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 Table of Contents  
Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 24-30

Assessment of risk factor associated with down syndrome

Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India

Date of Submission17-Jul-2020
Date of Acceptance30-Sep-2020
Date of Web Publication06-Nov-2020

Correspondence Address:
Dr. Anupam Kaur
Department of Human Genetics, Guru Nanak Dev University, Amritsar - 143 005, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpai.jpai_3_20

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Introduction: A large number of Down syndrome (DS) children are born every year in India and are the leading cause of morbidity and mortality in infants. The aim of the present study was to evaluate the possible risk factors in mothers for having DS. Methodology: A total of 217 DS cases were collected, and lymphocyte culturing was performed to confirm aneuploidy. Mothers having DS children (n = 213) with confirmed trisomy 21 and age-matched controls (n = 220) with normal children were collected. Results: Of 217 cases, 213 had confirmed trisomy 21 in children, and free trisomy 21 was observed in 91.71%, followed by mosaics in 3.68% and Robertsonian translocations in 2.30% of the cases. A double aneuploidy with chromosomal constitution 48, XXY,+21 (0.46%) was also seen. The mean maternal age in cases was 27.34 ± 5.2 years, while in controls, it was 27.75 ± 4.9 years. Logistic regression analysis showed that intake of folic acid (P < 0.0001) was associated with reduced risk while decreased parity (P = 0.01), intake of drugs in mothers (P = 0.002), and alcohol intake in fathers (0.032) were significantly associated with an increased risk of a DS child. Nearly 30.62% of the mothers experienced miscarriage before the birth of DS child but was not associated with an increased risk of trisomy 21. Conclusions: DS children were born to mothers younger than 30 years; intake of folic acid significantly reduced the risk, while intake of drugs in mothers and intake of alcohol in fathers significantly increased the risk of a DS child.

Keywords: Down syndrome, folic acid, free trisomy 21, maternal age, miscarriages

How to cite this article:
Kaur A, Kaur A. Assessment of risk factor associated with down syndrome. J Pediatr Assoc India 2020;9:24-30

How to cite this URL:
Kaur A, Kaur A. Assessment of risk factor associated with down syndrome. J Pediatr Assoc India [serial online] 2020 [cited 2023 Oct 3];9:24-30. Available from: http://www.jpai.in//text.asp?2020/9/1/24/300102

  Introduction Top

Down syndrome (DS) is the most frequently occurring chromosomal aneuploidy and leading genetic cause of mental retardation in humans. According to the WHO,[1] worldwide incidence of DS is 1 in 1000–1100 live births, while in India, 37,000 children with DS are born annually with the incidence of 1.4/1000 live births.[2] It has been evaluated that 1 in 150 conceptions have trisomy 21 and 80% are lost during pregnancy.[3] The third copy of chromosome 21 is the result of abnormal segregation during cell division and the mechanism is known as nondisjunction.[4] Nondisjunction is a maternal event in 95% of the cases arising due to errors in meiosis I or meiosis II, while 5% are of paternal origin.[5],[6] Trisomy 21 was allied with increased maternal age; however, current reports advocate that 92% of the DS children are born to younger mothers of <30 years of age, providing evidence that apart from advanced maternal age, other factors also contribute to the risk of DS.[3],[7] It is difficult to understand the exact mechanism behind nondisjunction due to complexity of pathways and variable phenotypes involved.[8] A very high number of DS children are born in India every year and are the leading cause of mental retardation which prompted us to carry out this study and to investigate the possible risk factors for DS.

  Methodology Top

To achieve proposed objective, 217 cases of DS children were collected, which were referred to the Department of Human Genetics, Guru Nanak Dev University, Amritsar, from various hospitals and special schools of Punjab. Cytogenetic investigations were carried out to confirm trisomy 21; after confirmation of trisomy 21, 213 case mothers and 220 age-matched control mothers having normal children and without any miscarriage were collected from urban and rural areas of Punjab for further investigations. The study was performed according to the Declaration of Helsinki and approved by the Institution Ethics Committee of Guru Nanak Dev University, Amritsar. A questionnaire was designed to record detailed family history, pedigree, and clinical features of a DS child. Before all investigations, written informed consent was obtained from all the participants.

Lymphocyte culture was set up for cytogenetic investigations according to the protocol[9] with laboratory modifications.[10] Fifty well-spread metaphases with sharp banding were scanned with Olympus BX51. Twenty metaphases were karyotyped using automated karyotyping system, CytoVision (Applied Imaging).

Statistical analysis

In cases and controls, age of parents at the time of birth of DS child was calculated and presented as mean ± standard deviation. Regression analysis was done for correction of confounding factors such as age, drugs, alcohol/smoking in fathers, parity, and folic acid. All the analyses were performed using SPSS software (Statistical Package for the Social Sciences Inc. 20, Chicago, IL, USA, 2011).

  Results Top

The present study was designed to investigate trisomy 21 in children and epidemiological factors among their mothers. For this purpose, 217 cases of DS children were collected and cytogenetic investigations were carried out to confirm trisomy 21. After confirmation, 213 mothers having DS children and 220 control mothers were collected for further investigations.

In the Department of Human Genetics, 217 cases were referred as DS for chromosomal analysis during the period of 3 years (2014–2017), of which 135 were males and 82 were females with a ratio of 1.6:1 and age ranged from 1 day to 32 years. Trisomy 21 was confirmed in 213 cases, and the remaining four cases (1.84%) showed normal chromosomal constitution. Chromosomal investigations revealed that 199 (91.71%) cases exhibited free trisomy 21, followed by mosaicism in 8 cases (3.68%) and Robertsonian translocations in 5 cases (2.30%) [Table 1]. One of the cases with free trisomy 21 exhibited extra material on short arm of chromosome 15, which was inherited from mother. In 5 cases, Robertsonian translocations t(21:21) were observed. One male child with double aneuploidy was reported with chromosomal constitution 47, XXY,+21 (0.46%). Although features of DS were prominent in this child, characteristics of Klinefelter syndrome were not apparent [Table 1]. The chromosomal analyses of parents and two sisters of proband were carried out and found to be normal.
Table 1: Percentage frequency of trisomy 21 in different categories

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DS is a genetic disorder that can be identified on the basis of clinical features. The features of DS are given in [Table 2].
Table 2: Clinical features in Down syndrome children

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Among cases, 78% of the mothers were below the age of 30 years and 22% were above 30 years, while in controls, 72% of the mothers were below 30 years and 28% were above 30 years. This suggested that more number of DS children were born to mothers < 30 years. In cases, 57.5% of the fathers were below 30 years and 42.5% had age more than 30 years, and in controls, 52% of the fathers were <30 years of age while only 48% were more than 30 years [Table 3].
Table 3: Mean ages in cases and controls

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Univariate regression analyses showed the effect of individual factors for the risk of a DS child. The mothers who had taken folic acid before and during pregnancy were protected from risk of having DS (P < 0.0001). Similarly, in mothers who took drugs for having a male child or for any other health issues (P = 0.002), decreased parity (P = 0.01) and alcohol intake in fathers (P = 0.032) had increased the risk for DS child [Table 4].
Table 4: Characteristics of mothers of Down syndrome children and controls

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Multivariate regression analyses also showed that insufficient folic acid, drug intake by mothers, and alcohol intake in fathers together significantly increased the risk for having a DS child [Table 5].
Table 5: Multivariate regression on characteristics of mothers of Down syndrome children and controls

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In the present study, 69.48% of the mothers did not experience any miscarriage, 22.07% had one induced or spontaneous miscarriage and 7.51% had two miscarriages, while only 0.94% had three miscarriages. The mean maternal age in mothers who experienced none and one miscarriage was 27.05 ± 5.3 years and 27.19 ± 4.6 years, respectively, while it was 30.25 ± 5.3 years in case of two miscarriages and 29.0 ± 2.8 years in mothers who had three miscarriages. However, no significant association was observed between number of miscarriages and risk of DS.

  Discussion Top

DS due to nondisjunction and translocation can be easily identified at birth with 100% accuracy as compared to 37% of the cases of mosaicism which could be due to mild dysmorphic features and are diagnosed later.[11] The confirmation through karyotyping is necessary to know the type of DS. In our study, of 217, trisomy 21 was confirmed in 213 cases and 4 (1.84%) cases were excluded due to their normal karyotype. The age of DS individuals ranged from 1 day to 32 years, and there were 132 males and 81 females, showing that males outnumbered females. Most of the studies observed a similar trend in which the male ratio is higher than females.[5],[7],[12],[13],[14] Of 213 cases, 199 (91.71%) cases exhibited free trisomy 21 and our results were consistent with various studies reporting that free trisomy 21 ranged from 90.5%–95%.[11],[15],[16],[17],[18],[19] The lowest frequency recorded was 60.6% in Mexico[20] and 68.0% and 87.71%, in India[21],[22] while it was 100% in Yemen.[23]

The mosaicism in the present study was observed in 8 (3.68%) cases [Table 1], and similar results with a range of 3.1%–3.9% were obtained by Devlin and Morrison,[11] Sheth et al.,[24] Kaur and Singh,[25] and Amayrehet al.[26] The lowest frequency for mosaicism was reported to be 0.6%,[27] and the highest frequency observed was 39.4% by Gonzalez.[20]

The translocations in the present study were found in 5 (2.30%) cases [Table 1], and in all the five cases, translocation appeared to be de novo as parents and siblings of proband were karyotypically normal. The lowest frequency of translocation in DS reported in the literature was 0.6%[28] and the highest being 20%.[29]

Event of double aneuploidy is very rare in the same individual, with a frequency of 3%–7%.[30] It occurs due to meiotic nondisjunction and is parental in origin.[31] DS and Klinefelter syndrome rarely occur together in the same individual, with a reported frequency of 0.27 − 0.7 × 10 − 5.[32] In the present study, one case of double aneuploidy with the chromosomal constitution 48, XXY,+21 was observed with a frequency of 0.46% [Table 1]. Only a few cases with such classical karyotypes have been reported with a frequency of 0.3%–2.4%.[17],[33]

The variable features associated with DS make diagnosis difficult, and it was recognized in 49.5% of the children based on phenotypic features such as simian crease, epicanthal folds, protruding tongue, gap between toes, and short and broad hands.[34] In the present study, common morphological features were epicanthal folds, protruding tongue, depressed nasal bridge, palpebral fissures, simian crease, anterior fontanelle, gap between toes, low set ears, short and broad hands, etc., [Table 2]. Adults with DS show typical clinical features such as palpebral fissures, Brushfield spots, fissured tongue, small rounded underdeveloped ear lobes, short broad neck, short stature, and obesity.[21] Besides these features, DS children have multiple comorbid conditions such as mental retardation, hearing and visual problems, bone abnormalities, and leukemia.[35]

Nearly 40%–60% of the DS children are presented with congenital heart diseases (CHDs).[36],[37],[38] In the present study, CHD was observed in 18 (8.45%) cases of DS children. A report from India demonstrated that 50% of the DS cases were having CHD, of which 66.6% were males and 33.3% were females.[39] In the Netherlands, 43% of the individuals were observed to have CHD,[40] which was quite higher than the Dutch population (0.62%). In Iran, it has been estimated that 50% of the cases of DS had CHD[41] while another study from Iran observed 41.8% of the cases of CHD in DS.[42] A recent study revealed that 83.3% of the cases with DS had CHD in Saudi Arabia.[43] It is the major cause of morbidity and mortality in DS children in their early years,[44] but due to advanced surgical treatments, life expectancy has gone up to 60 years.[45] However, Mottaghi Moghaddam et al.[46] reported that 43% of the DS children expired within 6 months of life.

Gastrointestinal abnormalities such as duodenal atresia and imperforate anus were found in 3.29% and 1.41% of the cases, respectively, in the present study [Table 2]. This frequency is quite low as compared to 6% and 7.3% as observed by Stoll[47] in France and Frid[48] in Sweden. Sleep disorders due to breathing are quite common in DS children and reported with a frequency of 31%–75%.[49],[50] In the present study, 28.17% of the cases had respiratory problems which fell in the range, as seen in the literature (3.3%–33.3%).[51] In a recent study, 24.09% of the DS cases had respiratory issues.[38] Sleep apnea was observed in 22.07% of the cases with DS in the present study, while 79% of the cases in Glasgow[52] and 95% of the cases in Indianapolis have been reported.[53] Other issues experienced by DS children in the present study were neurological problems (67.14%), jaundice (47.18%), asphyxia (8.45%), and leukemia (1.41%) [Table 2].

In the present study, the mean maternal age was 27.34 ± 5.2 years in cases while it was 27.75 ± 4.9 years in controls, indicating that majority of the DS children were born to younger mothers. Our results were consistent with various reports that indicated that 75%–82% of the DS children were born to mothers younger than 30 years.[7],[24],[25],[33],[54],[55],[56],[57],[58] Advanced maternal age was depicted by many other reports also.[5],[12],[15],[18],[26],[27],[51] Hahn and Shaw[59] observed a modest increase in prevalence of DS children among mothers younger than 35 years. Delport et al.[60] indicated 1.33 DS children per 1000 live births in Pretoria, and 52% of the mothers were of 35 years or above. With advanced age, there is a rapid deterioration of proteins involved in spindle formation required for normal segregation of sister chromatids, thus increasing the risk of nondisjunction in both meioses I and II. Studies from the USA suggested that chromosome 21 is prone to nondisjunction in the absence of chiasmata and/or if it is placed suboptimally. Telomeric exchange increases risk for meiosis I while pericentromeric exchanges result in errors in meiosis II.[61] Studies have suggested that younger mothers exhibited a higher proportion of telomeric exchanges at distal region in meiosis I while older mothers exhibited a single chiasma at proximal region in meiosis II. Nondisjunction is a complex and multifactorial event that can be age dependent or age independent. A single telomeric exchange puts the oocyte at risk for nondisjunction regardless of maternal age while age-dependent factors can be evident from pericentromeric exchanges among older women in meiosis II.[62] In older women, ovarian microenvironment becomes more error prone due to accumulation of both environmental and age-related insults.[63]

The mean paternal age was 30.55 ± 5.68 years among cases and 31.69 ± 4.51 years among controls in the present study [Table 3]. The effect of paternal age on DS is still controversial, but studies have suggested higher percentages of DS children born in families with advanced paternal age as well.[64] It has been reported that there is no influence of paternal age on aneuploidy (DS) in human sperm.[8],[65] Malini et al.[66] demonstrated that the age of fathers has a lesser effect on DS birth as spermatogenesis begins at puberty during which cells enter meiosis and moves from one stage to another without any delay in comparison to meiosis in women which remains halted for 10–50 years.

Another factor that influences the risk of a DS child is said to be maternal grandmother's age. It was observed to be 49.88 ± 5.64 years among cases and 47.86 ± 5.79 years among controls [Table 3] in the present study, which suggests that a mother of DS child was born when grandmother was in her 30's or above. This result was consistent with a report by Maliniet al.,[66] who observed that when a daughter was born to a mother with advanced age, the chances of that daughter giving birth to a DS child increase. This could be due to the fact that at advanced age, reproductive machinery fails to produce essential proteins and leads to improper meiosis I and II and malsegregation of chromosome 21. Failure to produce essential proteins in grandmother results in changes in meiosis I during the conception of daughter. Thus, advanced maternal age along with advanced grand maternal age may affect the risk of birth of a DS child.

It has been observed in the present study that the mothers who took folic acid supplementation before and during conception were at reduced risk of a DS child (P < 0.0001) [Table 4]. A decreased risk of DS was observed in a population-based study, after the use of high-dose folic acid periconceptionally by Czeizel and Pohó.[67] Folic acid deficiency is not only associated with abnormal segregation but also with developmental disorders such as neural tube defects and CHDs. Smithells et al.[68] first described that mothers of NTD children were deficient in folic acid and supplementation periconceptionally with micronutrients significantly prevents the disorder. Gazievet al.[69] suggested that intake of folic acid with 200 nM concentration significantly reduced chromosomal damage caused by folic acid deficiency and gamma irradiation by 55.5% and 51.7%, respectively. According to Beetstra et al.,[70] folate status has an important role in chromosomal stability and aneuploidy 21 is increased by decreasing concentration of folic acid.

In the present study, mothers who had drugs or desi medicines (unknown origin) for having male child or for any other reason (P = 0.002) significantly increased the risk of having a DS child [Table 4]. It has been observed that environmental toxins and drugs are potential inducers of malsegregation of chromosomes.[55] The drugs taken for having male child contain a high level of testosterone and progesterone, which changes the gender, particularly in favor of male, and put the fetus four times higher risk of having congenital malformations.[71] Low parity in mothers (P = 0.01) was found to be associated with a significant increased risk of DS in the present study [Table 4]. However, higher parity was considered to be the risk factor for DS among women under and above 35 years of age,[72],[73] whereas Chan[74] reported no effect of parity on risk of DS.

Alcohol intake in fathers (P = 0.032) was observed to be significantly associated with increased the risk of having a DS child [Table 4]. Multivariate analysis also showed that folic acid deficiency along with drug intake and alcohol intake significantly increased the risk of a DS child in the present study [Table 5]. Malini and Ramachandra[28] stated that tobacco smoking and alcohol drinking were very common among DS families and both smoking and drinking significantly increase the risk by 63% and 38%, respectively. It has been demonstrated that regular intake of alcohol is associated with intestinal malabsorption, reduced hepatic intake, and increased excretion of folic acid in urine resulting in long-term folate deficiency which is due to decreased activity of GCPII and RFC proteins that regulate folate absorption.[75] Similarly, Ghosh et al.[76] and Shalaby[55] reported that chewing tobacco, smoking, and having oral contraceptive have strong age-dependent effects on having DS children. However, a study on 687 DS children indicated that the use of alcohol during 1st-month pregnancy had no link with any abnormality in DS child.[77],[78]

Recurrent spontaneous abortions (RSAs) are commonly observed among mothers either before or after having DS children as reported by Warburton.[79] Miscarriages may occur due to genetic predisposition or due to exposure to environmental factors and was reported that RSA at the age of 30 years or less results in DS in the very next conception.[80] In the present study, detailed family history indicated that 22.07% of the women had one miscarriage while 7.51% had two and only 0.94% had three miscarriages before the birth of DS child and all are around or below 30 years of age. In a report, 22.8% of the mothers with DS child were below 30 years of age and 25.44% experienced a single miscarriage.[22] Studies have suggested that more number of miscarriages are associated with an increased risk of having a DS child.[81],[82],[83] This can be explained by the fact that mechanism that controls spontaneous abortions becomes less efficient with advanced maternal age; thus, the ability to identify and abort chromosomally abnormal fetus become faulty, and increasing age results in survival of abnormal fetus.[84] Stene et al.[85] observed more number of abortions due to abnormal fetus among younger mothers than older ones and demonstrated that reproductive history might play a role in predisposition of birth of child with abnormality. Rajangamet al.[81] observed 78.9% spontaneous abortions before the birth of DS child and reported that a significantly higher frequency of miscarriages occurs in DS families (18.9%) as compared to control families (14.5%).

  Conclusions Top

Various studies provide conflicting results, which could be due to ethnicity, lifestyle, gene–gene, and gene–environmental interactions. The present results indicated that majority of the DS children were born to younger mothers. Intake of drugs by mothers and intake of alcohol by fathers were significantly associated with an increased risk of having a DS child. Intake of folic acid before and during conception significantly reduced the risk; thus, the fortification of food products should be made mandatory. Since very few reports are available from North India, our study has generated baseline data which will assist in evaluating the risk of having a DS child and could provide insight to develop new strategies that would help in preventing DS.

Financial support and sponsorship

This study was financially supported by the Department of Science and Technology (DST) (SR/WOS-A/LS-348/2013) awarded to Amandeep Kaur.

Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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