Westergaard T, Andersen P K, Pedersen J B, Olsen J H, Frisch M, Sørensen H T, Wohlfahrt J, Melbye M
Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark.
J Natl Cancer Inst. 1997 Jul 2;89(13):939-47. doi: 10.1093/jnci/89.13.939.
The occurrence of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) during childhood may be influenced by factors operating in fetal life. Furthermore, childhood ALL has been suggested to be linked to patterns of infection during infancy.
To explore these hypotheses and other associations, we studied the impact of sibling patterns (e.g., birth order) and birth characteristics (e.g., birth weight) on the risk of childhood ALL and AML.
By linkage of records of population-based registries, a cohort of all children whose mothers were born in Denmark from April 1935 through March 1978 was established. Children who developed ALL or AML during the period from April 1968 through December 1992 were identified by linkage with the Danish Cancer Registry. Birth weights were obtained for children born during the period from January 1973 through December 1992 by linkage with the Medical Birth Registry.
The cohort of approximately 2.0 million children was followed for the diagnosis of ALL or AML for 20.9 million person-years. A total of 704 cases of childhood ALL were identified. Among 0-4 year olds, the relative risks (RRs) of ALL for birth order positions 1, 2, 3, and 4+ were 1.00 (reference), 0.85 (95% confidence interval [CI] = 0.68-1.07), 0.91 (95% CI = 0.66-1.25), and 0.57 (95% CI = 0.30-1.06), respectively (P for trend = .09). A decreasing trend was not observed among 5-14 year olds. A significant log-linear association between birth weight and the risk of ALL was observed for both age groups. Overall, the RR of ALL increased by a factor of 1.46 (95% CI = 1.18-1.81) (P = .0005) for each kilogram of increase in birth weight. A total of 114 cases of childhood AML were identified. Children born second or later in the birth order had an increased risk of AML (RR = 1.53; 95% CI = 1.01-2.32) compared with firstborns. A particularly high risk of AML at ages 2 (RR = 2.53; 95% CI = 1.46-4.40) and 3 years was associated with having siblings compared with being an only child at those ages. Similar to the findings for ALL risk, there was a significant association between birth weight and AML risk. The relative increase in AML risk per 1-kg increase in birth weight was 2.14 (95% CI = 1.19-3.85; P = .009).
The association between birth weight and childhood leukemia suggests the importance of intrauterine factors. A plausible explanation may be that increasing birth weight is associated with a higher rate of cell proliferation and/or a larger number of precursor cells being at risk of malignant transformation. The inverse association between birth order and ALL risk among 0-4 year olds was weak, but it was compatible with the hypothesis that delayed exposure to infection may increase the risk of ALL in this age group. The association of childhood AML with birth order and sibship size at young ages deserves further attention in the search for environmental factors that affect childhood AML risk.
儿童期急性淋巴细胞白血病（ALL）和急性髓系白血病（AML）的发生可能受胎儿期因素影响。此外，有研究表明儿童ALL与婴儿期感染模式有关。
为探究这些假设及其他关联，我们研究了同胞模式（如出生顺序）和出生特征（如出生体重）对儿童ALL和AML发病风险的影响。
通过关联基于人群的登记处记录，建立了一个队列，纳入1935年4月至1978年3月在丹麦出生的所有母亲所生的儿童。通过与丹麦癌症登记处关联，确定了1968年4月至1992年12月期间患ALL或AML的儿童。通过与医疗出生登记处关联，获取了1973年1月至1992年12月期间出生儿童的出生体重。
对约200万儿童的队列进行了2090万人年的随访，以诊断ALL或AML。共确定704例儿童ALL病例。在0至4岁儿童中，出生顺序为第1、2、3和4+的ALL相对风险（RR）分别为1.00（参考值）、0.85（95%置信区间[CI]=0.68 - 1.07）、0.91（95%CI = 0.66 - 1.25）和0.57（95%CI = 0.30 - 1.06）（趋势P值 = 0.09）。在5至14岁儿童中未观察到下降趋势。两个年龄组的出生体重与ALL风险之间均存在显著的对数线性关联。总体而言，出生体重每增加1千克，ALL的RR增加1.46倍（95%CI = 1.18 - 1.81）（P = 0.0005）。共确定114例儿童AML病例。与头胎相比，出生顺序为第二或更晚的儿童患AML的风险增加（RR = 1.53；95%CI = 1.01 - 2.32）。与该年龄段独生子女相比，2岁（RR = 2.53；95%CI = 1.46 - 4.40）和3岁时患AML的风险特别高。与ALL风险的研究结果相似，出生体重与AML风险之间存在显著关联。出生体重每增加1千克，AML风险的相对增加为2.14（95%CI = 1.19 - 3.85；P = 0.009）。
出生体重与儿童白血病之间的关联表明宫内因素的重要性。一个合理的解释可能是出生体重增加与细胞增殖率升高和/或更多有恶性转化风险前体细胞数量有关。0至4岁儿童中出生顺序与ALL风险之间的负相关较弱，但与延迟接触感染可能增加该年龄组ALL风险的假设相符。儿童AML与出生顺序和幼年同胞数量之间的关联在寻找影响儿童AML风险的环境因素方面值得进一步关注。
