The changing epidemiology of syndactyly in Chinese newborns: a nationwide surveillance-based study

Syndactyly (SD) is one common limb malformation characterized by soft tissue and/or osseous fusion of adjacent digits in either the upper or lower extremities, resulting from the embryological failure of phalanges to separate during limbs development [1]. Clinically, SD may affect one or more limbs, being a familial or sporadic, a symmetrical or asymmetrical condition. This malformation can be further categorized into ten subtypes depending on its genotype–phenotype features [2]. In epidemiological studies, SD cases are usually classified into non-syndromic (isolated) or syndromic forms (associated) [3]. The prevalence of syndactyly ranges from 0.90 to 7.40 per 10,000 live births, varying by sex, geographic region, and ethnic groups [4‐7].

The information on prevalence, phenotypes and outcome of SD is of great significance both from epidemiological and clinical perspectives. Although syndactyly has a strong genetic component, a growing body of evidence suggests that socioeconomic and environmental factors play a role in the occurrence of SD [8]. China’s economy, environment, maternal and child health have changed greatly in recent two decades [9]. Several studies using provincial or local hospital-based surveillance data have shown wide variability in SD prevalence in China [10, 11], whereas epidemiological studies based on national data are rare. To gain new insights into the epidemiology of syndactyly, we performed a prevalence study on syndactyly in Chinese newborns, with special interests in time trends and the involved limbs, using data from the Chinese Birth Defects Monitoring Network (CBDMN) from 2007 to 2019.

Table 1 shows the SD prevalence rates stratified by birth year, maternal residence, maternal age, geographic region, and infant sex. In the period of 2007–2019, a total of 13,611 syndactyly cases were identified among 24,157,719 newborns, giving the prevalence of 5.63 (95%CI: 5.54–5.73), 4.66 (95%CI:4.58–4.75) and 0.97 (95%CI:0.93–1.01) per 10,000 births for the overall, isolated, and associated syndactyly, respectively. Multivariate Poisson regression analysis confirmed the significant variations in prevalence by urban–rural areas, maternal age, geographic region, and infant sex. Moreover, both isolated and associated prevalence presented similar sociodemographic patterns (Table 1). Urban prevalence rates were significantly higher than rural rates (urban vs rural: overall, 6.69/10,000 vs 4.35/10,000; isolated, 5.64/10,000 vs 3.49/10,000; associated, 1.06/10,000 vs 0.86/10,000). A U-shaped pattern was found for maternal age-specific prevalence rates of overall, isolated, and associated SD, with higher rates in the maternal age group of 30–34 years and lower rates in the group of 20–24 years for overall and isolated while higher rates in the ≥ 35 years age group and lower rates in the 20–24 years group for associated SD. All the prevalence of overall, isolated, and associated SDs presented significant geographic variations. The highest rates were usually found in the eastern region, followed by the rates in the western or central regions. Considerable male predominance in prevalence was observed for syndactyly (male vs female: overall, 6.28/10,000 vs 4.86/10,000; isolated, 5.21/10,000 vs 4.05/10,000; associated,1.08/10,000 vs 0.81/10,000).

The annual prevalence rates of syndactyly were on the rise from 2007 through 2019 (Table 1 and Fig. 1), increasing from 4.24/10,000 to 7.66/10,000, from 3.51/10,000 to 6.44/10,000, and from 0.72/10,000 to 1.22/10,000 for the overall, isolated, and associated syndactyly, respectively. The overall prevalence rate was on a stabilization upward trend with an APC of 2.4% for the 2007–2014 period, followed by a significant increase during the period from 2014–2019, by 9.2%. The prevalence of isolated cases kept almost the same rising trend as overall cases, with an APC of 2.4% from 2007 to 2014 and an APC of 9.7% from 2014 to 2019. The prevalence rate of associated SD was slightly on an upward trend with an APC of 3.9% from 2007 to 2019.

Table 2 shows the basic characteristics and perinatal outcomes of SD cases in the current study. Preterm births accounted for 13.8% of overall SD cases, and more associated SDs were born prematurely than isolated cases (29.2% vs. 10.6%). Totally, 13.4% of SD cases were born with low birth weight (LBW). The LBW rate of associated SD (30.5%) was significantly higher than that of isolated SD (9.8%). Perinatal mortality of SD cases was 4.1%, and infants with associated SD were at a higher risk of perinatal death (16.4%) compared with those affected by isolated SD (1.4%). Both the stillbirth rate (intrauterine death, spontaneous abortion, and termination of pregnancy due to antenatally diagnosed birth defects) and early neonatal mortality rate of associated SD (12.2% and 4.4%) were 10 more times higher than those of isolated cases (1.0% and 0.4%). Among the cases, 92.7% were Han Chinese, and the rest were ethnic minorities. Majority of SD cases were singletons (95.8%), and the rest were twins or multiple-births (4.2%). About two-thirds of the affected children were born to primiparas women. More infants with associated SD (35.7%) were born to multiparous women compared with isolated SD (34.9%). Notably, only 2.8% of affected infants had a family history, and 97.2% were sporadic cases.

We further analyzed the laterality and limb involvements of SD cases. As shown in Table 3, the bilaterally, and unilaterally affected cases accounted for 18.4% and 76.7%, respectively. In those bilaterally affected cases, the feet were more frequently involved (64.3%), and lower limbs involvements were more common in associated SD compared with isolated cases (30.1% vs 17.4%). In unilateral cases, right side preference (right vs left: 53.8% vs 46.2%) and upper limbs preference (hand vs foot: 50.8% vs 48.0%) were found, with more feet involvements in unilateral isolated cases (51.0%) but more hands involvements (62.0%) in unilateral associated SD.

As shown in Table 4, a total of 2343 cases (17.2%) were accompanied by additional chromosomal or structural malformations. The most common congenital anomalies seen in associated SD cases by system included musculoskeletal system anomalies (69.9%) and circulatory system malformations (13.6%). Specifically, polydactyly was the most common additional deformity, accounted for 27.6% of total coexisting anomalies mentioned above, followed by reduction defects of upper limb (22.5%). SD cases rarely occurred with anomalies of respiratory system (0.6%), urinary system (1.9%) and chromosomal abnormalities (2.0%).

This study analyzed data from a large sample of syndactyly (SD) cases in contemporary Chinese population and found that the overall prevalence of SD was 5. 63 per 10,000 live births. This prevalence was lower than those reported in New York State (7.40 per 10,000 live births) [7], Chile (7/10,000) [15], and Hawaii Japanese (6.13/10,000) [16], but higher than those reported in northern Netherlands (4.7/10,000) [17], Italy (0.7/10,000) [18], other European countries (4.86 per 10,000 live births, from 1980 to 2012) [6], and some Asian countries such as Korean (3.09/10,000) [19], and Thai (2.1/10,000) [5]. Notably, the overall SD prevalence in this study was nearly comparable to the rates in Jiangsu and Zhejiang provinces of China that adopted same surveillance approaches and inclusion criteria of SD as CBDMN [10, 11]. The study also found that 17.2% of SD cases were associated with additional major anomalies, which is consistent with previous investigations [20]. Variations in SD prevalence across studies might be due to differences in population, data sources, inclusion criteria, study design, and research duration. High SD prevalence has been noted in Caucasian populations [1, 21]. The findings indicate that the Chinese population is also at a high risk of SD, supporting racial differences in SD prevalence.

Studies conducted in various regions or countries such as New York State [7], Chile [15], Spain [22], Ukraine [22], Korea [19], and several provinces in China [10, 11] have noted an increase in the prevalence of syndactyly over the last two decades. However, some European countries like the United Kingdom, Italy, and Belgium have shown a slight decline in SD prevalence [22]. The underlying causes for such changes in SD prevalence are unclear. Genetic variants such as mutations in HOXD13, FBLN1, LMBR1, FGFR2, BHLHA9, GLI3, and chromosomal aberrations can contribute to the development of SD [23, 24]. Recent studies indicate a positive association between maternal exposure to smoking, medication, and ambient air pollutants and offspring SD [25‐28]. Animal models suggest that the normal development of digits depends on precise regulation and interactions between multiple genetic pathways such as the SHH, WNT signaling pathway [29]. The SD prevalence data obtained in this study is relatively reliable, as the CBDMN system is stable and undergoes strict multi-level quality control annually. The increasing prevalence of SD in China and other places may be attributed to gene mutations related to environmental exposure or disruptions in genetic pathways in limb development.

Male excess in SD prevalence for isolated and associated SD suggested that male embryos might be more susceptible to SD [30], which is consistent with previous epidemiological studies and case reports [1, 7, 30]. The reason for distorted sex ratio in SD cases remains unknown. Significant urban–rural, geographic differences were also identified in SD prevalence. Women living in urban area or eastern region seemed to be at higher risk of giving birth to children with SD, although they generally had a better socio-economic status and perinatal health care [12, 31]. However, urban area, and eastern region in China are more polluted than the rural area, central and western regions [32]. These findings indicate a role of maternal environmental exposures in the causal pathway of offspring syndactyly. It is very important to carry out etiological studies and interventions targeting syndactyly in these areas.

Previous studies have noted a link between maternal age and syndactyly. Pregnant women over 40 years of age were found to be more likely to have infants with syndactyly compared to younger women [33]. This study identified a higher SD prevalence in the maternal age group of 30–34 years and the highest prevalence of associated SD in the advanced maternal age (AMA) group. One explanation is that AMA can increase the risk of chromosomal anomalies and accompanying syndactyly [34]. However, multivariate Poisson regression models showed that the association between maternal age and syndactyly became insignificant after adjusting for year and other factors, suggesting temporal variations in maternal age-specific prevalence of syndactyly. Another explanation could be the older paternal age, that is generally associated with AMA, can increase gene mutations in sperm, thus increase the risk of some offspring skeletal malformations like Apert syndrome caused by FGFR2 mutations [35]. Most SD cases could be caused by de novo genetic variants as only a small percentage of cases had a family history. These findings indicate that parental age could affect SD prevalence [36, 37], and further investigations are warranted to elucidate the causes and mechanisms.

Our study also found that infants affected by syndactyly had poor pregnancy outcomes, particularly those affected by associated SD. Significantly higher preterm birth rate and low birth weight rate were observed for affected infants as compared with the general birth population [38, 39]. More than 20% of infants with associated SD were born prematurely or weighing < 2500 g. These figures were considerable higher than those reported in high-income countries [40]. The high perinatal mortality of our study may be partly due to those termination of pregnancies included in our analysis, but grouped as stillbirths. Nevertheless, the higher rate of early neonate death (4.4% for associated SD, 0.4% for isolated SD) compared with general Chinese newborns [13], suggests an urgent improvement in perinatal care and efficient interventions.

Syndactyly is phenotypically complex. In consistent with most published reports, right side preference and upper limb preference were confirmed in both isolated and associated syndactyly [4, 41, 42]. However, upper limbs and lower limbs were equally involved in several studies [30]. Both hands and feet involvements were rare in the current study (4.9%), lower than the percentage of 8% reported in a study [30]. Comparable to other studies, more than three-quarters of SDs occurred on one side of limbs, and the bilateral limb involvements were less than 20% [20, 42, 43]. Notably, more associated SD involved bilateral limbs and feet than isolated cases. The phenotypic heterogeneities between different SD malformations suggest the need for further genotype–phenotype studies.

Syndactyly can be accompanied by a variety of congenital abnormalities. Consistent with previous studies, anomalies of the musculoskeletal and circulatory systems were frequently associated with syndactyly [19]. Polydactyly was the most common malformation co-occurring with SD cases, indicating that polydactyly and SD may share some common genetic bases [23, 44]. Other major malformations such as oral clefts, eye, ear, and craniofacial abnormalities were also commonly associated with SD cases. Only 2.0% of associated cases were accompanied by chromosomal disorders, which could be underestimated because most pregnant women refused further examination once SD was confirmed due to its treatability. It is clear that SD cases with major malformations usually have a higher risk of adverse perinatal outcomes. The spectrum of congenital disorders co-occurring with SD needs to be further investigated as it may serve as an important predictor of prognosis.

In conclusion, the prevalence of syndactyly in China appears to be higher than that reported in other Asian countries and most European countries. The prevalence of syndactyly varies by maternal residence, maternal age, geographic region, and infant sex. The rising trend in prevalence, coupled with the poor perinatal outcomes among affected infants and the phenotypic variability, highlights the necessity of further etiological, epidemiological, and clinical studies on syndactyly in the contemporary Chinese population.