevance to breast cancer aetiology

Pagona Lagiou1,2, Chung-Cheng Hsieh1,3, Dimitrios Trichopoulos1,2, Biao Xu4, Joanne Wuu3, Lorelei Mucci2, Rulla Tamimi2, Hans-Olov Adami2,5 and Sven Cnattingius5

1 Department of Hygiene and Epidemiology, School of Medicine, University of Athens, Greece.
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
3 University of Massachusetts Cancer Center, Worcester, MA, USA.
4 Department of Epidemiology, School of Public Health, Shanghai Medical University, Shanghai, China.
5 Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.

Correspondence: Dimitrios Trichopoulos, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. E-mail: dtrichop{at}hsph.harvard.edu


    Abstract
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 
Background There has been renewed interest about determinants of birth size following the propagation of hypotheses that birth size parameters may have long-term consequences on the occurrence of common diseases in adulthood, including breast cancer.

Methods In the context of a cohort study, 296 Caucasian pregnant women in Boston, USA and 329 Chinese pregnant women in Shanghai, China were followed to term. Birth size characteristics of the baby and maternal anthropometry were measured using standardized protocols. Analyses were conducted through multiple regression procedures.

Results No significant difference was found between US and Chinese newborns with respect to gestational age. Among US women, pregravid oral contraceptive use was strongly associated with higher birthweight. In both US and Chinese women, birthweight was positively associated with height, pre-pregnancy body mass index, and weight gain during pregnancy. More importantly, the difference in these three maternal variables between the two samples fully explains the birthweight difference between the two populations.

Conclusions We postulate that babies in China may have lower birthweight because their mothers’ anthropometry imposes constraints on the growth of the fetus. When Chinese women migrate to the US, they tend to grow taller and heavier so that their babies can reach, on the average, a higher birthweight. The recurrence of this process in successive generations could explain why eventually Chinese Americans tend to have comparable birth and adult anthropometric characteristics, as well as comparable breast cancer rates, to those of Caucasian Americans.


Keywords Birthweight, China, US, breast cancer

Accepted 13 June 2002

There is a vast literature concerning determinants of gestational duration and intrauterine growth.1–5 Most of the literature focuses on determinants and means of prevention of preterm birth and/or intrauterine growth retardation, which can affect survival as well as development in childhood.6 During the last 20 years, however, there has also been interest in the possibility that perinatal events and conditions, intimately linked to birth size parameters, may have long-term consequences on the occurrence of common diseases in adulthood, including cardiovascular diseases and some forms of cancer, particularly breast cancer.7–9

We have compared determinants of birthweight using an identical protocol in two populations, one Caucasian in Boston, USA and the other Chinese in Shanghai, China. Our objective was to gain insight into the causes of birthweight difference between these populations and the way this difference may be related to the contrasting incidence of breast cancer in the two populations.


    Materials and Methods
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 Materials and Methods
 Results
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Between March 1994 and October 1995, a total of 402 Caucasian and 424 Asian eligible women were identified respectively at the Beth Israel hospital in Boston, USA and the Shanghai Medical University in Shanghai, China. Authorized health professionals met all pregnant women coming for their first routine prenatal visit to the collaborating maternity clinic, ascertained whether the woman was eligible to participate, explained to her the objectives of the study and obtained informed consent. The study was approved by the Institutional Review boards of the Beth Israel Hospital, Shanghai Medical University, and Harvard School of Public Health. All women had to be less than 40 years old and have a parity of no more than two. Women were not eligible if they had taken any hormonal medication during the index pregnancy, if they had a prior diagnosis of diabetes mellitus or thyroid disease, or if the fetus had a known major anomaly. Of the 402 eligible women in Boston, 85 refused to participate in one or more aspects of the study or had crucial missing values, 9 were subsequently excluded because of a spontaneous or induced abortion in the index pregnancy, 2 were excluded because of twin birth, whereas only 10 were lost to follow-up after the initial meeting. Of the 424 eligible women in Shanghai, 78 refused to participate in one or more aspects of the study or had crucial missing values, 2 were subsequently excluded due to induced abortion in the index pregnancy, 2 were excluded because of twin birth, 6 were excluded because data on gestational duration were unreliable, whereas only 7 were lost to follow-up. Thus, 296 Caucasian and 329 Chinese pregnant women who delivered live single births were eventually included in the analysis. With respect to age and parity, women who refused to participate were not different from those who participated.

Baseline demographic information was abstracted from the medical records of consenting participants at the 16th week visit. In both Boston and Shanghai gestational age was defined as the time since the first day of the last menstrual period. At the 27th week visit, an authorized health professional conducted a confidential interview with the study participant and abstracted relevant routine data from her records. Maternal characteristics included the woman’s age (years), weight before pregnancy (kg), height (cm), body mass index (BMI) (kg/m2), education (up to high school or more than high school), and previous live birth (yes, no). Characteristics related to the pregnancy were also recorded. These included the weight gained by the time of the two visits (kg), history of smoking, coffee, tea and alcohol consumption, and administration of antibiotics during pregnancy. At delivery, the placenta was weighed (g) before discarding; additional information concerning the delivery and the newborn was ascertained from medical records and paediatric charts. This included total gestation duration (weeks), birthweight (g), birth length (cm), head circumference (cm), and gender. Information concerning questionnaire administration and medical record reviewing has also been given in an earlier publication.10 Smoking during pregnancy was coded as current smoker during pregnancy versus not current smoker during pregnancy. Caffeine intake was computed summing caffeine contents from daily intake of cups of coffee and tea together. Pre-eclampsia was based on physician’s diagnosis of this condition during pregnancy and urogenital infection was determined from the existence of a cervical or bladder infection.

The statistical analysis initially relied on simple cross-tabulations. Subsequently, birthweight was evaluated as a continuous variable through multiple linear regression. Analyses were undertaken first within study centre, that is, separately for Caucasian and Asian women. Direct comparison between the two study sites was performed with adjustment for different covariates. The analyses were conducted using SAS Software version 8.0.


    Results
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Table 1Go shows mean, median, and standard deviation values of weight, height, head circumference, and gestational age at delivery of newborns in Boston, USA and Shanghai, China. Newborn babies are clearly heavier and slightly longer in the US than in China. In contrast, there is no difference between Caucasian US newborns and Chinese newborns with respect to head circumference or gestational duration. It is of interest that the variability of birthweight is higher among US newborns than among Chinese newborns (F ratio = 1.39, P ~ 0.002).


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Table 1 Mean, median and standard deviation values of weight, height, head circumference, and gestational age of 296 newborns in Boston, USA and 329 newborns in Shanghai, China
 
Compared with the US pregnant women, Chinese pregnant women are younger and shorter, with lower BMI and less weight gain during pregnancy (Table 2Go). Almost all Chinese women are primiparous, few of them have used oral contraceptives, they rarely smoke, and their caffeine intake during pregnancy (including caffeine from tea) is minimal. Both pre-eclampsia and urogenitary infections are uncommon among Chinese women, although under-diagnosis cannot be excluded. The male to female ratio is higher among mature Chinese newborn than mature US newborn.


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Table 2 Maternal characteristics of US and Chinese study participantsa
 
Table 3Go differs from Table 2Go in that it concerns only babies born between 37 and 42 completed weeks of gestation and examines mean birthweight in the specified categories of the maternal characteristics among US women and, separately, Chinese women. The data in Table 3Go are univariate and, thus, inherently confounded. Nevertheless, they provide valuable descriptive information that can be used for comparative purposes, because data are frequently presented in this straightforward way in the literature.


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Table 3 Birthweight (g) of babies born between 37 and 42 weeks of gestation according to maternal characteristics of 267 Caucasian women from Boston, US and 303 Chinese women from Shanghai, Chinaa
 
The information presented in Table 4Go is aetiologically interpretable because results have been mutually adjusted through multiple regression. Because the distribution of maternal age is very different between US and Chinese women, all ages below 30 had to be combined among US women and all ages above 30 had to be combined among Chinese women. The remarkable findings in Table 4Go are the strong, statistically significant and apparently unconfounded association of pregravid oral contraceptive use with higher birthweight, evaluated only among US women, and the independent effects that height, pre-pregnancy BMI and weight gain during pregnancy have on birthweight, both in the US and China. There is also evidence for interaction between ethnic group and height (P = 0.10) and ethnic group and pre-pregnancy BMI (P < 0.05) with respect to birthweight. These interactions may indicate that the effects of height and pre-pregnancy BMI on birthweight may be approaching their upper limits within the group of the taller and heavier Caucasian US women.


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Table 4 Multivariate regression-deriveda coefficients showing changes in birth weight per indicated contrasts or changes in predictor variable. Newborns after a gestation lasting from 37 to 42 weeks, inclusive in Boston, USA and Shanghai, China
 
We examined whether difference in birthweight between US and China newborns could be explained by maternal anthropometric characteristics by adjusting successively for different covariates. When only one of the maternal anthropometric variables (height, BMI, or weight gain) was included in the model, the crude difference in birthweight was reduced, but not eliminated. Table 5Go, however, shows that the difference observed between US and Chinese newborns could be fully accounted for by the combined effects of differences in maternal height, pre-pregnancy BMI, and weight gain during pregnancy. Because the US study population has a small proportion of subjects who never used oral contraceptives (OC), analyses excluding OC users were not informative. We have also limited the analysis to primiparous women and the results were similar in that the observed crude difference in birthweight was eliminated after adjusting for the maternal anthropometric variables.


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Table 5 Birthweight difference comparing US and Chinese newborns, with adjustment for different covariates
 

    Discussion
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 Materials and Methods
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In this paper, we present data on birth size aspects and birthweight determinants derived from samples of pregnant women in Boston, USA and Shanghai, China. Although the samples studied were not representative of the respective populations, even at the city level, they provide a meaningful contrast. We have documented that height and pre-pregnancy BMI are important birthweight determinants, particularly among Chinese women, whereas weight gain during pregnancy is an important birthweight determinant, particularly among US women. More important, and uniquely demonstrable on a study design with parallel sampling in contrasting populations, the difference in height, pre-pregnancy BMI, and weight gain during pregnancy between the two samples fully explains the mean birthweight difference between the two populations. We have also found that pregravid oral contraceptive use is associated with higher birthweight, an unexpected finding that we intend to fully explore in another paper.

The present study is of moderate size, but the statistical power was sufficient to allow documentation of the important findings concerning maternal anthropometry in relation to birthweight. The data were collected in a standardized way and with an identical protocol in the two settings. There is also no evidence for the operation of important biases, since the findings were generally compatible with those reported by other investigators and those expected from the socio-cultural environment in the two populations.1–5

The results of our study complement those of an earlier paper by Wen and colleagues.11 These authors have compared birthweight distributions between Chinese and Caucasian infants and found that the lower mean birthweight in Chinese infants is due to slower fetal growth towards the end of the third trimester. We postulate that Chinese babies in China have lower birthweight because the lower height and pre-pregnancy BMI of their mothers imposes constraints on the growth of the fetus towards the end of the pregnancy. The literature concerning changes in somatometry and particularly birthweight among Chinese and Chinese migrating to the US is limited.12–14 The existing evidence, however, suggests that when Chinese women migrate to the US, they tend to grow taller and heavier and their babies tend to have higher birthweight.11–14 This is likely to recur in successive generations, so that eventually Chinese Americans have comparable anthropometric characteristics to Caucasian Americans and, indeed, comparable breast cancer rates.15–17

Established adult life risk factors for breast cancer explain little of the more than fourfold difference in the incidence of this disease between the US and China.18 This has led to the hypothesis that early life events and conditions may influence subsequent risk for breast cancer.19,20 Birthweight has been associated with breast cancer risk in a number of studies,21–23 but the breast cancer risk gradient in relation to birthweight is again too limited to explain the difference in breast cancer incidence between the US and China or Japan. It has been hypothesized, however, that a critical determinant of breast cancer risk may be mammary gland mass, which is indeed considerably larger among Caucasians than among Chinese.20,24 Indeed, mammary gland mass is likely to be a predictor of the number of immature mammary cells that are susceptible to carcinogenic initiation.24 In ethnic contrasts, but not necessarily in individual intra-ethnic comparisons, birthweight may be related to mammary gland mass in a non-linear way, so that small differences in birthweight (and pre-adolescence growth patterns) generate large differences in mammary gland mass in adult life. In this context and in an admittedly speculative way, our study provides support to the ideas that perinatal influences and mammary gland mass are important determinants of adult life breast cancer risk. Indeed, our findings could allow an explanation of the pattern of increase of breast cancer incidence among the Asian Americans over successive generations.16,17 The cycle whereby bigger women give birth to bigger babies who, in turn, may have a larger pool of stem cells for mammary gland development in adolescence is compatible with the increasing trends in breast cancer incidence that have been noted in most populations during periods of economic growth and prosperity.25


KEY MESSAGES

  • Newborns in China have lower birthweight in comparison to Caucasian newborns in the US.

  • The difference in birthweight between Chinese newborns in China and Caucasian newborns in the US is accounted for by maternal anthropometry.

  • Migration from China to the US is associated, in successive generations, with increasing birthweight and anthropometry, and this may underlie the increasing incidence of breast cancer in successive generations of Chinese migrants.

 


    Acknowledgments
 
Sources of funding: this study was supported in part by grant no. CA54220 from the National Institutes of Health.


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 Discussion
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