Bomback Miles, Everett Selin, Lyford Alex, Sahni Rakesh, Kim Faith, Baptiste Caitlin, Motelow Joshua E, Tolia Veeral, Clark Reese, Dugoff Lorraine, Hays Thomas
Feinberg School of Medicine, Northwestern University, Chicago, IL.
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington Medical Center, Seattle, WA.
Am J Obstet Gynecol. 2025 May;232(5):487.e1-487.e14. doi: 10.1016/j.ajog.2024.09.101. Epub 2024 Sep 23.
Early preterm (<34 weeks of gestation) small for gestational age infants (<10th percentile birth weight for sex and gestational age) experience high rates of morbidity and mortality, the causes of which are poorly understood. Mounting evidence suggests that genetic disorders contribute. Scarce data exist regarding the prevalence of genetic disorders and their contribution to morbidity and mortality.
This study aimed to determine the proportion of genetic disorders in early preterm small for gestational age infants (with and without congenital anomalies) compared to early preterm appropriate for gestational age infants and the association of genetic disorders with morbidity or mortality.
This is a retrospective cohort study of infants delivered at 23 and 0/7 to 33 and 6/7 weeks of gestation from 2000 to 2020 from the Pediatrix Clinical Data Warehouse. Data included diagnosed genetic disorders and congenital anomalies, baseline characteristics, and morbidity or mortality. We excluded cases of death in the delivery room before neonatal intensive care unit admission, multiple gestations, and cases transferred after birth or before death or discharge.
We identified 223,431 early preterm infants, including 21,180 small for gestational age. Genetic disorders were present in 441 (2.3%) of small for gestational age infants without congenital anomalies, in 194 (10.8%) of small for gestational age infants with congenital anomalies, and in 304 (4.5%) of small for gestational age infants that experienced morbidity or mortality (with or without congenital anomalies). Trisomies 13, 18, and 21 were the most prevalent genetic disorders in these groups, together accounting for 145 small for gestational age infants without congenital anomalies, 117 small for gestational age infants with congenital anomalies, and 166 small for gestational age infants with morbidity or mortality (with or without congenital anomalies). Less prevalent genetic disorders consisted of other aneuploidy (45, X and 47, XXY), copy number variants (13q14 deletion syndrome, cri du chat syndrome, DiGeorge syndrome), and single gene disorders (cystic fibrosis, Fanconi anemia, glucose-6-phosphate dehydrogenase deficiency, hemophilia, hypophosphatasia, sickle cell disease, and thalassemia). Comparatively, genetic disorders were found in 1792 (1.0%) appropriate for gestational age infants without congenital anomalies, in 572 (5.8%) appropriate for gestational age infants with congenital anomalies, and 809 (2.0%) appropriate for gestational age infants that experienced morbidity or mortality (with or without congenital anomalies). Genetic disorders were associated with an adjusted odds ratio (95% confidence interval) of 2.10 (1.89-2.33) of isolated small for gestational age and 12.84 (11.47-14.35) of small for gestational age accompanied by congenital anomalies. Genetic disorders were associated with an adjusted odds ratio of 2.24 (1.83-2.74) of morbidity or mortality.
These findings suggest that genetic disorders are more prevalent in early preterm small for gestational age infants, particularly those with congenital anomalies. These findings also suggest that genetic disorders are associated with increased morbidity and mortality. These associations were primarily driven by trisomies 13, 18, and 21. Genetic diagnoses in this cohort were made through routine clinical care, principally via karyotype, chromosomal microarray, and single gene testing. These findings support evolving clinical guidelines for genetic testing of small for gestational age infants. Our study is limited due to the lack of prospective, genome-wide testing.
极早早产儿（孕周<34周）小于胎龄儿（出生体重低于同性别、同孕周第10百分位数）的发病率和死亡率很高，但其病因尚不清楚。越来越多的证据表明遗传疾病是其中一个因素。关于遗传疾病的患病率及其对发病率和死亡率的影响，现有数据稀缺。
本研究旨在确定与极早早产适于胎龄儿相比，极早早产小于胎龄儿（有或无先天性异常）中遗传疾病的比例，以及遗传疾病与发病率或死亡率之间的关联。
这是一项回顾性队列研究，研究对象为2000年至2020年在Pediatrix临床数据仓库中孕周为23⁺⁰/⁷至33⁺⁶/⁷周出生的婴儿。数据包括已诊断的遗传疾病和先天性异常、基线特征以及发病率或死亡率。我们排除了新生儿重症监护病房入院前在产房死亡的病例、多胎妊娠以及出生后或死亡或出院前转诊的病例。
我们共识别出223,431例极早早产儿，其中21,180例为小于胎龄儿。在无先天性异常的小于胎龄儿中，441例（2.3%）存在遗传疾病；在有先天性异常的小于胎龄儿中，194例（10.8%）存在遗传疾病；在发生发病率或死亡率的小于胎龄儿（有或无先天性异常）中，304例（4.5%）存在遗传疾病。13、18和21三体是这些组中最常见的遗传疾病，在无先天性异常的小于胎龄儿中共有145例，在有先天性异常的小于胎龄儿中共有117例，在发生发病率或死亡率的小于胎龄儿（有或无先天性异常）中共有166例。不太常见的遗传疾病包括其他非整倍体（45,X和47,XXY）、拷贝数变异（13q14缺失综合征、猫叫综合征、22q11.2微缺失综合征）和单基因疾病（囊性纤维化、范可尼贫血、葡萄糖-6-磷酸脱氢酶缺乏症、血友病、低磷酸酯酶症、镰状细胞病和地中海贫血）。相比之下，在无先天性异常的适于胎龄儿中，1792例（1.0%）存在遗传疾病；在有先天性异常的适于胎龄儿中，572例（5.8%）存在遗传疾病；在发生发病率或死亡率的适于胎龄儿（有或无先天性异常）中，809例（2.0%）存在遗传疾病。遗传疾病与单纯小于胎龄儿的校正比值比（95%置信区间）为2.10（1.89 - 2.33），与伴有先天性异常的小于胎龄儿的校正比值比为12.84（11.47 - 14.35）。遗传疾病与发病率或死亡率的校正比值比为2.24（1.83 - 2.74）。
这些发现表明，遗传疾病在极早早产小于胎龄儿中更为普遍，尤其是那些伴有先天性异常的患儿。这些发现还表明，遗传疾病与发病率和死亡率的增加有关。这些关联主要由13、18和21三体驱动。本队列中的遗传诊断是通过常规临床护理做出的，主要通过核型分析、染色体微阵列和单基因检测。这些发现支持了不断发展的小于胎龄儿基因检测临床指南。由于缺乏前瞻性的全基因组检测，我们的研究存在局限性。
