Best Practice JCEM Screening Neonatal y usar solamente de TSH.pdf

8/10/2019 Best Practice JCEM Screening Neonatal y usar solamente de TSH.pdf

http://slidepdf.com/reader/full/best-practice-jcem-screening-neonatal-y-usar-solamente-de-tshpdf 1/13

6

Neonatal TSH screening: is it a sensitive and reliable tool formonitoring 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 School of Public Health, the University of Sydney, Sydney, NSW 2006, Australiab 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 fromthe 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 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.

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolismj o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / lo c a t e / b e e m

1521-690X/$ – see front matter Crown Copyright 2009 Published by Elsevier Ltd. All rights reserved.

doi:10.1016/j.beem.2009.08.007

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

mailto:[email protected]


http://www.sciencedirect.com/science/journal/1521690X

http://www.elsevier.com/locate/beem

http://www.elsevier.com/locate/beem

http://www.sciencedirect.com/science/journal/1521690X





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 theleading cause of preventablemental 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

Pregnancydemands a largeincrease in iodinerequirementsprincipally to keep pacewith theincreased

maternal thyroidal productionof thyroxine(T4).The maternal thyroidhormone pool (chiefly T4) increaseson 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 iodineand

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 tobe established, it isestimated to bein 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 contro-

versial 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 inthe 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 toiodine 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 iodine-

deficient environments.11

M. Li, C.J. Eastman / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 63–7564



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 toiodine-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 SACa

5.0–19.9% 20.0–29.9% 30%Median urinary iodine level (mg/L) SAC 50–99 20–49 <20

TSH >5 mIU/l whole blood Newborns 3.0–19.9% 20.0–39.9% 40%

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

M. Li, C.J. Eastman / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 63–75 65



iodine deficiency.17–19 From these studies, neonatal TSH screening was put forward as a population-

monitoring 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 theoutcome 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 Tylek-

Lemanska24 and colleagues were able to demonstrate that, from the CH screening programme, with thereintroduction 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 reachthe 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 (r2¼ 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 givingbirth 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 Frequency (%) Method UIE (m

Dried blood spot collected >48 hours after birth (>5 mIU/L)

Italy/Calabria Neonatal screening

program

22,384 14.4 Fluroimmunoassay

(DELFIA neonatal TSH kit Wallac, Finland)

65.6 (

Belgium/Brussels Neonatal screeningprogram

308,614 4.5

Estonia Neonatal screening

program

20,021 17.7 Fluroimmunoassay

(DELFIA neonatal TSH kit)

65b (S

Poland/Cracow Neonatal screening

program

634,179 20–5.7 Fluroimmunoassay (FIA) and

Luminoimmunoassay (LIA)

Argentina/Buenos Aires Neonatal screening

program

1,500 2.7 Immuno-flurometric assay

(IFMA, DELFIA neonatal

TSH kit Wallac)

143 (

30.0 IRMA (DPC)

Turkey/West Black

Sea Area

Neonatal screening

program

18,606 26.7 RIA (DPC, USA) Moth

neona

Switzerland Neonatal screening

program

259,035 2.9 (1992–98) Time-resolved

Fluroimmunoassay

Moth

249 (

SC

115 (

141 (

218,665 1.7 (1999–2004)

Ireland Neonatal screening

program

73,019 3.64–2.35

(1995–2006)

Dissociation-enhanced

fluroimmunoassay (DELFIA)

45–68

(preg

Thailand Neonatal screening

program

550,927 13.54 (2003) ELISA

543,121 15.28 (2004)

639,583 21.55 (2005)

766,392 19.56 (2006)

Australia/Sydney Teaching Hospital 1,316 8.1, 5.4 Dissociation-enhanced

fluroimmunoassay

(DELFIA Wallac, Finland)

109 (

1,457

USA/Atlanta Hospital 28 42.9 ELISA (Enzaplate N-TSH, Ciba

Corning Japan)

282

Australia/NSW Public hospitals

and local community

health centres

815 2.2 Fluroimmunoassay

(Auto DELFIA Wallac)

Moth

Thailand/Songkhla District hospitals 236 8.9 Immunoradiometric assay Gesta

75.5

28–30

34–36

72.1



Table 2 (continued)

Country/Region Settings Sample size Frequency (%) Method UIE (m

Dried cord blood spot sample collected at delivery (>5 mIU/L)

Malaysia/Kuching Major hospitals 195 52 ELISA (Spectra-Screen TSH,

IEM Diagnostics, USA)

33 (m

Philippines/Manila Major hospitals 750 32 ELISA (Spectra-Screen TSH,


40b (S

Pakistan/Islamabad

Quetta

Lahore

Karachi

Major hospitals 201

279

256

148

76

65

80

69

ELISA (Spectra-Screen TSH,


Kyrgyzstan

Bishkek

Osh

Major hospitals 90

92

74

47

ELISA (Spectra-Screen TSH,


30 (S

Bangladesh Local hospitals 208 84 ELISA (Enzaplate N-TSH,

Ciba Corning Japan)

96 (m

73 (S

Guatemala Local hospitals 141 58 ELISA ((Enzaplate N-TSH,

Ciba Corning Japan)

120 (

181 (

USA Local hospitals 243 82 ELISA (Enzaplate N-TSH,

Ciba Corning Japan)

105 (

282 (Argentina/Buenos Aires Neonatal screening

program

186 11.3 Immuno-fluorometric assay

(DELFIA Wallac, Finland)

143 (

Cord blood serum collected at delivery (>10 mIU/L unless specified)

Thailand/Chiangmai

Nan

Bangkok

Provincial and

district hospitals

Teaching hospital

(Bangkok)

10,150

8,603

7,688

20.0

15.3

7.2

Immunoradiometric assay

(Department of Health

Science, Thailand)

64b

Hong Kong Teaching hospital 253 22 Immunochemilumino-metric

assay (ACS Ciba Corning

Diagnostic Corp, USA)

z122

Sudan/Omdurman Local hospital 76 70d TR-FIA (DELFIA Wallac, Finland)

Turkey/Kayseri Teaching hospital 70 27.1 IRMA (Amersham, UK) 30.2 (

India/West Bengal Local hospital 267 2.9

d

ELISA (Pathozyme Diagnostics, India) 144 (Thailand/Bangkok Neonatal screening

programs

5,114 31e Electro-chemiluminescence immunoassay

(Roche Diagnostics, Germany)

85

a School aged children.b Indirectly quoted data.c and from personal communication.d TSH > 5 mIU/L.e TSH > 11.2 mIU/L.



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 ¼0.10, 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 perday 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). Thestudy 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, partic-

ularly 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 innewborn 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 exac-

erbate 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 numberof 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 havepresented 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.




In a study from the United States, Lott and colleagues60 analysed results from 16144 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 isparticularly 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 hadpalpable 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-con-

taining 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-iodine-

containing antiseptics prior to birth, including intravenous infusion, epidural insertion and catheter-

isation. Simsek confirmed that all hospitals in the area of their study used povidone as a local skinantiseptic 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 hasshowed 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 non-

iodine-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 supple-

mented 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,




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 ¼0.67, P < 0.01).

In a larger-scale study involving seven provinces in China, it was shown that while the medianurinary iodine excretion level in pregnant women was within the optimal range (246 mg l1), signifi-

cant 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 methodologyTable 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

(n¼ 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 broadas 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).




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 someencouraging 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 pro-

grammes 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.

References

*1. Zimmermann MB, Jooste PL & Pandav CS. Iodine deficiency disorders. Lancet 2008; 372: 1251–1262.2. Andersson M, Takkouche B, Ines Egli I et al. Current global iodine status and progress over the last decade towards the

elimination of iodine deficiency. Bulletin of the World Health Organisation 2005; 83: 518–525.3. The United Nations Children’s Fund. Sustainable elimination of iodine deficiency. New York: UNICEF, 2008.4. Glinoer D. The importance of iodine nutrition during pregnancy. Public Health Nutrition 2007; 10: 1542–1546.

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.




5. Untoro J, Mangasaryan N, de Benoist B et al. Reaching optimal iodine nutrition in pregnant and lactating women andyoung children: programmatic recommendations. Public Health Nutrition 2007; 10: 1527–1529.

*6. WHO Assessment of iodine deficiency disorders and monitoring their elimination: a guide for programme managers. 3rd ed.Geneva: WHO, 2007. Available from: http://whqlibdoc.who.int/publications/2007/9789241595827_eng.pdf .

7. Morreale de Escobar G, Obregon MJ & Escobar del Rey F. Is neuropsychological development related to maternal hypo-thyrodism, or maternal hypothyroxinemia? Journal of Clinical Endocrinology and Metabolism 2000; 85: 3975–3987.

8. Morreale de Escobar G, Obregon MJ & Escobar del Rey F. Role of thyroid hormone during early brain development.European Journal of Endocrinology 2004; 151: U25–U37.9. Delange F. The disorders induced by iodine deficiency. Thyroid 1994; 4: 107–128.

10. Delange F, Dalhem A, Bourdoux P et al. Increased risk of primary hypothyroidism in preterm infants. Journal of Pediatrics

1984; 105: 462–469.*11. Delange F. Neonatal screening for congenital hypothyroidism: results and perspectives. Hormone Research 1997; 48:

51–61.12. American Academy of Pediatrics, Rose SR, Section on Endocrinology and Committee on Genetics, American Thyroid

Association, Brown RS, Public Health Committee, Lawson Wilkins Pediatric Endocrine Society, Foley T, Kaplowitz PB, KayeCI et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006; 117: 2290–2303.

13. Dussault JH. The anecdotal history of screening for congenital hypothyroidism. Journal of Clinical Endocrinology andMetabolism 1999; 84: 4332–4334.

14. WHO Indicators for assessing iodine deficiency disorders and their control through salt iodisation. Geneva: WHO, 1994. WHO/NUT/94.6.

15. WHO Assessment of iodine deficiency disorders and monitoring for their elimination – a guide for program managers . 2nd ed.

Geneva: WHO, 2001. Available from: http://www.who.int/nutrition/publications/en/idd_assessment_monitoring_elimination.pdf .

*16. Zimmermann MB, Aeberli I, Toni Torresani T et al. Increasing the iodine concentration in the Swiss iodized salt programmarkedly improved iodine status in pregnant women and children: a 5-y prospective national study. American Journal of Clinical Nutrition 2005; 82: 388–392.

17. Thilly CH, Delange F, Lagasse R et al. Fetal hypothyroidism and maternal thyroid status in severe endemic goitre. Journal of Clinical Endocrinology and Metabolism 1978; 47: 354–360.

18. Delange F, Iteke FB & Ermans AM. Nutritional factors involved in the goitrogenic action of cassava . Canada: InternationalDevelopment Research Centre, 1982. 1–100.

19. Kochupillai N, Pandav CS, Godbole MM et al. Iodine deficiency and neonatal hypothyroidism. Bulletin of the World HealthOrganisation 1986; 64: 547–551.

*20. Delange F. Screening for congenital hypothyroidism used as an indicator of the degree of iodine deficiency and of itscontrol. Thyroid 1998; 8: 1185–1192.

21. Delange F. Neonatal thyroid screening as a monitoring tool for the control of iodine deficiency. Acta Paediatrics Supplement 1999; 88: 21–24.

*22. Rajatanavin R. Iodine deficiency in pregnant women and neonates in Thailand. Public Health Nutrition 2007; 10: 1602–1605.

*23. Burns R, Mayne PD, O’Herlihy C et al. Can neonatal TSH screening reflect trends in population iodine intake? Thyroid 2008;18: 883–888.

24. Tylek-Lemanska D, Rybakowa M, Kumorowicz-Kopiec M et al. Iodine deficiency disorders incidence in neonates based onthe experience with mass screening for congenital hypothyroidism in southeast Poland in the years 1985–2000. Journal of

Endocrinological Investigation 2003; 26(Suppl. 2): 32–38.25. Wa chter W, Mvungi MG, Triebel E et al. Iodine deficiency, hypothyroidism, and endemic goitre in southern Tanzania. A

survey showing the positive effects of iodised oil injections by TSH determination in dried blood spots. Journal of Epidemiology and Community Health 1985; 39: 263–270.

26. Carta Sorcini M, Diodato A, Fazzini C et al. Influence of environmental iodine deficiency on neonatal thyroid screeningresults. Journal of Endocrinological Investigation 1988; 11: 309–312.

27. Delange F, Bourdoux P, Laurence M et al. Neonatal thyroid function in iodine deficiency. In: Delange F, Dunn J & Glinoer D(eds.). Iodine deficiency in Europe: a continuing concern. New York: Plenum Publishing, 1993, pp. 199–209.

28. Nordenberg D, Sullivan K, Maberly G et al. Congenital hypothyroid screening programs and the sensitive thyrotropinassay: strategies for the surveillance of iodine deficiency disorders. In: Delange F, Dunn J & Glinoer D (eds.). Iodine defi-ciency in Europe: a continuing concern. New York: Plenum Publishing, 1993, pp. 211–217.

29. Rajatanavin R, Unachak K, Winichakoon P et al. Neonatal thyrotropin profile as an index for severity of iodine deficiencyand surveillance of iodine prophylactic program. Thyroid 1997; 7: 599–604.

30. Sullivan KM, May W, Nordenberg D et al. Use of thyroid stimulating hormone testing in newborns to identify iodinedeficiency. Journal of Nutrition 1997; 127: 55–58.

*31. Costante G, Grasso L, Ludovico O et al. The statistical analysis of neonatal TSH results from congenital hypothyroidismscreening programs provides a useful tool for the characterization of moderate iodine deficiency regions. Journal of Endocrinological Investigation 1997; 20: 251–256.

32. Elnagar B, Gebre-Medhin M, Larsson A et al. Iodine nutrition in Sudan: determination of thyroid-stimulating hormone infilter paper blood samples. Scandinavian Journal of Clinical Laboratory Investigation 1997; 57: 175–181.

33. Mikelsaar RV & Viikmaa M. Neonatal thyroid-stimulating hormone screening as an indirect method for the assessment of iodine deficiency in Estonia. Hormone Research 1999; 52: 284–286.

34. Copeland DL, Sullivan KM, Houston R et al. Comparison of neonatal thyroid-stimulating hormone levels and indicators of

iodine deficiency in schoolchildren. Public Health Nutrition 2002; 5: 81–87.35. Kurtoglu S, Akcakus M, Kocaoglu C et al. Iodine status remains critical in mother and infant in Central Anatolia (Kayseri) of

Turkey. European Journal of Nutrition 2004; 43: 297–303.36. Simsek E, Karabay M & Kocabay K. Neonatal screening for congenital hypothyroidism in West Black Sea area, Turkey.

International Journal of Clinical Practice 2005; 59: 336–341.


http://whqlibdoc.who.int/publications/2007/9789241595827_eng.pdf


http://www.who.int/nutrition/publications/en/idd_assessment_monitoring_elimination.pdf







37. Charoensiriwatana W, Srijantr P, Janejai N et al. Application of geographic information system in TSH neonatal screeningfor monitoring of iodine deficiency areas in Thailand. Southeast Asian Journal of Tropical Medicine and Public Health 2008;39: 362–367.

*38. Glinoer D. The regulation of thyroid function during normal pregnancy: importance of the iodine nutrition status. Best Practice & Research Clinical Endocrinology & Metabolism 2004; 18: 133–152.

39. Ojule AC & Osotimehin BO. Maternal and neonatal thyroid status in Saki, Nigeria. African Journal of Medicine and Medical

Sciences 1998; 27: 57–61.40. Kung AW, Lao TT, Low LC et al. Iodine insufficiency and neonatal hyperthyrotropinaemia in Hong Kong. Clinical Endo-

crinology (Oxford) 1997; 46: 315–319.41. Jaruratanasirikul S, Sangsupawanich P, Koranantakul O et al. Maternal iodine status and neonatal thyroid-stimulating

hormone concentration: a community survey in Songkhla, southern Thailand. Public Health Nutrition 2009; doi:10.1017/S1368980009005205.

42. Travers CA, Guttikonda K, Norton CA et al. Iodine status in pregnant women and their newborns: are our babies at risk of iodine deficiency? Medical Journal of Australia 2006; 184: 617–620.

43. McElduff A, McElduff P, Gunton JE et al. Neonatal thyroid-stimulating hormone concentrations in northern Sydney:further indications of mild iodine deficiency? Medical Journal of Australia 2002; 176: 317–320.

44. Nøhr SB & Laurberg P. Opposite variations in maternal and neonatal thyroid function induced by iodine supplementationduring pregnancy. Journal of Clinical Endocrinology and Metabolism 2000; 85: 623–627.

45. Shi LX, Ma QL & Zhang JX. Influence of perinatal factors and sampling methods on thyroid stimulating hormone andthyroid hormone levels in cord blood. Zhonghua Fu Chan Ke Za Zhi 1994; 29: 714–716 [Article in Chinese].

46. Rashmi Seth A, Sekhri T et al. Effect of perinatal factors on cord blood thyroid stimulating hormone levels. Journal of

Pediatric Endocrinology and Metabolism 2007; 20: 59–64.47. Herbstman J, Apelberg BJ, Witter FR et al. Maternal, infant, and delivery factors associated with neonatal thyroid hormone

status. Thyroid 2008; 18: 67–76.48. Ordookhani A, Pearce EN, Mirmiran P et al. The effect of type of delivery and povidone-iodine application at delivery on

cord dried-blood-specimen thyrotropin level and the rate of hyperthyrotropinemia in mature and normal-birth-weightneonates residing in an iodine-replete area: report of Tehran Province, 1998–2005. Thyroid 2007; 17: 1097–1102.

49. Fuse Y, Wakae E, Nemoto Y et al. Influence of perinatal factors and sampling methods on TSH and thyroid hormone levelsin cord blood. Endocrinologia Japonica 1991; 38: 297–302.

50. Eltom A, Eltom M, Idris M et al. Thyroid function in the newborn in relation to maternal thyroid status during labour ina mild iodine deficiency endemic area in Sudan. Clinical Endocrinology (Oxford) 2001; 55: 485–490.

51. McElduff A, McElduff P, Wiley V et al. Neonatal thyrotropin as measured in a congenital hypothyroidism screeningprogram: influence of the mode of delivery. Journal of Clinical Endocrinology and Metabolism 2005; 90: 6361–6363.

52. Gunton JE, Hams G, Fiegert M et al. Iodine deficiency in ambulatory participants at a Sydney teaching hospital: is Australiatruly iodine replete? Medical Journal of Australia 1999; 171: 467–470.

53. Li M, Ma G, Boyages SC et al. Re-emergence of iodine deficiency in Australia. Asia Pacific Journal of Clinical Nutrition 2001;10: 200–203.

54. Working Group on Neonatal Screening of the European Society for Paediatric Endocrinology. Revised guidelines forneonatal screening programmes for primary congenital hypothyroidism. Hormone Research 1999; 52: 49–52.

55. American Academy of Pediatrics Section on Endocrinology and Committee on Genetics & American Thyroid AssociationCommittee on Public Health. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics1993; 91: 1203–1209.

56. Ogunkeye OO, Roluga AI & Khan FA. Resetting the detection level of cord blood thyroid stimulating hormone (TSH) for thediagnosis of congenital hypothyroidism. Journal of Tropical Pediatrics 2008; 54: 74–77.

57. Vela M, Gamboa S, Loera-Luna A et al. Neonatal screening for congenital hypothyroidism in Mexico: experience, obstacles,and strategies. Journal of Medical Screening 1999; 6: 77–79.

58. Elbualy M, Bold A, De Silva V et al. Congenital hypothyroid screening: the Oman experience. Journal of Tropical Pediatrics1998; 4 4: 81–83.

59. Feleke Y, Enquoselassie F, Deneke F et al. Neonatal congenital hypothyroidism screening in Addis Ababa, Ethiopia. Eastern

African Medical Journal 2000; 77: 377–381.

60. Lott JA, Sardovia-Iyer M, Speakman KS et al. Age-dependent cutoff values in screening newborns for hypothyroidism.Clinical Biochemistry 2004; 37: 791–797.*61. Grun eiro-Papendieck L, Chiesa A, Mendez V et al. Neonatal TSH levels as an index of iodine sufficiency: differences related

to time of screening sampling and methodology. Hormone Research 2004; 62: 272–276.62. Theodoropoulos T, Braverman LE & Vagenakis AG. Iodide-induced hypothyroidism: a potential hazard during perinatal

life. Science 1979; 205: 502–503.63. Fisher DA & Klein AH. Thyroid development and disorders of thyroid function in the newborn. New England Journal of

Medicine 1981; 304: 702–712.64. Gru ters A, l’Allemand D, Heidemann PH et al. Incidence of iodine contamination in neonatal transient hyper-

thyrotropinemia. European Journal of Pediatrics 1983; 140: 299–300.65. Robuschi G, Montermini M, Alboni A et al. Cord blood iodothyronine and thyrotropin concentrations in newborns of

mothers exposed to povidone iodine in the last trimester. Journal of Endocrinological Investigation 1987; 10:183–186.

66. Novaes Junior M, Biancalana MM, Garcia SA et al. Elevation of cord blood TSH concentration in newborn infants of mothers exposed to acute povidone iodine during delivery. Journal of Endocrinological Investigation 1994; 17:

805–808.67. O1tarzewski M & Szymborski J. Neonatal hypothyroid screening in monitoring of iodine deficiency and iodine supple-

mentation in Poland. Journal of Endocrinological Investigation 2003; 26(Suppl. 2): 27–31.68. Dong H & Zheng Q. Study on the neonate umbilical cord blood thyroid stimulating hormone level in the universal iodized

salt areas and its application. Zhonghua Liu Xing Bing Xue Za Zhi 2002; 23: 250–253 [article in Chinese].




69. Department of Health and Human Services & Centre for Disease Prevention and Control. Newborn Screening QualityAssurance Program 2008 Annual Summary Report. Available from: http://www.cdc.gov/labstandards/pdf/nsqap/nsqap_summaryreport_2009.pdf ; January 2009.

70. Chakraborty I, Chatterjee S, Bhadra D et al. Iodine deficiency disorders among the pregnant women in a rural hospital of West Bengal. Indian Journal of Medical Research 2006; 123: 825–829.


http://www.cdc.gov/labstandards/pdf/nsqap/nsqap_summaryreport_2009.pdf




Best Practice JCEM Screening Neonatal y usar solamente de TSH.pdf

Documents

Transcript of Best Practice JCEM Screening Neonatal y usar solamente de TSH.pdf