European Journal of Cardiovascular Medicine

Congenital hypothyroidism (CH) represents a heterogeneous group of thyroid disorders that manifests as thyroid hormone deficiency present at birth. It is most commonly caused by a problem with thyroid gland development or a disorder of thyroid hormone biosynthesis resulting in primary hypothyroidism whereas a deficiency of thyroid stimulating hormone (TSH) results in secondary or central hypothyroidism.1,2 In India the prevalence has been reported to be 1 in 2640.3

Commonest causes of Permanent CH include thyroid dysgenesis probably due to inactivation of thyroid receptors maternal cytotoxic antibodies and genetic mutations lead to inactivation of thyroid receptors.1 It affects 1 in 4000 live births. Secondly, synthetic defects in thyroid hormone accounting for 10% of all permanent CH cases. These disorders usually manifest as goitrous hypothyroidism. Furthermore, Permanent CH develops due to Iodine deficiency that is responsible for endemic cretinism and hypothyroidism in some regions of India. Lastly, hypothalamic- pituitary hypothyroidism that has an incidence of 1 in 100,000. It may be isolated or associated with concomitant deficiency of other pituitary hormones and present with hypoglycemia and microphallus.1

On preliminary examination, the most common signs are umbilical hernia, macroglossia and cold or mottled skin. 2 Wide posterior fontanel of greater than 5 mm has also been reported. This, along with persistent jaundice and poor feeding are the most striking clinical features.3A few infants with CH may have a palpable goiter, usually found in thyroid. The babies with CH are quiet and may sleep through the night. Additional symptoms include a hoarse cry and constipation. Neonatal hyperbilirubinemia for more than three weeks is common. Some forms of CH are associated with defects in other organ systems; these are classified as syndromic hypothyroidism.1 The high prevalence of dysmorphic features (94%), congenital heart disease (29%), and spina bifida occulta (41%) in the patients associated with CH in India has also been reported.4,5 Other associated malformations include spiky hair, cleft palate, neurologic abnormalities and genitourinary malformations.6

The incidence of congenital hypothyroidism before the invention of newborn screening programs, as diagnosed after clinical manifestations, was about 1;7,000 to 1:10,000.7

Moreover, the most essential factors that influence CH-frequency are due to different approaches used for neonatal thyroid screening. For instance, primary T4-Screening programs produce lower incidence rates than primary TSH-programs. Lastly regional differences also call attention to environmental and possibly ethnic factors influencing the occurrence of CH. However, references on a minor variety in CH-incidence, which may be higher in individuals from arabic and hispanic and lower from black origin, if iodine supply is sufficient, are not confirmed yet.8

Ideally universal screening at 3-4 days of age is done for detecting CH. Alternatively cord blood can also be used if screening is being done only for CH and no other inborn errors of metabolism. Three approaches are being used for screening: primary TSH, back upT4, primary T4, back up TSH and concomitant T4 and TSH. In the first approach, TSH is measured first. T4 is measured only if TSH is > 20mu/L. This approach is likely to miss central hypothyroidism, thyroid binding globulin deficiency and hypothyroxinema with delayed elevation of TSH. In the second approach, T4 is checked first and if low TSH is also checked. This is likely to miss milder/ subclinical cases of CH in which T4 is initially normal with elevated TSH. Concomitant measurement of T4 and TSH is the most sensitive approach but incurs a higher cost. Babies who are screened must have a Family history of CH, history of thyroid disease or antithyroid medicine intake in mother and the presence of other conditions like Down‘s syndrome, trisomy 18, neural tube defects, congenital heart disease, metabolic disorders, familial autoimmune disorders and Pierre- Robbins syndrome which are associated with higher prevalence of CH .9

Congenital hypothyroidism is one of the more common preventable causes of mental retardation.10 The clinical features of congenital hypothyroidism are often subtle and many newborn infants remain undiagnosed at birth. The two main goals of the neonatal thyroid screening programme (NTS), early identification preferably within 1-2 months of birth and early adequate treatment, have been achieved to a great extent in the Western world. Hence, in our study we studied the incidence of congenital hypothyroidism in term inborn neonates using cord blood thyroid stimulating hormone level.

AIMS AND OBJECTIVES

To use cord blood TSH as a marker for screening of congenital hypothyroidism in term neonates.

STUDY DESIGN: Prospective observational study.

STUDY AREA: Department of  Paediatrics, Gayathri Vidya Parishad Institute of Health care and Medical Technology, Visakhapatnam.

STUDY POPULATION AND SAMPLE SIZE:

The study will be conducted on all term inborn delivered in hospital from over a period of 18 months from May 2023 to October 2024.

TENTATIVE STATISTYCAL ANALYSIS PLAN

Descriptive statistical analysis was done using SPSS version 17.0 software. Continuous variables presented as mean ± SD. Categorical variables were expressed as frequencies and percentages. The Pearson's chi-square test or the chi-square test of association was used to determine if there is a relationship between two variables.

EXCLUSION CRITERIAS:

1.             Mother on any antithyroid drugs

2.             Preterm (<37wks)

3.             Any major congenital anomaly

4.             Critically ill neonates (on ventilator, inotropes, temperature instability, tachycardia (HR >160), Bradycardia (HR<95) (25), severe sepsis.

5.             TSH Level < 1mU/l (Central Hypothyroidism)

INCLUSION CRITERIA:

1.             All term neonates delivered at. Gayathri Vidya Parishad Institute of Health care and Medical Technology, Visakhapatnam.

METHODOLOGY

This observational Study will be conducted in all term inborn delivered in the hospital keeping the inclusion criteria in mind. Parent/guardian asked for permission of their children to participate in the study. After written & informed consent, detailed history were taken, physical examination was done, Umbilical (and if required,venous) bloodsample is collected from the patients for investigations, and sent to the pathology department. Pre structured proforma used to record the details of patient at birth.

For all term inborn neonates participating in the study, 2-3 ml of cord blood was collected in a sterile serum separating tubes (BD vaccutainer SST II advance) immediately after birth of babies, drawn from a 15-20 cm length of umbilical cord incised while severing it at the time of birth of the baby. Thus a mixed umbilical cord blood sample containing blood both from umbilical arteries and veins was obtained. Later, the Thyroid Stimulating Hormone values was determined by Electrochemiluminescence immuno assay method.

If the value of cord blood Thyroid Stimulating Hormone is >/= 20 mU/mL, thyroid profile of the baby shall be sent by peripheral venous sample between 3rd to 7th day of life, and if Thyroid Stimulating Hormone level is still >/= 20 mU/mL ,it will be considered as congenital hypothyroidism.

Table 1. Gender wise distribution of study subjects

Table 2. Maternal history wise distribution of study subjects

Table 3. Mode of delivery wise distribution of study subjects

Table 4. Mean of parameters of study subjects

Table 5. Mean TSH (mU/L) of study subjects at birth

Table 6. Gender wise distribution of suspected congenital hypothyroidism study subjects

Table 7. Maternal history wise distribution of suspected congenital hypothyroidism study subjects

Table 8. Mode of delivery wise distribution of suspected congenital hypothyroidism study subjects

Table 9. Mean of parameters of suspected congenital hypothyroidism study subjects

Table 10. Comparison of mean TSH (mU/L) of suspected congenital hypothyroidism study subjects at birth and 3^rd day follow-up

Table11. Mean TSH (mU/L) of suspected congenital hypothyroidism study subjects at 3^rd day follow-up

Table12. Birth weight distribution of study subjects

Congenital hypothyroidism (CH) signifies hypothyroidism present at birth and is one of the most common preventable causes of mental retardation.7 It is now generally agreed that screening of newborns for congenital hypothyroidism should be orientated to the detection of primary hypaothyroidism. This can be achieved by measurement of thyroxine in filter-paper blood spots, supplemented by TSH assay if the thyroxine concentration is found to be low. TSH screening program being the more sensitive of the two methods was disputed recently.

As far as the type of screening method is concerned, some countries use T4 while others prefer TSH as the tool since maternal diseases affecting placental dynamics influence T4 levels.  Neonatal TSH has the major advantage of being the single indicator allowing prediction of possible impairment of mental development at a population level. With a properly collected specimen, primary TSH screening provides a cost-effective program with the highest detection rate and a very acceptable low recall rate.11 On the other hand, few use both T4 and TSH. Technically, using both T4 and TSH will be superior but would increase the cost of screening.

Some workers consider the threshold value for a significant TSH elevation to be 20- 25 mU/l for blood samples taken from heel pricks.11 Some other workers take all cord blood samples with TSH values 30 mU/l and above were assayed for their T4 levels. They also guaranteed that no case of congenital hypothyroidism would have been missed if the detection limit of cord blood TSH had been set at 90 mU/l as per their ROC curve. This set value can improve the efficiency of the screening programme and can lead to significant cost saving.35 Other researchers have also studied different CB TSH cut off levels varying between 20-90 for recall with an objective to keep cost of rescreening low and making it more cost effective. In Indian setup, cord blood TSH value of >20mU/L is seen as safe cut off for recall.  Recently, another study from India by Gurjit Kaur et al 2010 12 from Chandigarh has taken 9mU/l as the TSH cut-off value. Ruth V Mikelsaar et al 199813 from Estonia have taken the TSH cut-off value for neonatal screening as 12 mU/L, which is a still lower cut-off value as compared to our study. Therefore, balancing the false positivity by applying the right cut-off value is extremely important to reduce the risk of missing true cases. In our study we have considered our cases to be suspected of CH if the TSH value is greater than 20 mU/L. AAP recommends ensuring total participation of all newborns and obtaining blood specimen from every neonate before baby is discharged or transferred from nursery, regardless of nature or status of infant‘s feeding or age; and that timing of specimen collection should be as close to time of discharge for full-term neonate.12In our study there were in total of 625 study subjects out of which 53.1% (n=332) were female and 46.9% (n=293) were male subjects showing a female predominance. The similar amount of study subjects were taken in Ilamaran V et al 201414(n=785), Grant DB et al 198215n=493). In most studies female subjects are more than males such as Ilamaran V et al 201414 (M and F=376 and 409 respectively),

Out of 625 subjects 13 patients were suspected for congenital hypothyroidism. The distribution showed 61.5 % male subjects (n=8) and 38.5 % female subjects (n=5). Other studies have also reported more male: female ratio such as Reddy JM et al 202116(n=17 M=9 F=8), Raj S et al 201417, later stated the M:F ratio was 1:1.35. Some studies have reported no significant differences in the mean cord blood TSH level between males and females. These studies include Ilamaran V et al 201414 (males = 7.0±4.9mIU/L and females = 6.8±4.7m IU/L), Raj S et al 201417(p=0.814) and Gupta G et al 201418. Advanced maternal age and multiparity are high risk factors for birth defects multiparous mothers have high risk of genital tract infection, which may affect the environment and nutrition of embryo. With regard to maternal history, in our study 36.6% (n=229) were multipara and 63.4% (n=396) are primi. None of the studies reported such variations. In our study, when the maternal history was recorded in mothers with suspected patients it came out to be 5 multiparous mothers and 8 primiparous mothers.

In our study 65.8% (n=411) mothers undergone Caesarean Section and 34.2% (n=214) have Normal Vaginal Delivery. Several studies have investigated the effect of delivery type on the level of blood TSH, which has led to different results. In some works, higher prevalence of congenital hypothyroidism in neonates born with NVD is reported. On the other hand, there are some studies that claim that the prevalence of congenital hypothyroidism in neonates born with C/S is higher. Raj S et al 201417found no correlation. On multivariate analysis requirement of resuscitation, mode of delivery and fetal distress as indication for lower segment cesarean section (LSCS) were found to be significant factors in a study by Gupta G et al 201418.

Our study has revealed that the mean body weight of the study cases born was 2.89 kg ranging from 2.5kg to 3.3kg. The mean body weight in 68.96% (n=431) study subjects ranged between 2.51kg to 3.00kg, whereas, 31.04% (n=194) subjects weighed between 3.01-3.50 kg. In the suspected subjects the mean body weight is 2.79 kg ranging from 2.5kg to 3.3 kg. Many studies have shown almost same mean body weight for the babies born with congenital hypothyroidism including Raj S et al 201417(2.77kg), Bhatia R et al 201819(2.811 kg) and Chaudhary M et al 201820(2 and 4 kg/ 93.25%). Many studies have shown a significant link between the body weight of the patients who are born with congenital hypothyroidism.

As far as maternal age is concerned it is noticed in our study that the mean age of all the mothers was 28.29 years, ranging from 21 years to 34 years, and the mean age of mothers of suspected patients is 29.54 years, ranging between 27 years to 32 years. Some studies found a significant relationship with advanced maternal age and the incidence of congenital hypothyroidism including Rashmi Seth A et al 200721, (P < 0.0001).

The mean TSH values found at the birth was 8.07 mU/MI ranging between 2.30 to61.00 mU/MI as was depicted by several studies such as Gupta A et al 201418(1.01- 63.74 mU/L with median at 8.75). In entire cohort 1.2 and 100 mU/m Bhatia R et al 201819depicted the mean TSH value was 7.725 mU/L. Cord blood TSH less than 10mIU/L was noted in 656 neonates (83.6%) by Ilamaran V et al 201414later depicted the mean to be 6.9±4.8mU/L.21

The mean TSH at 3rd day after birth is noted to be 3.5 mU/L, ranging from 5 to 7.6 mU/L. As we have considered the cut of TSH value to be greater than 20 mU/L, our study resulted in 0/625 patients with congenital hypothyroidism. Some reported the mean to be higher such as the mean value of TSH was 12.88 mU/L in a study by Raj S et al 201417. In 17 in-term babies Wong SLJ 201522reported that all had cord blood TSH> 25 mU/L.

The differences in the mean TSH value at birth and at 3rd day after birth showed significant relationship (p<0.01*). On the other hand some studies showed that there was no significant relation between the both. These studies include Chaudhary M et al 201820who in their study showed no co-relation: No correlation between very high cord TSH levels and true hypothyroidism. None of the babies in their study with cord TSH levels >50 mU/L had true hypothyroidism.

Resultantly, the incidence in our study to be 0:625. The estimated incidence of congenital hypothyroidism was 1:2860, which is high but not statistically different from the incidences reported in the most countries in Europe (1:4000). In areas of severe iodine deficiency and endemic goitre, the incidence of thyroid failure in the newborn can be as high as 1 in 10.Only 49 of the infants identified as being at risk were confirmed with subnormal blood T4 levels and clinical assessment as being hypothyroid. This gives a population incidence of 34/100 000 or 1 : 2931 live births and a false positive diagnosis rate of 1.02% which is much higher than rates of 0.05–0.3% reported from other primary TSH screening programmes.

However, in our study, no significant difference was found in CB TSH values in male and female neonates; nor any positive correlation found with the birth weight.

Various authors have correlated an increase in TSH values with factors like birth asphyxia and difficult deliveries, perinatal stress events, birth weight, male infant sex and instrumental delivery, and negatively with cesarean sections as mode of delivery22 but the mechanism are poorly understood. Our figures have shown a comparable trend with the normative data for cord blood TSH values as reported by various workers across the globe.

To conclude, we cansafely use a cutoff of cord blood TSH value of >20 mU/L for the purpose of screening for congenital hypothyroidism. Large population-based studies are required to establish normative values for cord blood TSH in our country.

1.       Vandana J et al. Congenital Hypothyroidism. Indian Journal of Pediatrics. 2008;75(4):363-67.

2.       Grant DB et al. Congenital hypothyroidism detected by neonatal screening: relationship between biochemical severity and early clinical features. Arch Dis Child. 1992;67(1):87-90.

3.       3.Delange F et al. Neonatal screening for congenital hypothyroidism: results and perspectives. Horm Res. 1997;48(2):51-61.

4.       Reddy PA et al. High Prevalence of Associated Birth Defects in Congenital Hypothyroidism. International Journal of Pediatric Endocrinology. 2010;940980:5 pages.

5.       5.Roberts HE et al. Population study of congenital hypothyroidism and associated birth, defects, Atlanta, 1979-1992. Am J Med Genet. 1997;71(1):29-32.

6.       Olivieri A et al. A population-based study on the frequency of additional congenital malformations in infants with congenital hypothyroidism: data from the Italian Registry for Congenital Hypothyroidism (1991-1998). J Clin Endocrinol Metab. 2002;87(2):557-562.

7.       Alm J, Larsson A, Zetterstrom R: Congenital hypothyroidism in Sweden. Incidence and age at diagnosis. Acta PaediatrScand 1978, 67(1):1-3.

8.       Martin Klett et al 22. Epidemiology of congenital hypothyroidism. Exp Clin Endocrino! Diabetes. 1997;105(4).

9.       Fisher DA. Disorders of the thyroid in childhood and adolescence. In Sperling MA, ed. Pediatric Endocrinology, 2nd ed. Philadelphia, Saunders. 2002;187-210.

10.    Fisher DA et al. Second international conference on neonatal thyroid screening: Progress report. J Pediatr. 1983;102:653-654.

11.    Y Mekonnen et al. Thyroid Stimulating Hormone values from cord blood in neonates. Ethiop J Health Dev. 2003;17(2):125-130.

12.    Kaur G et al. Preliminary Report on Neonatal Screening for Congenital Hypothyroidism, Congenital Adrenal Hyperplasia and Glucose-6-Phosphate Dehydrogenase Deficiency: A Chandigarh Experience. Indian J Pediatr. 2010;77:969–973.

13.    RV Mikelsaar et al. Neonatal screening for congenital hypothyroidism in Estonia. J Med Screen. 1998;5:20–21

14.    V. Ilamaran et al. Neonatal screening for congenital hypothyroidism using cord blood thyroid stimulating hormone. Curr Pediatr Res. 2014;18(2):76-78.

15.    Grant DB et al. Survey of neonatal screening for primary hypothyroidism in England, Wales and Northern Ireland 1982–4. BMJ 1988;296:1355–8.

16.    Reddy JM et al. Umbilical cord blood TSH level: correlation with congenital hypothyroidism. Int J Contemp Pediatr. 2021;8(7):1204-1208.

17.    Raj S et al. Cord Blood TSH Level Variations in Newborn – Experience from A Rural Centre in Southern India. Journal of Clinical and Diagnostic Research. 2014;Vol-8(7):18-20.

18.    Gupta G et al. Cord blood thyroid stimulating hormone level-interpretation in light of perinatal factors Indian Pediatr. 2014;51(1):32-6.

19.    Bhatia R et al. Congenital Hypothyroidism Screening in Term Neonates using Umbilical Cord Blood TSH Values. Indian Journal of Endocrinology and Metabolism. 2018;22(2).

20.    Chaudhary M et al. Incidence of Congenital Hypothyroidism in Western Rajasthan Using Cord Blood Thyroid stimulating Hormone Levels as a Screening Tool: A Cross sectional Hospital based Study. Indian Journal of Endocrinology and Metabolism. 2018;22(3).

21.    Rashmi Seth A et al. Effect of perinatal factors on cord blood thyroid stimulating hormone levels. J Pediatr Endocrinol Metab. 2007;20:59- 64.

22.    Wong SLJ. Congenital Hypothyroidism: An Audit and Study of Different Cord Blood Screening TSH Values in a Tertiary Medical Centre in Malaysia. Advances in Endocrinology. 2015;387684:6