Systematic Reviews to Inform Practice, March/April 2025

Age-related pregnancy outcomes on both ends of the childbearing spectrum can reflect differences in risk factors for certain maternal or neonatal conditions. Congenital anomalies include structural and functional defects that develop during pregnancy and are the most common cause of neonatal and infant morbidity and mortality.¹ Although numerous research studies have demonstrated a relationship between advanced maternal age and chromosomal anomalies, data on the association with nonchromosomal congenital anomalies (NCAs) have provided inconsistent findings.^1,2 For example, a 2017 study found no association between maternal age and major congenital anomalies and may reflect an “all or nothing”^{3(p 221)} survival of fetuses with normal anatomy. Furthermore, studies examining very young maternal age (<20 years) is limited and have indicated associations with a limited number of birth defects, namely those of the abdominal wall.⁴ Population data demonstrating increased maternal age at birth in recent decades warrant a closer look at the role of maternal age in the prevalence of NCAs.^5-7

Recognizing that no previous meta-analysis has specifically examined the relationship between maternal age and NCAs, Pethő et al¹ conducted a systematic review and meta-analysis to explore maternal age as a key factor in occurrence of NCAs. The study protocol was submitted to the International Prospective Register of Systematic Reviews. They included studies that collected data on associations between maternal age and congenital anomalies. They excluded studies that highlighted chromosomal anomalies as well as case reports and cohort and case control studies. The authors hypothesized that very young and more advanced ages would be associated with higher rates of NCAs.

Their analysis was based on 72 population-based studies conducted from 1967 through 2021 with population sizes ranging from 4220 to almost 25 million. Most studies were from the United States (n = 29), European countries (n = 14), China (n = 7), and Canada (n = 4), with the remaining from countries throughout Southeast Asia, South America, Australia, and other regions. The authors compared age groups <20, 30 to 35, >35, and >40 years with the reference group of age 20 to 30 years. The prevalence of NCAs was the primary outcome of the analysis; secondary outcomes included defects of various organ systems and common birth defects.

Accounting for all NCAs, the authors found an increased risk of all studied NCAs due to age >35 (risk ratio [RR], 1.31; 95% CI, 1.07-1.61) and, notably, age >40 (RR, 1.44; 95% CI,1.25-1.66). The increased risk of total NCAs for age >40 years was significant when examined individually without the influencing effects of chromosomal anomalies (RR, 1.25; 95% CI, 1.08-1.46). When chromosomal anomalies and NCAs were considered together, the risk of NCAs was 1.26 times higher for maternal age >35 (95% CI, 1.12-1.42) and 1.63 times higher for age >40 (95% CI, 1.26-2.09), with risk increasing by each year of age. An increase in risk of almost 2 times for NCAs of the circulatory system was detected in the age >40 category (RR, 1.94; 95% CI, 1.28-2.93). For congenital heart defects, an increased risk of 1.5 times was detected beginning at age 35 (95% CI, 1.11-2.04) with a further increased risk at ages >40 (RR, 1.75; 95% CI, 1.32-2.32). Young maternal age <20 had a protective effect against congenital heart defects (RR, 0.87; 95% CI, 0.78-0.97).

Other anomalies that were associated with age >40 years included cleft lip and cleft palate (RR, 1.57; 95% CI, 1.11-2.20), digestive system anomalies (RR, 2.16; 95% CI, 1.34-3.49), and omphalocele (RR, 2.57; 95% CI, 1.77-3.73). The risk of omphalocele (RR, 1.44; 95% CI, 1.08-1.92) and gastroschisis (RR, 3.08; 95% CI, 2.74-3.47) were also associated with age <20. No age effects were found for anomalies in the urinary, nervous, and musculoskeletal systems, and there were not enough studies that provided data to detect age-related associations with NCAs of the eyes, ears, face, neck, respiratory system, and genitalia.

Strengths of this analysis included the span of years and geographical locations of the studies included in the analysis. Further, the risk of bias was low to moderate in all studies and the majority of studies were deemed high quality. The authors also examined smaller age subgroups compared to previous meta-analyses. Limitations included the retrospective designs of the included studies, significant variations in sample sizes, and heterogeneity of outcomes measured. The authors also cite the time span of included studies and associated differences in reporting and screening as possible factors contributing to heterogeneity. Nevertheless, this meta-analysis provides some helpful insights into the trends regarding maternal age at birth and associations with NCAs.

With more pregnancies occurring at advanced maternal age, strategies for the identification of anomalies that allow for timely interventions are warranted. The diagnosis of nonchromosomal anomalies relies on the visualization of anatomical defects, and these are missed by the chorionic villus sampling and amniocentesis options offered for diagnostic testing in pregnancy. Although offering these diagnostic options is the current standard of care when age at birth is >35 years, there are no current recommendations for increased ultrasound surveillance based on maternal age alone or completing the current routine fetal anatomic ultrasound screening at a later gestation when many nonchromosomal anomalies are more visible and more accurately diagnosed.^5,8 Nutritional deficiencies and lack of awareness about folic acid supplementation might play a role in NCAs for pregnancies at younger ages.⁸ Providers caring for patients younger than 20 years and beyond 35 years should engage in shared decision-making to adjust screening protocols, which might include added ultrasound anatomy scans.⁸