Neonatal TSH screening: is it a sensitive and reliable tool for monitoring iodine status in populations?

Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 63–75

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Neonatal TSH screening: is it a sensitive and reliable tool for monitoring iodine status in populations? Mu Li, PhD, Senior Lecturer a, *, Creswell J. Eastman, MD, Clinical Professor, Vice Chairman of ICCIDD and Regional Coordinator Asia Pacific Region b,1 a b

School of Public Health, the University of Sydney, Sydney, NSW 2006, Australia Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia

Keywords: newborns thyroid stimulating hormone (or thyrotropin) monitoring iodine deficiency

Iodine deficiency is the most common cause of preventable brain damage in the newborn. The indicators for assessing iodine nutritional status include urinary iodine excretion, thyroid size, thyroid stimulating hormone (TSH) and thyroglobulin (Tg) concentrations in the blood. Neonatal TSH concentration is increased when the supply of thyroid hormone and iodine from the maternal circulation to the foetus has been compromised. The World Health Organization (WHO) has suggested that when a sensitive assay is used on samples collected 3–4 days after birth, a <3% frequency of TSH concentrations >5 mIU l1 indicates iodine sufficiency in a population. However, many studies have attempted to apply the frequency of neonatal TSH values >5 mIU l1 in determining population iodine status and monitoring intervention programmes, and although some have proven to be successful, most have provided conflicting or uncertain data. This is due to the many technical issues that remain unresolved on the use of neonatal TSH screening for monitoring iodine status, making it doubtful as a sensitive and reliable quantitative tool. More research is required to resolve these issues. In the interim, WHO should consider withdrawing its current guidelines for neonatal TSH screening for monitoring iodine deficiency in populations. Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.

* Tel.: þ61 2 9351 5996; Fax: þ61 2 9351 5049. E-mail addresses: [email protected] (M. Li), [email protected] (C.J. Eastman). 1 Tel.: þ61 2 9439 9396; Fax: þ61 2 9436 1505. 1521-690X/$ – see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2009.08.007

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Iodine nutrition in pregnant women and newborns Iodine requirement in pregnancy Iodine of maternal origin is essential for foetal and neonatal brain development. At a population and global level, iodine deficiency is the leading cause of preventable mental handicap. At an individual level, the developing brain is extremely vulnerable to even minor degrees of maternal hypothyroxinaemia secondary to iodine deficiency or maternal thyroid disease. Even mild, clinically unrecognisable, hypothyroxinaemia can cause serious irreversible neuromotor deficits rendering a child handicapped for life.1 The invisibility of the deficiency during pregnancy and neonatal development makes it all the more dangerous in both developing and developed societies. Despite enormous efforts to conquer iodine deficiency, it remains a serious public health problem. The World Health Organisation (WHO) estimates that almost 2 billion people worldwide, comprising over 300 million children in 54 countries, still have inadequate iodine intake.2 The United Nations Children’s Fund (UNICEF) estimates that presently over 38 million newborns annually are not protected from iodine deficiency.3 Pregnancy demands a large increase in iodine requirements principally to keep pace with the increased maternal thyroidal production of thyroxine (T4). The maternal thyroid hormone pool (chiefly T4) increases on average by 50% due to the need to saturate the increased thyroxine-binding globulin produced by the liver and maintain a normal free T4 concentration. Increased T4 production is facilitated by enhanced thyroidal stimulation from human chorionic gonadotropin during early pregnancy.4 Additional demands on the thyroid come from passage of T4 from mother to foetus and increased degradation of T4 by the placenta.4 Enhanced renal clearance of iodine during pregnancy results in maternal wastage of iodine and contributes to the demand for increased iodine intake. While the foetal thyroid commences synthesis of thyroid hormone at the end of the first or early second trimester, most of the T4 in the foetal circulation is derived from maternal passage until very late in pregnancy. In addition to maternal transfer of T4 to the foetus, there is also transfer of iodine in the latter weeks of gestation. Although the precise quantity of this transfer has yet to be established, it is estimated to be in the range of 50–75 mg per day, based on the known requirement of 90 mg per day in the neonates and infants (0–12 months).6 The recommended daily intake (RDI) of iodine in the non-pregnant state is 150 mg, increasing to 250 mg during pregnancy.5,6 The infant will require around 90–100 mg iodine per day, mandating a requirement of approximately 250 mg iodine daily in the breastfeeding mother.5,6 The iodine content of human breast milk varies with maternal iodine intake, emphasising the need to ensure iodine intake is boosted during lactation to protect the infant from hypothyroxinaemia. Monitoring of iodine intake and use during pregnancy and lactation in mothers remains a controversial and poorly researched issue. Urinary iodine excretion, serum concentrations of free T4, TSH and thyroglobulin (Tg) provide direct or indirect indices of thyroid function and iodine intake during pregnancy. Each of these tests is prone to methodological problems and artefactual interference during pregnancy. The simplest test at a population level, but not in an individual, is the urinary iodine excretion concentration (UIC). Most of the iodine absorbed through the gut is eventually excreted in the urine. One can calculate iodine intake using the simple assumption that 90% of intake is excreted within the next 24 h. The current convention of judging UIC measurements in pregnant women against non-pregnant adults is misleading. If the RDI for iodine during pregnancy is 250 mg per day, then this intake would correspond to a UIC of 150 mg l1.4 Physiology and pathophysiology of use of iodine in the foetus and neonate An adequate iodine intake in the mother is essential for the normal synthesis of maternal and foetal thyroid hormones important for foetal brain development.7,8 Insufficient iodine supply from the mother can result in a decreased synthesis of both T4 and 30 ,3,5-triiodothyronine (T3), with an increased concentration of TSH in the newborn. In most cases, the impaired thyroid function due to iodine deficiency is transient.9 Infants, especially if born prematurely, are susceptible to transient hypothyroxinaemia10, a condition characterised by a transient elevation of newborn TSH level in conjunction with a normal T4 concentration. It occurs at higher frequency in mild-to-moderate iodinedeficient environments.11

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Neonatal TSH screening Neonatal screening for Congenital Hypothyroidism The incidence of sporadic congenital hypothyroidism (CH) is around 1 in 3000 to 1 in 4000 live births.11,12 The symptoms and signs of sporadic congenital hypothyroidism are often non-specific and, unless tested for biochemically, CH will be frequently overlooked, resulting in irreparable neurological damage from thyroid hormone deficiency during this crucial period of brain development. To address this problem and permit early detection and implementation of thyroid hormone therapy, systematic screening programmes for thyroid function were introduced in many countries in the early 1970s.11,13 The initial screening method was measurement of T4 in heel-prick blood samples. This has been superseded by measurement of thyrotropin (TSH) in most programmes around the world. Convincing arguments can be made for the superiority of either one of these tests as the primary screening method. The major disadvantage of using TSH is that it will not detect central (hypothalamic or pituitary) hypothyroidism, a rare disorder occurring in approximately 1 in 20 000 neonates, that can be picked up by T4 testing. TSH testing does detect subclinical or transient primary hypothyroidism that will be missed by T4 screening and may cause brain damage.12 TSH testing results in neonates born in iodine-deficient environments The newborn thyroid has limited iodine stores, and even mild deficiency during pregnancy will compromise neonatal thyroidal secretion of T4 causing increased pituitary TSH secretion. It follows that an elevated TSH in the neonate is a sensitive indicator of an inadequate supply of thyroid hormone to the developing brain. This principle underpins the application of newborn TSH screening as an indicator of maternal and hence population iodine nutrition. Thus, neonatal TSH screening may be a powerful and underused tool in monitoring iodine nutrition in mothers and babies. However, multiple factors other than maternal iodine status can influence measurement of newborn TSH, including prematurity, the timing of the heel-prick collection, maternal or newborn exposure to iodine-containing antiseptics (povidone), the collection paper employed for the bloodspot and the TSH assay methodology. Consequently, the original recommendations of categorising the severity of iodine deficiency using measurement of neonatal TSH promulgated by WHO in 199414 (Table 1) have not been included in the more recent recommendations.6,15 The Swiss experience showed neonatal TSH was sensitive to even marginal improvement of iodine nutrition status of pregnant women, following the increase of iodine concentration in iodised salt. This was demonstrated in the reduction of the frequency of newborn TSH values >5 mIU l1 from 2.9% to 1.7%.16 Newborn TSH screening as a tool for assessing iodine deficiency Monitoring tool in iodine-deficient environments In contrast to sporadic CH, elevated TSH levels, accompanied by either normal or low T4 levels occur much more commonly in neonates born in iodine-deficient environments. Studies performed in the 1980s in Zaire and India, where iodine deficiency is endemic, confirmed neonatal TSH concentrations were grossly elevated in the cord blood of the offspring of mothers suffering from moderate-to-severe Table 1 WHO/ICCIDD/UNICEF Indicators for Assessing Iodine Deficiency Disorders. Indicator

Target population

Severity of public health problem (prevalence) Mild

Moderate

Severe

Thyroid volume >97 centile by ultrasound Median urinary iodine level (mg/L) TSH >5 mIU/l whole blood

SACa SAC Newborns

5.0–19.9% 50–99 3.0–19.9%

20.0–29.9% 20–49 20.0–39.9%

30% <20 40%

Adapted from WHO/NUT/94.6, 1994 (14). a School aged children

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iodine deficiency.17–19 From these studies, neonatal TSH screening was put forward as a populationmonitoring tool for iodine deficiency, in addition to its role as a case-detection tool for diagnosing individual neonates with congenital hypothyroidism.20 Delange advocated neonatal thyroid screening as an indicator of the degree of iodine deficiency at a population level and as a monitoring tool in programmes of iodine supplementation.20,21 In his reviews, Delange concluded that neonatal TSH screening is the only indicator that allows prediction of a possible impairment of mental development.20,21 However, in the context of declining urinary iodine concentration reported from several countries, where the frequency of TSH >5 mIU l1 is often below 3%, it is uncertain whether neonatal TSH screening results can truly reflect the current iodine intake trend in these populations.22,23 Published reports of neonatal TSH screening for monitoring population iodine nutrition Table 2 is a summary of published reports using TSH screening for assessment of iodine-deficiency status or monitoring the outcome of iodine prophylaxis programmes in countries or sub-national regions, with reference to the WHO criteria.6,14,15 One good example is in southeast Poland, where TylekLemanska24 and colleagues were able to demonstrate that, from the CH screening programme, with the reintroduction of iodised kitchen salt in 1992, the prevalence of neonatal TSH results 5 mIU l1 dropped from above 20% in 1991 to just over 5% between 1995 and 2000. There have been other examples of using newborn TSH screening to assess iodine-deficiency status.16,25–37 In Thailand, with the application of a geographic information system to their neonatal TSH screening programme, which covers 760 000 live births annually (94% of total), it is possible to identify iodine deficiency down to the sub-district level.37 In Table 2, reported studies are listed under three categories, according to the timing and nature of the blood samples. Majority of the published reports have employed dried blood spot samples collected >48 h after birth, as recommended for neonatal screening for CH. Greater than 3% of TSH >5 mIU l1 is the arbitrary indicator for iodine deficiency in a population.6,15 Some studies have used dried cord blood spots, particularly the two multi-nation studies by Sullivan30 and Copeland,34 which also used TSH >5 mIU l1 as the cut off. Other studies used cord blood serum samples. In addition, multiple methods, and the same technique by different assay manufacturers, have been used. In the following, we look at these issues closely to see how they may impact on the TSH test results. Influencing factors of newborn TSH measurements Maternal iodine status Maternal iodine nutrition and thyroid function status can have significant impact on foetal and newborns’ TSH levels.38 In a study comparing maternal and neonatal thyroid status in Nigeria,39 it was found that women from a known iodine-deficient area (Saki) had significantly lower UIC levels and higher goitre rates compared with women from the control area. Their plasma total T3 (TT3) and total T4 (TT4) were lower and TSH was higher than the values of the controls, although they did not reach the statistically significant level. The mean plasma neonatal TSH of babies from Saki, however, was significantly higher than the control value. Data from newborn screening in Europe have shown that the frequency of serum TSH >50 mU ml1 (mIU l1) for recall was inversely related to maternal urinary iodine level.9 This was further evidenced by the Costante study,31 which showed a negative relationship between the frequency of TSH >11 mU ml1 (mIU l1), the 97% cut off of neonatal TSH and the median UIC of schoolchildren living in the same area (r2 ¼ 0.86, P ¼ 0.007). A study conducted in the West Black Sea area of Turkey showed that the maternal median UIC was different for mothers living in three different cities (from 31 mg l1 to 75 mg l1). The proportion of neonatal heel blood TSH >5 mIU l1 and the median neonatal Tg concentration correlated inversely with the maternal UIC.36 A study of a cohort of 253 healthy pregnant women in Hong Kong has clearly demonstrated that mothers had lower urinary iodine levels giving birth to infants with higher TSH level, compared with mothers with normal urinary iodine excretion levels. Furthermore, women, who had given birth to infants with cord blood serum TSH >16 mIU l1, had significantly lower urinary iodine concentrations and serum FT4 levels compared with mothers who had given birth to newborns with normal TSH levels.40 A recent study from three districts of

Table 2 Reported Neonatal TSH with Reference to Iodine Deficiency. Country/Region

Settings

Sample size

Turkey/West Black Sea Area Switzerland

Neonatal screening program Neonatal screening program

Ireland

Neonatal screening program Neonatal screening program

Thailand

Australia/Sydney

Teaching Hospital

USA/Atlanta

Hospital

Australia/NSW

Public hospitals and local community health centres District hospitals

Thailand/Songkhla

18,606 259,035 218,665

73,019 550,927 543,121 639,583 766,392 1,316 1,457

Method

UIE (mg/L)

Goitre prevalence (%)

Reference

14.4

Fluroimmunoassay (DELFIA neonatal TSH kit Wallac, Finland)

65.6 (SCa)

37 (SC)

31

4.5 17.7

20

30.0 26.7

Fluroimmunoassay (DELFIA neonatal TSH kit) Fluroimmunoassay (FIA) and Luminoimmunoassay (LIA) Immuno-flurometric assay (IFMA, DELFIA neonatal TSH kit Wallac) IRMA (DPC) RIA (DPC, USA)

2.9 (1992–98) 1.7 (1999–2004)

Time-resolved Fluroimmunoassay

3.64–2.35 (1995–2006) 13.54 (2003) 15.28 (2004) 21.55 (2005) 19.56 (2006) 8.1, 5.4

Dissociation-enhanced fluroimmunoassay (DELFIA) ELISA

20–5.7 2.7

28

42.9

815

2.2

236

8.9

65b (SC)

33 24

143 (SC)

4.5 (SC)

Mothers 40, neonates 85 Mothers 138 (1999), 249 (2004) SC 115 (1999) 141 (2004) 45–68a (pregnant women)

61

36 16

23 37

Dissociation-enhanced fluroimmunoassay (DELFIA Wallac, Finland) ELISA (Enzaplate N-TSH, Ciba Corning Japan) Fluroimmunoassay (Auto DELFIA Wallac)

109 (mothers)

Mothers 85

42

Immunoradiometric assay

Gestation12–16 weeks 75.5 28–30 weeks 87.6 34–36 weeks 72.1

41

282

c

43

2

34

67

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Dried blood spot collected >48 hours after birth (>5 mIU/L) Italy/Calabria Neonatal screening 22,384 program Belgium/Brussels Neonatal screening 308,614 program Estonia Neonatal screening 20,021 program Poland/Cracow Neonatal screening 634,179 program Argentina/Buenos Aires Neonatal screening 1,500 program

Frequency (%)

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Table 2 (continued) Country/Region

Settings

Sample size

Frequency (%)

Philippines/Manila

Major hospitals

750

32

Pakistan/Islamabad Quetta Lahore Karachi Kyrgyzstan Bishkek Osh Bangladesh

Major hospitals

201 279 256 148 90 92

76 65 80 69 74 47

Local hospitals

208

84

Guatemala

Local hospitals

141

58

USA

Local hospitals

243

82

Argentina/Buenos Aires

Neonatal screening program

186

11.3

Major hospitals

Cord blood serum collected at delivery (>10 mIU/L unless specified) Thailand/Chiangmai Provincial and 10,150 20.0 Nan district hospitals 8,603 15.3 Bangkok Teaching hospital 7,688 7.2 (Bangkok) Hong Kong Teaching hospital 253 22

Sudan/Omdurman Turkey/Kayseri India/West Bengal Thailand/Bangkok a b c d e

Local hospital Teaching hospital Local hospital Neonatal screening programs

School aged children. Indirectly quoted data. and from personal communication. TSH > 5 mIU/L. TSH > 11.2 mIU/L.

76 70 267 5,114

70d 27.1 2.9d 31e

UIE (mg/L)

ELISA (Spectra-Screen TSH, IEM Diagnostics, USA) ELISA (Spectra-Screen TSH, IEM Diagnostics, USA) ELISA (Spectra-Screen TSH, IEM Diagnostics, USA)

33 (mothers)

ELISA (Spectra-Screen TSH, IEM Diagnostics, USA)

30 (SC)

49 (SC)

30

ELISA (Enzaplate N-TSH, Ciba Corning Japan) ELISA ((Enzaplate N-TSH, Ciba Corning Japan) ELISA (Enzaplate N-TSH, Ciba Corning Japan) Immuno-fluorometric assay (DELFIA Wallac, Finland)

96 (mothers) 73 (SC) 120 (mothers) 181 (SC) 105 (mothers) 282 (SC) 143 (SC)

27 (SC)

34

15 (SC)

34

2

34

4.5 (SC)

61

Immunoradiometric assay (Department of Health Science, Thailand)

64b

15.7b 36.4b 6.2b

29

Immunochemilumino-metric assay (ACS Ciba Corning Diagnostic Corp, USA) TR-FIA (DELFIA Wallac, Finland) IRMA (Amersham, UK) ELISA (Pathozyme Diagnostics, India) Electro-chemiluminescence immunoassay (Roche Diagnostics, Germany)

z122 (0.98 mmol/l)

40

30.2 (mothers) 144 (mothers) 85

50 35 70 22

40b (SC)

Goitre prevalence (%)

Reference

30 2b (SC)

30 30

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Dried cord blood spot sample collected at delivery (>5 mIU/L) Malaysia/Kuching Major hospitals 195 52

Method

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Songkhla, southern Thailand has revealed a negative correlation between neonatal TSH concentrations and urinary iodine concentrations in their mothers, although it failed to reach a statistical significant level (r ¼ 0.10, P ¼ 0.068).41 Studies from Australia and Denmark with mild-to-borderline iodine deficiency, however, could not find the expected negative correlation between neonatal whole blood TSH and maternal UIC.42–44 Although WHO recommends that the iodine intake in pregnancy should be increased to 250 mg per day to ensure a corresponding urinary iodine level of 150 mg l1,6 this has been challenged by a recent Thai study that found a decrease in the median urinary iodine concentration in pregnant women did not directly impact on the median newborn TSH concentration. Despite that median maternal UIC level has more than halved in the Dan Sai district, northern Thailand in 2003 compared with 1998 (106 mg l1 from 249 mg l1) and the median maternal UIC in Bangkok was as low as 85 mg l1, there was no substantial difference in cord blood serum TSH concentrations in the corresponding newborns.22 A number of studies have used measurement of Tg as part of the assessment of neonatal thyroid function in relation to iodine status. Kung’s study in Hong Kong40 showed there were significant differences in both neonatal TSH and Tg of babies born to mothers who had UIC <0.44 mmol l1 (50 mg l1) or >0.79 mmol l1 (100 mg l1). Furthermore, in neonates with TSH >16 mIU l1 their Tg levels were significantly higher than those with TSH levels <16 mIU l1 (32.0 vs. 25.6, P < 0.05). The study in the West Black Sea area of Turkey showed a positive relationship between percentage neonatal TSH >5 mIU l1 and median Tg (r ¼ 0.51, P < 0.01).36 Mode of delivery Many studies have explored the impact of delivery characteristics on neonatal TSH levels, particularly in cord blood. This is most relevant in countries where cord blood, either serum or dried blood spot, is used for the neonatal thyroid screening. The reports are still controversial. Neonates born with assisted vaginal delivery, including vacuum or forceps extraction, were reported to have higher TSH values than those of normal vaginal delivery.45–47 Furthermore, newborns by vaginal delivery had higher TSH levels compared with babies delivered by caesarean section.45–48 This may relate to stress associated with vaginal delivery.47 Studies in Japan and Sudan, however, found no difference in newborn TSH levels in relation to vaginal delivery, assisted or non-assisted, or caesarean section, and they claimed that the TSH was less influenced by perinatal factors.49,50 An interesting study from Sydney, Australia, described a phenomenon that newborns delivered by caesarean section were more likely to have TSH levels >5 mIU l1 on day 3 after birth than those born by vaginal delivery.51 There could be a number of implications of this finding. First, more babies delivered by caesarean section were born before 37 weeks’ gestation, so their thyroid glands might be less mature in handling topical iodine used to prepare for the caesarean section.51 Second, Sydney is a mild iodine-deficient area.43,52,53 As discussed further in this article, iodine deficiency might exacerbate the ability of the thyroid to handle excessive iodine in preterm babies. Third, based on the guidelines, most reported heel blood samples were collected between day 2 and 4; this phenomenon could, therefore, have an impact on the results of TSH screening and IDD monitoring. Last, the number of babies delivered by caesarean section is increasing in many countries, suggesting this should be taken into consideration in interpreting neonatal TSH results. Time of sampling: cord blood vs. heel blood taken in the first few days of life The recommended time of sampling for screening of CH is before day 5 of life. It is most highly desirable at 48 h to 4 days due to the neonatal TSH surge in the first 24 h after birth.12,54,55 Some neonatal screening programmes use cord blood samples collected at delivery for convenience or for better acceptance of the test by parents.40,56 In some countries, both cord blood and heel blood samples are used to achieve higher coverage.29,57 Another issue has been the early discharge of mothers and babies within 48 h of birth for various reasons, including cultural practices in some countries where women return home within 24 h after giving birth.58,59 Samples collected at different times have presented a major challenge for setting the appropriate cut-off points for neonatal screening. Evidence shows that the mean TSH level sampled less than 24 h after birth was significantly higher than the mean TSH level of neonates after the first 24 h.59,60 This poses an even bigger challenge for monitoring IDD programmes, as we are looking at a narrowly defined level, that is, <3% of neonates TSH >5 mIU l1.

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In a study from the United States, Lott and colleagues60 analysed results from 161 44 newborn blood samples collected between <24 h and >95 h of life in 24-h intervals and found that the mean TSH levels progressively reduced from 15.20 mIU l1 to 3.24 mIU l1, highlighting the necessity of establishing the age-dependent cut-off values. Other studies also showed the median TSH levels of samples collected in the days beyond 48 h after birth were significantly lower than the level in cord blood,34,61 suggested that it was inappropriate to apply the same cut-off point for samples collected at different time points. This is particularly important in assessing the iodine-deficiency status when cord blood spot samples are used, but the same criteria still apply as for blood spot samples collected >48 h after birth. This could lead to overestimation of the problem if the results were looked at in isolation from other indicators. Using TSH >5 mIUl1 as the cut-off, Copeland34 found the proportion of TSH concentrations above this cut-off in dried cord blood varied between 58% in Guatemala and 84% in Bangladesh, which is much higher than the reported results using dried heel-prick blood spots collected >48 h throughout the world. Furthermore, there was a marked discrepancy between neonatal TSH and other iodine-deficiency indicators, namely urinary iodine excretion level and total goitre rates in schoolchildren. For instance, in Bangladesh, 84% neonates had TSH >5 mIU l1, while median UIC in schoolchildren was 73 mg l1 and 26% of children had enlarged thyroids by ultrasound, indicating mild-to-moderate iodine deficiency. In Guatemala, the UIC of schoolchildren was in the normal range (181 mg l1) and 15% children had palpable goitre, but the proportion of neonatal TSH values >5 mIU l1, however, was as high as 58%. Maternal or neonatal exposure to iodine-containing antiseptics Maternal or neonatal exposure to iodine-containing antiseptics is a common cause of transient hyperthyrotropinaemia and/or hypothyroidism in newborns.11,62–66 Only a few newborn TSH screening programmes, however, have reported information on maternal or neonatal exposure to iodine-containing antiseptics before or during delivery.24,34,36,67 Copeland34 reported that a very high percentage (82%) of newborns at the Crawford Long Hospital in Atlanta, Georgia, in the United States, had cord blood TSH levels above 5 mIU l1. This was partially attributed to maternal exposure to beta-iodinecontaining antiseptics prior to birth, including intravenous infusion, epidural insertion and catheterisation. Simsek confirmed that all hospitals in the area of their study used povidone as a local skin antiseptic in mothers or in newborns.36 Telek-Lemanska24 commented that information on the use of iodine-containing disinfectants was not available. This is likely to be the case for many screening programmes where the information was either not collected or not well managed and reported. One study from Poland, in particular, is of interest as it highlights the strong influence of using iodine-containing antiseptics in obstetric practice on the results of TSH screening.67 Based on a survey, there were 71% of obstetric clinics in 1998 and 58% in year 2000 in Poland using iodine as a skin disinfectant. When the neonatal TSH data was examined for the ‘iodine-free hospitals’ and those using iodine-containing antiseptics separately, the authors found more than a threefold increase in TSH levels greater than the cut-off (15 mIU l1) in the hospitals using iodine. Many reported cases of transient perinatal hyperthyrotropinaemia resulting from iodine exposure occurred in countries where there was mild-to-moderate iodine deficiency.65 A recent study in an iodine-replete area of Iran has showed that povidone disinfection at delivery did not affect TSH measurement from cord dried blood spot or the rate of hyperthyrotropinaemia among mature and normal-birth-weight neonates.48 Instead of exposure to iodine-containing antiseptic products, a study from Denmark44 found 41% of the neonates whose mothers were exposed to regular daily iodine-containing supplements during pregnancy had cord blood serum TSH level greater than 10 mIU l1, compared with 31% in the noniodine-supplemented control group. The median urinary iodine excretion of mothers (60 mg l1 in I group vs. 34.5 mg l1 in non-I group) and babies (63 mg l1 in I group vs. 31 mg l1 in non-I group), clearly indicating that the iodine supplement was inadequate and both mothers and babies in the supplemented group were still mildly iodine deficient. The authors have postulated that iodine deficiency might predispose the foetal and neonatal thyroid gland to the inhibitory effect of an excessive iodine load on thyroid hormone synthesis, leading to elevated neonatal TSH concentrations. Type of samples: dried cord blood spot vs. cord blood serum vs. dried heel blood spot In a small study in Japan, Fuse and colleagues49 found that there was a significant linear correlation of the TSH concentration in dried cord blood spots and cord venous blood samples in the same neonate,

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suggesting that the cord blood collected on filter paper might be a feasible alternative for a TSH screening programme using cord blood. This was supported by a study in southwest China, an iodine-deficient endemic area.45 The study showed that there was not only a good correlation of TSH levels between the dried cord blood spots and the cord venous blood samples (r ¼ 0.84, P < 0.01) but also a good correlation between the dried cord blood and dried heel blood obtained 3–5 days after birth (r ¼ 0.67, P < 0.01). In a larger-scale study involving seven provinces in China, it was shown that while the median urinary iodine excretion level in pregnant women was within the optimal range (246 mg l1), significant variations were found in dried cord blood spot TSH levels. Furthermore, the TSH levels were also significantly affected by the type of delivery.68 The authors concluded that the neonatal dried cord blood TSH was influenced by many factors; therefore, it was not a suitable indicator for IDDs surveillance in areas where iodine nutrition was adequate.68 In Thailand, both dried blood spot collected from 48 h (national programme)37 and cord blood serum (in Ramathibodi Hospital, Bangkok)22 are used for the neonatal TSH screening. Comparing data from the two programmes, it has been concluded that the whole blood collected from a heel prick on day 3 was not sensitive enough to assess the status of iodine nutrition in neonates.22 TSH assay methodology Table 2 reveals that there is a large range of assay methodologies used for measuring neonatal TSH. In a study from Buenos Aires, Argentina, 1500 samples collected more than 48 h after birth were tested by the standard immunofluorometric assay (IFMA, DELFIA Wallac). A proportion of the samples (n ¼ 238) were also measured by an immunoradiometric assay method (IRMA, Diagnostic Products Corp). The median TSH value measured by the immunofluorometric assay was 1.28 mIU l1, with 2.7% of TSH levels greater than 5 mIU l1 dried whole blood. This was in keeping with other indicators, that is, goitre rate (4.5%) and median urinary iodine level (146 mg l1) in schoolchildren, indicating that Buenos Aires was iodine sufficient. However, in the 238 samples tested by the IRMA, the frequency of samples with TSH level >5 mIU l1 was as high as 30%, representing a more than 10-fold increase.61 In the current CDC Newborn Screening Quality Assurance Program, there are no less than 13 assay methodologies accepted in the programme.69 The variation of the assays’ performance can be as broad as 15%. This highlights the difficulties in interpreting and comparing data, particularly when attempting to determine if the proportion >5 mIU l1 is below or above the 3% cut-off.43 As illustrated

Fig. 1. TSH Measurement Variation by Methods (Quarter 3, 2008).

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in Fig. 1, there is a wide range of variation among the assays. More importantly, these assay are designed to detect CH, which are usually optimised at higher cut-off values (10–20 mIU l1) than needed for assessing iodine nutritional status (5 mIU l1). This has been demonstrated by Elnagar32 that there was a poor correlation of the TSH levels obtained from serum and dried blood spot below 5 mIU l1 in the DELFIA TSH ultra assay. In conclusion, despite what is recommended in the WHO/UNICEF/ICCIDD guidelines and some encouraging successes in countries such as Belgium and Switzerland, there are still some serious technical issues in relation to using the frequency of neonatal TSH values greater than 5 mIU l1 as a tool for assessing population iodine nutrition status and monitoring iodine deficiency control programmes confidently. To establish valid guidelines for neonatal TSH screening in these situations, more research is required with adherence to standardised protocols to minimise the large number of variables that can influence the neonatal TSH concentration. Practice points  The neonatal TSH should only be used as one of the indicators for assessing the status of iodine nutrition in a population if the screening system is robust, adheres to a strict protocol with strict quality assurance and the data is routinely collected for the primary purpose of screening for CH.  Neonatal TSH should not be used as the sole indicator for monitoring iodine deficiency control programs, especially when samples are collected less than 48 hours after birth, as there are no established reference intervals.  The current WHO/UNICEF/ICCIDD criteria for iodine deficiency, i.e. >3% of neonatal TSH greater than 5 mIU/L, does not specify assay methods when this should be an essential requirement. Marked variation in assay results question the validity of these data. It is important to bear this in mind when interpreting or comparing neonatal TSH results by different methods.  The continuing decline of iodine intake in many developed countries warrants closer monitoring of the subtle increases in neonatal TSH levels, even when the proportion of TSH >5 mIU/L that may be less than 3%.  It appears that the neonatal TSH measurement may not be a reliable monitoring tool for iodine deficiency control programs due to the many potential confounding factors which may discredit the data and its interpretation. WHO should reconsider their published guidelines until these issues have been resolved.

Research agenda  Continuing research is necessary to explore sensitive and reliable indicators for assessing mild to moderate iodine deficiency conditions and monitoring intervention programs.  Further research is required to establish the recommended cut off levels for using mixed dried cord blood spot samples, as they are used in many countries where heel prick blood sample collection is not possible.  Research is needed to quantify the variations among different assay methods in order to guide the interpretation and comparison of the neonatal TSH data.

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