Need for neonatal screening program in India: A national priority.

In India, out of 342 districts surveyed, 286 have been identified as endemic to iodine deficiency (ID). Research studies conducted in school age children (SAC), Adolescent girls, Pregnant Mothers (PMs) and Neonates have documented poor iodine nutritional status. As observed by total goiter rate of more than 5% and median urinary iodine concentration level of <100 μg/l in SAC and <150 μg/l in PMs as prescribed cutoff of World Health Organization. And higher thyroid stimulating hormone levels among neonates. ID leads to compromised mental development and hence which remain hidden and not visible to family, program managers and administrator. The present review describes the current status of ID in different parts of the country. With a view to strongly recommend the implementation of Neonatal screening program for ID so that the optimal mental development of children can be achieved.

INTRODUCTION

Iodine deficiency (ID) is the single most important and preventable cause of mental retardation worldwide.[1] ID in fetus results in miscarriages, stillbirths, brain disorders, retarded psychomotor development, speech and hearing impairments.[2345] People living in areas affected by severe ID may have an intelligence quotient (IQ) of up to 13.5 points below that of those from areas where there is no ID.[6] ID Disorders (IDD) have been found to be associated with at least six of the 8 millennium development goals.[78] ID directly affects human resource development which in-turn greatly affects the human productivity and country's development at large.

METHODOLOGY

In order to identify relevant studies for this review, an initial search was conducted using the U.S. National Library of Medicine's PubMed website (http://www.ncbi.nlm.nih.gov/PubMed) using the keywords ID, school age children (SAC), pregnant mothers (PMs), adolescent girls, neonates, neonatal hypothyroidism (NH) and India. The titles and abstracts of the articles identified were reviewed, and full copies of the most relevant articles were obtained. Studies on ID in relation to SAC, PMs and neonates and studies on NH were also reviewed. Additional articles were identified in several different ways: From the list of citations in relevant publications, by searching the table of contents of journals that contained relevant articles but were not indexed in PubMed, and from internet based searches other than PubMed, using the keywords “ID, NH and India.

RESULTS

Magnitude of iodine deficiency

Iodine deficiency disorders constitute a major nutrition deficiency disorder in India. It has been estimated that 200 million people in India are exposed to the risk of ID and more than 71 million suffer from goiter and other IDDs. A survey conducted by the Central and State Health Directorates, Indian Council of Medical Research and Medical Colleges has demonstrated that not even a single state is free from the problem of IDD. Out of 582 districts, district-level surveys have been conducted in 325 districts. It has revealed that IDD is a major public health problem in 263 districts, that is, prevalence of IDD was above 10% in the population. The status of urinary iodine concentration (UIC) levels in different regions of India has been extensively assessed by district-level surveys in recent years. More than 86% of districts had median UIC levels of >100 μg/l indicating success of National IDD control program.[9]

Iodine status amongst school age children

School age children are the preferred group as they are easily accessible, vulnerable to ID and respond to salt iodization program. According to World Health Organization (WHO)/United Nations Children's Fund/International Council for the Control of Iodine Deficiency Disorders, if >5% SAC (6–12 years) are suffering from goiter, region should be classified as endemic to ID.[10]

Table 1 depicts the UIC levels amongst school age children in different parts of the country. Table 2 depicts the iodine content of salt samples collected at beneficiary level in selected districts of India.

Table 1

Urinary iodine excretion levels in selected districts of India

Table 2

Iodine content of salt samples collected at beneficiary level in selected districts of India

Iodine status amongst pregnant mothers

Pregnant mothers are most vulnerable to ID because their requirement is the highest. The recommended daily Allowance of iodine of PMs is higher (250 μg/d) as compared to normal adult (150 μg/d). During pregnancy, recommended dietary allowance of iodine is increased by 50% due to (i) physiological increase in maternal and fetal thyroid hormone production and (ii) increase in renal iodine losses.[10] Consequently, if PM is iodine deficient there is decrease synthesis of thyroxin by fetal thyroid that leads to compromised mental and physical development of the fetus. According to WHO, the median UIC level of <150 μg/l amongst PMs indicates ID in the community.[10] Pregnant women with normal thyroid stimulating hormone (TSH) levels often have low free T4 levels, even in areas in which iodine intake is sufficient within the general population. This condition is termed as hypothyroxinemia. Recent findings suggest that the hypothyroxinemia can negatively affect child health outcomes, including neonatal behavior and infant cognitive functioning.[1112]

Studies conducted in various regions of the world with varying iodine status have assessed the impact of maternal iodine status on that of neonates and on thyroid function and neuropsychiatric development of neonates.[1314] A study conducted on overt and subclinical thyroid dysfunction among Indian pregnant women and its effect on maternal and fetal outcome reported significant adverse effects on maternal and fetal outcome. Thus, emphasizing the importance of routine antenatal thyroid screening. There is limited data on the prevalence of ID among the PMs in India.

Table 1 depicts the UIC levels among PMs in different parts of the country. Table 2 depicts the iodine content of salt samples Collected at Beneficiary Level in Selected Districts of India.

Iodine status amongst newborns

Neonatal hypothyroidism is one of the most common preventable causes of mental retardation in children. The complications of NH such as intellectual impairment and neurodevelopment delay present later in life when it is too late to be treated or reversed. Timely treatment is very important to effect adequate neurocognitive development during the critical first 3 years of life. The earlier the treatment is started, the higher the IQ levels are achieved later in life.

The neonatal brain is only a third of the size of the adult's brain, if ID and neonatal thyroid failure continue for about 3 months, this condition can lead to irreversible brain damage. Based on scientific data available, it is estimated that about 10% or more of newborns in severe goiter endemic areas are at risk of NH and resultant compromised physical and mental development.[90] Infants born to mothers, who have thyroxin concentration below the 10th percentile before the 13th week of gestation, have impaired neuropsychological development and maturation of the central nervous system.[91] The recognized role of thyroid hormones in brain development and the irreparable nature of brain damage caused by untreated hypothyroidism early in life.[92]

The incidence of NH observed strikingly different in the endemic and non-endemic areas. It has been observed that the incidence (4% or more) of NH in endemic goitrous areas of Gonda (UP) is 100–300 fold higher than reported from developed countries with no environmental ID (EID) or goiter.[9394]

In areas with a high incidence of NH and ID, a significant proportion of the population may have varying degrees of mental sub-normality and sensory neural hearing loss. These consequences are regarded as the hallmark of ID related brain damage.

Indian scenario

Neonatal hypothyroidism is due to inadequate thyroid hormone production in newborns and its exact incidence in India is unknown. Universal neonatal screening (NS) is still not practiced in developing countries. There is a lack of data on the NS for hypothyroidism from India. Earlier studies conducted in India reported the incidence of congenital hypothyroidism (CH) as 1:476, 1:1700, 1:2481 and 1:2804, respectively.[95969798]

Nutritional ID and endemic goiter are widely prevalent in developing countries, affecting an estimated 1 billion people. It continues to affect hundreds of millions of people in the developing world, even though simple and effective methods of eradication.

Neonatal Hypothyroidism is the most treatable cause of mental retardation. A pilot neonatal hypothyroid screening program carried out in three areas of India showed that the incidence of NH in severely iodine deficient areas is between 4% and 15%. This is 80–300 times more than the reported average incidence of NH in medically advanced countries, which have eradicated endemic goiter, endemic cretinism and other effects of ID by effective iodine supplementation program.

One of the studies has shown that the incidence of NH as reflected in cord-blood T4 and TSH levels in endemic goiter regions is more than a hundredfold higher than that observed in non-endemic regions of India or reported from developed countries of the West. The reported incidence of NH in endemic regions of India and its neighboring countries ranges from 6 to 130/1000 births.[99]

In early 80s by screening the cord blood of over 20,000 newborns, it was discovered that one out of every 10 newborns from the Tarai regions of UP were hypothyroid at birth. The study was conducted by Kochupillai et al. in which they screened newborns from three different regions of India that is, (i) three severely iodine deficient, endemic district of the Gangetic Plains of Uttar Pradesh (Deoria, Gorakhpur and Gonda) (ii) the hospitals of the capital city of Delhi; where a mild degree of EID and endemic goiter are prevalent; and (iii) two coastal districts (Aleppey and Quilon) of the southern state of Kerala. The results showed an incidence of NH as 133, 85 and 75, respectively in the three endemic districts of UP, much higher than in Delhi and in coastal Kerala/1000 births.[100]

The incidence of NH, as reflected in cord-blood thyroxin and thyrotropin levels, varied from 0.6% to 13.3% in iodine deficient and normal regions of India, depending on the degree of EID as assessed by the pattern of urinary iodine excretion in the affected population.[99]

Another study was conducted to reevaluate the incidence of NH in the same three districts of UP in the postiodation phase. The results showed the incidence of NH was 16.17 and 9/1000 birth, respectively, which was impressively declined.[99]

The impact of ID related NH on brain development in non-cretinous population has also been assessed by determining the IQ and the prevalence of nerve deafness among children in the population of severely iodine deficient villages in areas with a very high incidence of NH. The results showed a much higher gross shift to the left of the distribution of IQ scores among primary school children from endemic-goiter villages than in children from non-endemic. The audiometric testing revealed sensory neural hearing loss in one of every five subjects screened from the endemic goiter villages.[99]

One of the studies conducted in Mumbai in which 12,407 neonates were screened over 26 months for their cord blood thyrotrophin level TSH, reveled a higher incidence (1:2481) of NH.[96] Data on NS for NH with cord blood T4 studies on more than 25,000 newborns in the same area of Mumbai have shown the incidence of 1 in 2,804.[97]

Currently, there are no national programs for NH screening in India.[98]

Global scenario

The worldwide incidence of CH is 1:3000–1:4000.[99] The incidence has racial and global topographic differences, being highest in Europe 1:3300 and as low as 1:5700 live births infants in Japan with an average of 1:4500 live births in most other parts of the globe.[100]

Neonatal thyroid screening in the United Kingdom has shown a significantly higher incidence of NH in Asian families in comparison with non-Asians (1/918 in Asians compared 1/3391 within non-Asians).[101] The incidence is lower among African American newborns and higher among Hispanic newborns compared with the rate among white newborns.[102] International studies have revealed that the incidence of NH is approximately 1:3500 in iodine sufficient areas.[103]

Incidence of NH in several countries has been well documented. Earlier studies reported an Incidence of NH as 3:1207 (Ethiopia), 1:1446 (Italy), 1:1667 and 1:3670 (Latin America), and 1:4000 (United States), respectively.[104105106107] Newborn screening in Brazil had revealed consistent lowering in the incidence of NH in 3 consecutive years (1:3616 in 2005, 1:1369 in 2006 and 1:1030 in 2007).[108] Thus, this high prevalence of NH is indicative of widespread IDD throughout the globe at different intensities.

The incidence of NH has been reported as 1 in 3,800–4,000 births worldwide with some racial and geographic variations.[109] Based on ongoing screening program, the incidence of NH in developed countries has proved to be high and varies from 1 in 2,000 to 6,000 births.[110] It has also been reported that the incidence of NH in developed countries without ID or endemic goiter varies from 1 in 3,000 to 1 in 12,000 births.[111112113] The worldwide incidence of NH was found to be one in 3000–4000 births, based on the results of screening in parts of the world where screening is mandatory.[99]

Data of an earlier study on NS have showed a prevalence of goitrous hypothyroidism in 10–15% of patients with primary CH approximating 1 in 30,000–50.000 live births in Europe and in North America.[114] One of the studies conducted in the region of Sicily examined the cord blood samples of 180 newborns, and it showed that the prevalence of NH was 9.3% at birth with endemic goiter and cretinism.[115]

High incidences of NH in iodine deficient areas with endemic goiter and/or cretinism have been documented from other countries. Thilly et al. reported 10% incidence of NH in Zaire, as reflected in cord blood hormone levels during birth.[116] One of the studies conducted on 20107 newborns in Tehran and Damavand showed the estimated incidence of CH as one in every 914 births.[117] The routine cord blood thyrotrophin TSH screening of neonates at 6–10 days in Birmingham (England), reported the incidence of NH as 1:5540.[118]

One of the studies conducted in Saki (Nigeria), reported the incidence of neonatal chemical hypothyroidism as 14.7/1000 birth in the cord blood samples obtained from the babies at the time of delivery for thyroid function tests.[119] Another study conducted in Bhutan screened 650 newborns for TSH and results showed that the overall incidence of NH among newborns was 115/1000 births.[120]

Need for newborn screening program

Neonatal hypothyroidism screening has been identified as a potential method for early detection and prevention of the adverse effects of thyroid deprivation on the brain development of neonates, thus promoting an early intervention. Worldwide, NS program for NH have significantly reduced the intellectual deficits in the hypothyroid children treated early. Newborn screening and thyroid therapy if started within 2 weeks of age can normalize cognitive development. As hypothyroid fetuses often perish in the womb and many affected infants die within a week of birth.

Newborn screening for NH has been implemented in the United States, Canada, Western Europe, Japan, Australia, New Zealand, Taiwan, parts of China, Mexico and Israel.[121] NH screening programs have been instituted to allow its early detection and initiation of therapy.[105] It resulted in bringing down worldwide incidences of NH from 1:7000 to 1:3000 to 4000.[122] Under this, the newborns are subjected to screen for hypothyroidism by estimation of serum thyrotrophic TSH levels. TSH level of more than 20 μl/dl in neonates indicates insufficient supply of thyroid hormones to the developing brain.

Newborn screening is ultimately a public health program. Successful screening programs results from collaborative efforts of different sectors. If a program is accepted as Government responsibility, advocacy efforts can be broad. These organizations can provide support through established networks. The Government agencies can be asked to include topics related to newborn screening in curricula of health allied services. As in Thailand and Manila, Government funds were helpful in supporting NH programs.

The non-Governmental Organizations (NGOs) can be roped together as academic institutes, insurers, civic organizations, media, religious groups, etc., As, in USA, The Clinical and Laboratory Standard Institute has been active in publishing guidance on procedures related to the collection of neonatal data for standardization of NS.

Counseling of future parents about NS can also be useful. A comprehensive institutionalization of NS program within the public health system is a key step in implementing and sustaining an NS program.[123] The objective of NS programs is the commencement of treatment of affected neonates with hypothyroidism within the first 2 weeks of life. The early detection can improve prognosis and lead to full brain development of the newborn. Screening is not a confirmatory diagnosis, it will require further investigations.

Limitations of neonatal screening program in India

A vicious cycle exists, that prevents the early identification and subsequent management of NH in India. Despite its simplicity, accuracy and cost effectiveness, NH screening as mandatory primary health care activity in India is yet awaited. This could be due to contributing factors such as (i) high home delivery rate, (ii) early discharge from hospitals (iii) cultural taboos related to newborns (iv) lack of reliable laboratories on a large scale, and (v) non-availability of baseline data in our population has added to the challenge. These limitations have reduced the utility of the screening program which otherwise have been estimated to be the best method to trace out neonates affected with hypothyroidism in large populations.

The way forward in India is to prioritize districts identified endemic to ID and implement a compulsory NS program in these areas. The endemic areas can be listed through Hospital based as well as Institution based studies. Apart from this mass education, media propagation and training centers will be required for the smooth implementation and enhanced the efficacy of screening programs. NGOs already stationed in the periphery can be roped in for better execution. In the absence of a national program, organizations like Indian Academy of Pediatricians should bring out guidelines for NH screening and institutions should develop local guidelines for screening all newborn.

Neonatal Hypothyroidism Screening if properly timed and performed has the potential for preventing catastrophic health outcomes, including death.[94] The vast majority of children with NH cannot be diagnosed on the basis of clinical features. The best measure to identify NH is extensive NS. The specimen used for newborn screening tests can be blood collected from umbilical cord or a heel-prick (collected between 2 and 5 days of age) on filter paper. We believe that the cord blood filter paper method for TSH assessment is a viable option for the ‘universal screening’ of newborns for NH in India.

CONCLUSION

Thus, the current scenario indicates the presence of ID in the country. We have limited data on the status of IDD among newborns. Hence, there is a need of developing NS program to establish the status of ID in newborn. This would help in early detection of children with IDD/NH.