During the period from August 1995 till December 2020, a total of 194,167 newborns were monitored from 192,822 deliveries, which include 1318 twins, 12 triplets and one quadruplet in hospital units of NLNRA and HLNRA of Kerala coast. Age at birth of the mothers ranged from 15 to 45 years with a mean age of 24.7 ± 3.8 years and about 83% were in the age group of 20-29 years. Majority (~ 92%) of the births was either from first (46.2%) or second (45.6%) gravida/delivery. The overall sex-ratio of the newborns monitored was 1042 males to 1000 females. Among these, congenital malformations were detected in 4668 (24.04‰) newborns of which 1774 (9.14‰) had major congenital malformations. About 59% (114,764) newborns were from HLNRA and 41% (79,403), from NLNRA. Major malformations (0.92% v/s 0.91%), stillbirths including born alive but died immediately after birth (0.38% v/s 0.34%), down syndrome (0.065% v/s 0.065%) and live singleton newborns with low birthweight of < 2500 g (8.13% v/s 8.15%) were observed to be similar in HLNRA and NLNRA, respectively. The prevalence of paternal smoking habit was 35% and it was not associated with the risk of any of the end-points considered. Maternal smoking was rare (< 1%) in the study population.

A total of 533 infants were born dead, either as still birth or intrauterine death and were excluded from the analysis of congenital heart disease (CHD) among the live births. Among 193,634 live newborns, a total of 289 newborns were identified as CHDs (138 males; 151 females) with a frequency 1.49‰ of which 23 newborns with CHD (15 males; 8 females) died within few days without any physical stress. Though male newborns with CHD died immediately after birth, which is twice as often as their female counterpart, the difference was not statistically significant (RR = 2.05, 95% CI: 0.90-4.69). CHD constituted 6.03% of overall malformations and 16.29% of major congenital malformations with serious structural, functional, or developmental disability. About 86% of the newborns had CHD alone and the remaining 14% had other major malformations involving central nervous, musculoskeletal, genitourinary, gastrointestinal, respiratory systems or syndromes.

Maternal age at birth, gravida status, gender of the newborns and radiation dose levels at the area of parental residence were found to be associated with overall as well as major congenital malformations. However, the variation observed in the frequency of malformations across different religious groups was well within the limits of random fluctuation (Table 1). While there was statistically significant difference in the frequency of overall congenital malformation among different ethnic groups within Hindu religious group, the frequency of major congenital anomalies was statistically similar among them (Table 1).

Table 1 Overall and major malformations and heart diseases among newborns according to maternal and newborn characteristics

Detailed analysis of the frequency of congenital heart disease (CHD) among live births was carried out among the newborns monitored. CHD was least frequent in the maternal age group of 20-21 years (0.86‰) and most frequent (1.92‰) in the age group of ≥30 years (Table 1). Chi-square test suggested that the associations of maternal age at birth with CHD was statistically significant (P = 0.026) with increase in CHD after the maternal age at birth of 26 years and a statistically significant maternal age at birth related linear trend (Trend χ2 = 10.7, P < 0.01). Newborns of mothers with gravida status of 4 or more had the highest frequency of CHD (3.42‰) as compared to 1.33‰, 1.59‰ and 1.67‰ among mothers with gravida status of 1, 2 and 3, respectively (P = 0.057). Female newborns had relatively higher frequency of CHD (1.59‰) as compared to male newborns (1.40‰), but the difference was not statistically significant (P = 0.291). Newborns from consanguineous (1.83‰) and non-consanguineous marriage groups (1.49‰) had statistically similar frequency of CHD (P = 0.778). The variation in the CHD frequency across the three religious groups i.e., Hindu, Christian and Muslim as well as that among different ethnic groups within Hindu religious group was within the limits of chance fluctuations/ occurrences.

The data was stratified based on background radiation level at the area of parental residence and was grouped as ≤1.50, 1.51-3.0, 3.01-6.0 and > 6.0 mGy/year. The CHD rates among the newborns of mothers belonging to these areas were 1.79‰, 1.30‰, 0.98‰ and 1.64‰ respectively (Table 1). Chi-square test suggested that the difference in the incidence of CHDs in the four radiation dose groups to be statistically significant (P = 0.024). The overall frequency of CHD in HLNRA was 1.28‰, which was significantly (P = 0.005) different from the frequency 1.79‰ observed from NLNRA.

The odds ratio (OR) was estimated using multiple logistic regression analysis to assess the individual contributions of maternal age at birth, gravida status, gender of the newborn, consanguinity, religion and ethnicity together with background radiation dose to the risk of CHD and is depicted in Table 1 with OR of 1 indicating reference category. The analysis suggested that maternal age at birth and radiation levels at the area of parental residence is associated with CHD. The risk of CHD was less in the age group of 20-21 years as compared to the reference group of 22-23 years (OR = 0.59, 95% CI: 0.37-0.94). The risk of CHD in all the other age groups was statistically similar to that in the age group of 22-23 years. The risk of CHD among newborns from areas with background dose levels of 1.51-3.0 mGy/year was significantly lower as compared to NLNRA (OR = 0.72, 95% CI: 0.57-0.92). The risk was statistically similar in the dose group of ≤1.50 mGy/year and in the HLNRA dose groups of 3.01-6.0 mGy/year (OR = 0.55, 95% CI: 0.31-1.00) and ≥ 6.0 mGy/year (OR = 0.96, 95% CI: 0.50-1.85).

The background dose at the parental residence was further subdivided to assess the dose response of CHD with respect to radiation dose. The odds of CHD in each dose group together with its 95% CI is depicted in Fig. 1. The line of best linear fit of the odds, estimated using logistic regression by using the geometric mean of the doses in each dose group, does not seem to suggest any trend in the risk of CHD with increasing background dose. An apparent statistically non-significant reduction was observed in the first few dose groups of 1.51-2.50, 2.51-3.50, 3.51-4.50, 4.51-6.0 and 6.01-15.0 mGy/year relative to that in ≤1.50 mGy/year, the NLNRA.

Fig. 1
figure1

Odds of congenital heart disease (CHD) among live newborns with +/− 95% CI by geometric mean dose in dose categories fitted with logistic regression estimate of the odds (dotted line). CHD odds ratio per mGy = 0.998, P = 0.912

Effect of paternal age on CHD

Of the 193,634 live newborns, paternal age was not available for 55 cases and it was less than maternal age in 380 (0.2%) cases. Hence, analysis was done on 193,199 newborns to find out the influence of paternal age at birth. As maternal age and paternal age were highly correlated, the effect of paternal age at birth was analysed by grouping the newborns whose paternal age is more than the maternal age by 4 years or less (36.9%), 5-9 years (54.1%) and ≥ 10 years (9%). The analysis was carried out separately in the maternal age groups of 15-19, 20-21, 22-23, 24-25, 26-27, 28-29 and ≥ 30 years. The risk of CHD among newborns whose paternal age is more than the maternal age by 5-9 years and ≥ 10 years relative to those who were within 4 years was assessed by using odds ratio. The results as depicted in Fig. 2, do not seem to suggest any statistically significant influence of paternal age at birth, though mothers aged 28 or more appear to have a higher risk of having a newborn with CHD, if the paternal age is greater by 10 years or more. The influence of paternal age at birth seems to be minimal for maternal age at birth of 27 years or less.

Fig. 2
figure2

Influence of paternal age at birth on the risk of congenital heart disease. The risk was estimated among newborns with paternal age more than the maternal age by 5-9 years & ≥10 years relative to those who were within 4 years, separately within each maternal age group. Horizontal axis gives the maternal age group and number of newborns in each group, grouped by the difference between parental age, together with number of newborns with CHD in parenthesis

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