Archives of Medical Research 38 (2007) 1e14

REVIEW ARTICLE
Goiter and Other Iodine Deficiency Disorders: A Systematic Review of
Epidemiological Studies to Deconstruct the Complex Web
Atul Kotwal,a,b Ritu Priya,b and Imrana Qadeerb
a
Management Information Systems Organization, Integrated HQ Min of Defence (Army), New Delhi, India
b
Center for Social Medicine and Community Health, School of Social Sciences, Jawaharlal Nehru University, New Delhi, India
Received for publication May 6, 2006; accepted August 21, 2006 (ARCMED-D-06-00185).

A systematic review of the available literature on goiter and other iodine deficiency disor-
ders (IDDs) was carried out with the aim of analyzing available evidence and providing in-
puts to the policy makers and program formulators regarding the entire issue. The findings
point to major issues such as the following: methodological issues in epidemiology of goiter
and other iodine deficiency disorders (IDDs); lacunae in causal linkages; inadequate atten-
tion to multicausality; flawed assessment of the impact of intervention, i.e., iodized salt; and
harmful effects of iodine not given due cognizance. Most of the research to date has been
unidirectional and does not provide comprehensive data on all aspects of IDDs. To further
compound the issue, many independent researchers, on finding something different from the
existing dominant paradigm (iodized salt as panacea for goiter) have tended to ignore these
in their final conclusions and recommendations. Thus, evidence from this systematic review
demonstrates enough basis to start a debate on the entire issue, recognizing opposing re-
search findings while continuing with the present strategy. This imposes specific problems
and necessitates area-specific solutions instead of a universal solution, which apart from be-
ing less effective may be harmful in the long run. Ó 2007 IMSS. Published by Elsevier Inc.
Key Words: Goiter, Iodine deficiency disorders, Iodized salt, Micronutrient, Health policy.

Introduction tion of IDD is within reach and would constitute an

unprecedented global success story in the field of noncom-
Goiter and other iodine deficiency disorders (IDDs) have
municable diseases, but continuing vigorous action is
been known since antiquity and much has been written
required to attain this goal (6).’’
about the subject. The existence of endemic goiter in an ex-
Across the world, some countries have resorted to uni-
tensive belt along the southern slopes of the Himalayas,
versalization of iodized salt (USI), whereas others have
Alps and Andes has long been described. The early pio-
not done so and instead focused on making it available as
neers in the study of endemic goiter included Sir Robert
a community choice. Although the Government of India
McCarrison (1,2) and Stott (3). Both pointed to the complex
initiated the National Goiter Control Programme (NGCP)
etiology of goiter and commented on various causative fac-
in 1962, the program, however, faltered on many accounts
tors. The role of iodine in the causation of goiter was elu-
and various reviews of the program specified different as-
cidated by various researchers working in these areas.
pects and reasons for not achieving the aim. Whatever the
The results from different geographical areas and few stud-
strategies adopted for the control of goiter and other IDDs,
ies formed the basis of control and prevention activities of
the problem has increased rather than showing any decline,
goiter (4,5). As per a recent review ‘‘Sustainable elimina-
as shown in Table 1 (7,8). The scientific backbone of uni-
versal iodization has also been challenged by pointing out
Address reprint requests to: (Lt Col) Atul Kotwal, MD, Classified the weaknesses in the science and politics of the interven-
Specialist, Preventive and Social Medicine and Epidemiologist, Joint Di- tion to control IDDs. Few papers have also challenged the
rector (Medical and Health), Management Information Systems Organiza-
tion, Integrated HQ Min of Defence (Army), West Block-III, RK Puram,
research forming the basis of the information on the magni-
New Delhi-110066, India; E-mails: atuljyoti2710@hotmail.com and tude of the problem and effectiveness of the intervention
dratulkotwal@gmail.com (9,10).

0188-4409/06 $esee front matter. Copyright Ó 2007 IMSS. Published by Elsevier Inc.
doi: 10.1016/j.arcmed.2006.08.006

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2 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14

Table 1. Total goiter prevalence in various regions of World Health
Organization over a period of time
Total goiter prevalence (%) Percentage change
between 1993
WHO region 1993 1997 2004
Africa 15.6 20.0 28.3
Americas 08.7 05.0 04.7
Southeast Asia 13.0 12.0 15.4
Europe 11.4 15.0 20.6
Eastern Mediterranean 22.9 32.0 37.3
Western Pacific 09.0 08.0 06.1
Total 12.0 13.0 15.8
Adapted from WHO documents (7,8).
This prompted us to carry out a systematic review of the
available literature with the aim of initiating a healthy
debate and providing input for a mid-course correction.
The objectives were to highlight the lacunae in research
on etiology; efficacy/effectiveness of the intervention; eval-
uation strategy adopted; the direction in which the program
is progressing; the problems when one solution is supposed
to be a panacea for all regions/communities rather than giv-
ing due recognition to multicausality while planning any in-
tervention; and the contrasting views of organizations/
individuals involved in various aspects of IDDs control over
a period of time. This review in no way tries to belittle the
importance of iodization in preventing the spread or
reducing the problem and of the research carried out on var-
ious aspects of IDDs. Because rational measures for the
prevention and control of any disease depend upon the
adequacy of knowledge about its etiology and pathogenesis,
the availability of an effective intervention, appropriate
conceptualization, implementation and subsequent evalua-
tion and feedback/review of the program, as the acolytes
of evidence-based medicine, we must take steps to prevent
our medical successors, using the long lens of history, from
judging us as harshly as we might judge the early history of
prevention and control of IDDs.
As per available evidence, the issues related to IDDs can
be classified into four main groups: 1) magnitude of the
problem and evidence for multicausality, 2) evidence for
benefit of iodized salt, 3) assessment of intervention, and
4) harmful effects of iodine.
Methodology of the Review
More than 120 studies (1906 to the present) from various
parts of the world were reviewed. These included published
as well as unpublished works from various journals, inter-
net sites, institutions/organizations and governmental sour-
ces. We searched the following from inception to May
2005: MedLine, EMBASE, Index Medicus, Cochrane con-
trolled trials register, and the Nursing and Allied Health
Collection. In addition, we searched for unpublished and
on-going studies and also publications of International
Council for Control of Iodine Deficiency Disorders (IC-
CIDD). All available studies were included in this review.
and 2004 None of the available studies was excluded as we wanted
to capture the diversity of methodology and interpretations
þ81.4
46.0
being used in research on goiter and IDDs. Due to the het-
þ18.5 erogeneity of the study methodologies in this review it was
þ80.7 not possible to apply the meta-analysis techniques; thus,
þ62.9 a systematic review was conducted. The studies were clas-
32.2 sified based on their study design (community based/hospi-
þ31.7
tal based, cross sectional/longitudinal, nonexperimental/
experimental) and also the focus (assessment of the prob-
lem, assessment of program, intervention) to assess the four
major issues mentioned above. The Indian scenario was
analyzed in detail in the overall global context.
Magnitude of the Problem and Evidence
for Multicausality
Issues in Epidemiology of Goiter and Other IDDs
The problems encountered by epidemiological studies of
thyroid disorders are those of misclassification (e.g., overt
and subclinical hypothyroidism); mode of sampling in pop-
ulations; various confounders (age, gender, environmental
factors, etc); different classifications (Perez, WHO, Stan-
bury, etc.) used for the measurement of thyroid size; diffi-
culty in carrying out certain tests leading to lack of data
on thyroid function; and focus on monocausality or ignor-
ing multicausality on finding. Thus, results of epidemiolog-
ical surveys carried out in various states, countries and over
a period of time within the same community or country are
often difficult to compare. This is further compounded by
different methods to present the results and investigators’
interpretation of classification criteria in their own way.
Criteria for Identifying Goiter
Estimation of breadth, volume, palpability or visibility of
a thyroid gland is subjective as it depends on many factors:
certain characteristic of subjects (shape of neck, thickness
of subcutaneous fat, disposition of SCM muscle, etc.); in-
vestigators approach (interpretation of classification crite-
ria, experience, fatigue, etc); and on the circumstances of
examination (illumination of the subject’s neck, position
of neck in relation to investigators eye, time devoted to
examination, etc.). Furthermore, goiter measurements are
hampered by the fact that soft glands are fairly common
and any estimate will depend on the finger pressure (11).
The most important factors affecting the accuracy of
estimation of goiter frequency are intra- and inter-observer
variability, and studies have shown different levels of con-
cordance or discordance among observers and in an
observer over-repeated measurements. It has been shown

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 A Systematic Review of Goiter and Other Iodine Deficiency Disorders 3

that observation variation is greatest in deciding whether Mean

a thyroid that is palpable but not visible is normal or en- 95% CI Upper
70 95% CI Lower
larged (12). There was also considerable overlap between
Total Goiter Prevalence
the various grades when compared with thyroid volume es-
timated by ultrasonography (USG), which increased the 60
sensitivity of the test because 30% of individuals were
found positive by USG but only 14.6% by conventional
50
methods (13,14). USG also increased the correlation and
agreement between observers (15); however, USG has not
been extensively used in field studies. It is therefore impor- 40

tant to know the estimates of variability before embarking

on any tests of statistical significance. 30
Classifications have also changed over a period of time
with each one having its characteristics, e.g., difficulty in 20
Perez et al. classification was in defining at which degree
of enlargement one considers a sufficient pathological alter-
10
ation of the gland in order to classify as goiter (16,17). Even
after modification, the distinction between grade 0 and I was
unsettled for a long time. The Caracas, WHO/FAO group 0
tried to resolve some of the issues and concluded that some l1 l2 j1 j2 j3 j4 j5 ar1 ar2 h1 ri1 ri2 ild
of the small thyroid hypertrophies do not have sufficient path- De De Gu Gu Gu Gu Gu H H Ma O O Ch
o tal
ological significance to be classified as goiter but should also T
Area of study
not be classified as normal. Thus, two subgrades, 0a and 0b,
were defined, creating more confusion during community Figure 2. Total goiter prevalence: pre-iodization studies among children in
surveys and when comparing historical data. various states of India. Del, Delhi; Guj, Gujarat; Har, Haryana; Mah,
Figures 1 and 2 depict the total goiter prevalence (TGP) Maharashtra; Ori, Orissa.
along with 95% confidence intervals as per few of the In-
dian studies carried out in various states of India prior to biases as discussed earlier. Figure 3 depicts a few of the
the USI (18e28). Most of these studies reported a high pro- studies from other countries (29e33).
portion of goiter in lower categories that are subject to
Criteria for Identifying Regions Endemic
for Iodine-Deficiency Disorders
80
Mean
The classification of endemias according to severity has
95% CI Upper been done with the premise that goiter is physiological in
95% CI Lower about 5% of young girls at puberty. Therefore, arbitrarily
Total Goiter Prevalence a population having a prevalence of 10% of any grade is
60 considered endemic (34). It has been estimated that goiter
and endemic cretinism prevalence in India have been over-
estimated by a multiplicatory factor somewhere between 3
and 6 due to bias in the mathematical model used (35).
40

Etiology of Goiter and Other IDDs

20
Etiology of endemic goiter is complex and not fully eluci-
dated. The fact that goiter persists in many areas despite io-
dine supplementation for prolonged periods reiterates the
importance of doing so. After studying goiter in Chitral
0 and Gilgit valleys in the then undivided India, McCarrison
showed the association of goiter prevalence with contami-
Assam Guj1 Guj2 Guj3 Guj4 Guj5 Mah1 Mah2 Mah3 Total nated water supplies in a trial in Himachal Pradesh (one of
adults the Northern states of India) where prevalence of goiter
Area of study among school children decreased by changing the water sup-
Figure 1. Total goiter prevalence: pre-iodization studies among adults in ply from contaminated to uncontaminated, the other factors
various states of India. Guj, Gujarat; Mah, Maharashtra. (iodine content of water, soil, etc.) being unchanged (1,2).

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4 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14
Mean
95% CI Upper
70 95% CI Lower
Total Goiter Prevalence
60
50
40
30
20
10
0 in the form of tube wells and other types of wells. The role of
l1 l2 j1 j2 j3 j4 j5 ar1 ar2 h1 ri1 ri2
De De Gu Gu Gu Gu Gu H H Ma O O
o tal
T obtained water from dug wells as compared to children
Area of study
Figure 3. Total goiter prevalence: studies from a few countries. Del, Delhi;
Guj, Gujarat; Har, Haryana; Mah, Maharashtra; Ori, Orissa.
A majority of the initial studies tried to assess the issue of
causality along with assessing the extent of the problem.
A few hospital/community-based studies on causality
are shown in Table 2 (4,5,36e42), whereas others have
been described in text. A high TGP, with a high proportion
of grade 0b goiter (subject to classification bias), was found
among a tribal population in a coastal area on the Eastern
coast of India, which either shatters the myth of iodine
deficiency as a causal factor in goiter as marine fauna is
rich in iodine or it is an inflated figure due to lack of inter-
nal validity of the study (43). Similar results have also been
found from other coastal areas, pointing to some effect
modifier or confounder in the entire issue of iodine as
a causal factor of goiter. This lack of correlation between
iodine and goiter was also found in a study where a majority
of the children with growth failure had dysgenetic thyroid
gland, showing that factors other than pure iodine defi-
ciency are at play in goitrogenesis and hypothyroidism
(36). Another study found no correlation between grade
of goiter and urinary iodine in pregnant women (37).
Goiter was found to be more prevalent among the poor-
est, field laborers and cultivators, after rains, after food fam-
ines, and among those consuming water with high levels of
calcium in the then United Provinces of India, and no asso-
ciation was found between goiter and diet and iodine con-
tent of water (3). In other goiter prevalence studies in
different areas, no association was found with iodine intake.
The researchers also did not find any association of goiter
with cretinism, deaf mutism, and other aspects of physical
and mental growth retardation (19,22). This association of
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goiter with socioeconomic and life style factors has also
been demonstrated in Denmark (44).
There are innumerable descriptions of goiter attributed to
drinking water. Microorganisms contaminating water sup-
plies have been implicated as a causative factor in few ende-
mias. Studies supporting similar findings were done in India
in the 1970s and 1980s but were not given due recognition
and thus were not repeated later. Antithyroid activity has
been shown in cultures of E. coli isolated from polluted
streams of highly endemic areas. Organic compounds with
antithyroid activity have also been isolated from water. A
similar association of goiter with contaminated drinking wa-
ter, low literacy and socioeconomic levels was found in many
studies in different geographic areas across India
(18,19,21e23,26). Few of these areas were free of goiter until
about 10 years prior to the study period. An important change
during this period was the introduction of new water sources
pollutants in water has also been demonstrated in the U.S.
ild
Ch where goiter prevalence was higher in children whose homes
whose homes were served by piped water supply ( p
!0.025). The majority of the dug wells were polluted and
the iodine content was adequate in both populations (45).
Worldwide, there are several endemias attributed to
environmental goitrogens—Tasmania, Finland, Nigeria,
Chile, West Virginia, etc. The vehicle for goitrogens in
the majority was water and milk. Environmental factors
other than nutritional iodine deficiency are responsible for
the persistence and development of new cases in certain
endemias and also for the differences observed in goiter
prevalence among communities with similar iodine intake.
Iodine deficiency must act in conjunction with other goitro-
genic factors to produce a goiter endemia. Environmental
goitrogens when low in concentration may normally be in-
effective but may become significant when iodine supply is
restricted. In other situations they may be sufficiently po-
tent in themselves to cause goiter despite an abundance
of iodine. Adequate iodine intake of 75e300 mg/day does
not always eradicate goiter because 6e40% prevalence
existed in certain areas despite these intakes (46). The goi-
trogenic action of calcium has been well established under
experimental conditions but the evidence for calcium in
drinking water and food having practical importance for
the development of endemic goiter is conflicting (47).
The increase in prevalence of goiter in Papua New Guinea,
subsequent to economic recession despite a well-imple-
mented intervention by iodized oil (48), shows that multi-
causality has been ignored for IDDs. Similar studies on
multicausality have also been reported from Denmark
(49,50). Studies are also available showing high goiter rates
despite lack of iodine deficiency (51,52).
A survey in the U.S. in Tecumseh, MI indicated relatively
high goiter prevalence without convincing evidence of iodine
deficiency. Similar results were obtained during studies in
 Table 2. Results and comments on studies regarding causal linkages of goiter and other iodine deficiency disorders
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Serial no. Ref (year) Study area Study population and design n Results Remarks

1 4 (1961) Punjab (I) Ie12e16 PBI uptake Overinterpretation of causality

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based on a cross-sectional study

Bihar (II) IIe8e12 Ie33 Ie62.5%
Bihar (III) IIIe12e15 IIe43 IIe62.9%
India All goitrous in I and II IIIe18 IIIe39.05%
Non-goitrous in III
All euthyroid
2 5 (1973) UP, India Goitrous controls 26 TSHebetween grades p !0.05; linear relation with grade Wide and overlapping 95% CI,
(case-control) of goiter p !0.02; compared with controls p !0.001 invalid controls
46

A Systematic Review of Goiter and Other Iodine Deficiency Disorders

3 36 (1989) Delhi, India Patients of thyroid Hypo 117 Hypo Hyper Euthy No correlation found with iodine
clinic from 1983e88 deficiency
(case series)
Hyper 10 Goiterþ 19 10 30
Euthy 30 Goiter 98 0 0
Iodine 3 0 19
deficiency
4 37 (1990) Municipal Pregnant women of 479 Goiterþ Goiter No association between goiter
Hospitals, low socioeconomic and iodized salt; urinary iodine
Maharashtra, strata attending ANC excretion and iodized salt
India in a 3-month period
Iodized saltþ 9 17
Iodized salt 106 347
Odds ratio 5 1.73 (0.69e4.26)
Cross-sectional Goitrous 27.3% p 5 0.193
UI !50 UI O50
Iodized saltþ 3 23
Iodized salt 30 423
Odds ratio 5 1.84 (0.41e6.97)
p 5 0.411
5 38 (1977) Delhi, India Goitrous and I TCR I RCR PII UI AIU Number of cases and
nongoitrous children controls not provided
(Case/Control)
Cases 88.39 23.33 0.0695 20.0 2.532
Controls 22.2 21.675 0.1372 76.4 1.646
p5 0.001 0.7 0.01 0.001 0.05
6 39 (1982) Neonates TSH mIU/L T4 mg/dl T3 ng/dl rT3 ng/dl No correlation found between
goiter and cretinism
UP 20 14.6 4.28 96.34 168.42
UP, India Delhi 89 9.8 6.41 59.78 174.3
Delhi, India p5 0.01 NS 0.001 NS
7 40 (1984) UP, Delhi, Neonates TSH T4 Hypo T4 T4 higher in Kerala, rT3 not used
Kerala,
India
UP 646 15.5 5.75 5 6.09
(Continued)

5
6 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14

et al. but 0.4 per thousand after

I TCR, radioactive iodine thyroidal clearance rate (mL/min); I RCR, radioactive iodine renal clearance rate (mL/min); PII, plasma inorganic iodide levels (mg%); AIU, absolute iodine uptake rates (mg/h);
UI, urinary iodine (mg/g); CH, congenital hypothyroidism; WI, iodine content of watermg/L; T3, in nmol/L; T4, in nmol/L; TSH, mIU/L; TGP, total goiter prevalence; CI, 95% confidence interval; PBI,
Kentucky. Dietary iodine deficiency (corrected for age and

Incidence 28/1000 as per TSH

gender, as well as analysis of iodine in daily food samples)

values used by Kochupillai

Mild hypothyroidism in CH
could not be implicated. Goiter was found even in those

difference in IQ levels
showed no significant
households that had been consuming iodized salt for more
Remarks

than 20 years. All water samples were polluted and there

were no goitrogens in the diet (53). Many other studies in dif-
follow-up
ferent areas of the U.S. yielded similar results. In Mexico,
studies concluded that iodine deficiency may be the main
but not the only cause of goiter. Also, no correlation was
found between the average iodine intake and prevalence of
goiter (54). The prevalence of goiter in Greece was
40e60% in 1966 and 21% in 1996. This decrease was despite
not having a program of IDD control and was due to changes
7.57

in food habits, etc. An interesting observation was that

8.3

O80

48

increased urinary iodine levels were associated with antithy-

roid antibodies in children, which may lead to autoimmune
thyroiditis. This might be the reason for residual goiter espe-
cially among children with sufficient iodine intake (55). Even
manual)
107.6
115.5

118.2
Mean IQ
12057
1

302

345

experimental and clinical studies have suggested a link

(non
30e80

CHe

between the level of iodine intake and the development of

Results

autoimmune thyroid disease (56).

In India, a nationwide survey was conducted to assess the
(manual)

97.5
8.5

109.1

109.8

problem before Universal Salt Iodization (57). Thus, the goal

Mean IQ
!30

12057

5
0

of universal iodization was already formulated a priori. The

CHþ

states and districts were purposely selected, i.e., those where

information was already available about high prevalence of
goiter. The results thus might have been valid for the partic-
Cases !42.8
Cases O42.8
T4
TSH O30
TSH !30

ular districts but neither generalizable to the states from

8.7

Controls

which the districts were selected nor to other parts of the

TSH

country. The question raised is why probability sampling

techniques were not used in a nationwide survey. Despite this
purposeful sampling, overall total prevalence was only
427
575

361
315
12407

21.1%. The report mentions probable underreporting of 0b,

n

thus accepting an observer or other bias at play, raising the is-

sue that there could have been an overreporting of 0b. Many
0a were classified as 0b due to the ultimate goal of USI being
Study population and design

National register of children

with CH compared with

validated by the survey. Water samples were also drawn with-

out any sampling procedure and were tested only for iodine
but not for other pollutants (organic and inorganic) or other
Matching controls
(case-control)

possible goitrogens. Urine samples were collected but not

All neonates

analyzed (possibly due to transportation problems or other

administrative challenges), which reflects operational failure
Cohort
Kerala
Delhi

of the survey. These failures also might have affected other

areas like training, quality assurance, etc., thus questioning
the internal validity of the survey. Whatever the possible
Study area

Maharashtra,

London, UK

flaws, the survey clearly shows that goiter and cretinism were
India

not correlated, e.g., prevalence of goiter in two of the north-

east states of India (65.8 and 19.8%, respectively) did not
correlate with prevalence of cretinism (2.2 and 6.1%, respec-
Serial no. Ref (year)

41 (1987)

42 (1994)

protein bound iodine.

tively). Cretinism also was not apparent in areas where iodine

Table 2. Continued

deficiency was supposedly more prevalent.

Many researchers have compared different aspects of
endemic and nonendemic areas. In one such study, higher
uptake of iodine was shown in school children with visible
goiter. However, the sample size was small in each group,
8

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 Table 3. Details of studies on assessment of intervention for control of goiter and other iodine deficiency disorders
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Results
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Population studied; study design; year; class used n Present study

Serial Ref. Area/region/ year
no. (year) of iodination Previous study Present study Previous Present Previous study (TGP%) TGP (%) UI !10 (%) IS !15 (%)

1 84 (1987) Northeastern General population; General population; CS 5573 3248 68.6 72.5 (cretinism 3%)
state 1978 CS; 1978
2 85 (1993) Northeastern General population; General population NA 4375 17 38.38
state 1987 CS; 1970 CS; WHO
3 86 (1994) Northeastern General population; General population; CS; NA 11523 TGP
state 1987 CS; 1970 Perez (Iae75.9,

A Systematic Review of Goiter and Other Iodine Deficiency Disorders

Ib-20.5, IIe3.0,
IIIe0.55)
23.32
City A 7.3 20.4
City B 7.3 20.3
City C 13.2 20.8
4 90 (1998) Coastal area Children 6e11 years NA 2065 NA 2.6l 24.1 69
age; CS
5 91 (1998) Island group Children 7e18 years; CS NA 900 NA 16.5 81.9 7.5
in Bay of Bengal
6 95 (1995) Northern state General population; CS General population: CS NA NA
Dist A 1966 1930 1988 40.0 21.9
Dist B 1966 1930 1966 3.7 18.7
Dist C 1960 1860 1969 23.2 23.6
Dist D 1966 1965 1969 39.7 16.3
Dist E 1986 1973 1989 65.0 31.2
Dist F 1966 1930 1989 3.7 19.1
Dist G 1966 1930 1974 40.0 24.3
7 96 (1996) Northern General population; General population; CS NA 5000 60 50.3
state 1980 CS; 1980
8 97 (1997) Eastern General population Children 6e12 years NA
state 1976 age; CS
Dist A 662 57.2 12.8 49.3 26.7
Dist B 666 64.5 10.4 48.8 34.2
9 98 (1998) Northern state Children 5e15 years Children 8e10 years age; NA 6897 41.2 8.8 32.8 10.8
1976 age; CS; 1956
10 99 (1997) Northern state General population; School children NA 1358 41.2 5.8 23.7 23.4
1976 CS; 1954 8e10 years age;
CS; WHO
11 100 (1997) Delhi School children School children, 3200 1684 55.0 20.5 24.9
10e21 years; CS; 10e14 years; CS;
1980

CS, cross-sectional; UI, urinary iodine (mg/gm); IS !15eproportion of salt samples having !15 ppm of iodine; TGP, total goiter prevalence; Dist, District.

7
8 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14
increasing the possibility of chance error. Moreover,
goitrous children from endemic areas were compared with
adults from non-endemic areas. They also found lower pro-
tein-bound iodine (PBI) in goitrous children as compared to
nongoitrous children. Contrasting results of no difference in
ankle jerk reflex as well as PBI in goitrous as compared to
nongoitrous children were found by another group (58).
Higher TSH levels were actually compared with controls
in England. However, when T4 levels were found to be
higher in Indian cases as compared to English controls, this
was dismissed as controls being from a different country.
Moreover, the higher value of T3 in cases was not assigned
any importance. The subgroup analysis with small numbers
in each group increased the chance error in the estimates.
Thus, an inference of convenience was drawn and many
studies in later years quoted this study as a milestone and
a basis for the problem of goiter in the Himalayas (5).
Another study found decreased iodine excretion, increased
TSH values, decreased T4 and increased T3 in endemic as
compared to non-endemic areas (29). However, both areas
differed in many other factors like geophysical characteris-
tics, dietary patterns, etc. A conclusion of cretinism in Zaire
due to severe iodine and selenium deficiency was made based
only on cross-sectional data in a study dealing with neonatal
hypothyroidism and comparing biochemical parameters
between neonates from Zaire and Malawi. The results of
Zaire neonates were compared with Belgian neonates, whose
number is also not provided. However, the authors somehow
conclude that etiopathogenesis of goiter is multifactorial (59).
A hospital-based case-control study presumed hospital
and home diets to be similar. An interesting finding was
a positive iodine balance among all cases. Despite this,
iodine deficiency was being reported as a major cause of
goiter. The researchers mention this towards the end of their
discussion but do not give due recognition to this important
finding (38). Multiple regression analysis in two studies
(r2 5 0.57 and 0.51, respectively) showed that goiter size
depends on iodine uptake, age and vitamin A and thus
inferred that vitamin A nutrition is as important as iodine
status. Decreased vitamin A stores play a causal role in goi-
trogenesis, and iodine itself contributes to goiter formation
due to indiscrete iodine intake (60,61).
Experimental studies have consistently shown the role of
other factors in the causality. Experiments on rats showed
that environmental goitrogens (thiocyanates, etc.) might
be significant determinants in the etiology/prevalence of en-
demic goiters (62). In another study, it was shown that apart
from or along with iodine deficiency the goitrogens present
in staple foods may be important contributory factors (63).
Goiter, Congenital Hypothyroidism and
Endemic Cretinism
Despite the well-researched and accepted linkage, the
evidence in favor of maternal hypothyroidism and infantile
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cretinism is conflicting. Some studies have shown more
stillbirths, infant deaths and endemic cretinism among off-
spring of women showing biochemical evidence of iodine
deficiency (decreased T4 and T3, increased TSH) but with-
out clinical evidence of hypothyroidism (64). Against
the maternal hypothyroidism hypothesis is the fact that
thyroid hormone transfer across the placenta is minimal and
thyroidepituitary feedback mechanisms are autonomous in
mother and fetus. A literature review of pregnancies in
hypothyroid women indicated an excess of congenital
anomalies but no case in which deaf mutism, diplegia or
congenital hypothyroidism (CH) was present (65,66).
A group of researchers found pockets of endemic cretin-
ism in Himalayas with prevalence of 1e4% (67), but another
study found prevalence to be !1% in many areas of the Hi-
malayas (68). In the newer areas of goiter endemias, e.g.,
Delhi (India) (25), endemic cretinism is not seen at all but ref-
erence is made to subclinical cretinism. The methodology
adopted for proving this new hypothesis involves develop-
ment and intelligence testing. In one such study, children of
goitrous mothers and controls were compared by Gessel de-
velopment score. It was concluded that development quotient
(DQ) and language development were lower in children of
goitrous mothers (69). The mean DQ for controls was 98.4
as compared to 94.4 in other groups; this small difference
was shown as statistically significant and profound conclu-
sions were drawn. This approach is highly controversial
and has been riddled with a priori assumptions, conscious
fraud and politics, so that its very value and scientific
objectivity have been questioned (9).
Studies assessing causality and studying other factors like
CH have used statistical significance on an as-required basis
apparently to fit into their hypothesis and taking very low cut-
off values for CH. No statistically significant difference in
rT3 and T4 in cord blood samples among neonates in one
of the endemic districts of Bihar (India) and Delhi (India)
was found, but inference was still drawn that all values in
children of endemic areas were several fold higher as com-
pared to Delhi children (nonendemic area) (39). Incidence
of CH is another area of dispute. By using TSH as a marker,
one group found incidence of CH as 4% in endemic areas and
0.1% in nonendemic areas and tried to find a correlation be-
tween goiter prevalence and congenital hypothyroidism (40).
However, studies by the same researchers showed that en-
demic areas had a goiter prevalence of 64% as compared to
52% in nonendemic areas. The authors discussed the impor-
tance of rT3 in their previous study in the same areas and in-
ferred that rT3 levels faithfully reflect thyroid status of
newborns in endemic area (53) but did not use that in this
study. Although prevalence of goiter was shown to be much
less in Kerala (India) as compared to other areas, the mean
value of T4 was less in Kerala as compared to Delhi, thus rais-
ing doubts on the validity of using biochemical parameters in
these studies. In Bangladesh as well, no association was
found between cretinism (0.5%) and goiter (47%), despite
 A Systematic Review of Goiter and Other Iodine Deficiency Disorders
a high prevalence of the latter. This is contrary to assumptions
by researchers in India, as per which the cretinism prevalence
in that area would be O2% (30).
Hospital-based studies in a coastal city in India showed
that positive predictive value of using 50 mIU/L of TSH as
cut-off for CH was quite low and leads to overestimation of
the problem. A 2.81% incidence of CH was initially found,
which dropped considerably (0.000403% or 1:2481) after 2
years of follow-up with neonates having TSH O250, only
eventually developing hypothyroidism. The study also raised
another important issue of some other factors responsible for
TSH surge in newborns (41). Thus, previous studies (52,53)
did not take transient neonatal hypothyroidism into account
while studying TSH values for CH. The same authors
referred to transient neonatal hypothyroidism in one of their
later papers and mentioned that it could be an important issue
in iodine-deficient areas (70). However, starting thyroxine
for babies based on a single result of a high TSH is unethical,
as European as well as Indian studies have shown this phe-
nomenon of transient neonatal hypothyroidism (29). Well-
designed follow-up studies need to be carried out in areas
already studied to determine the real incidence of CH.
Work has been done in this direction by a few groups of
scientists who have shown evidence for the role of maternal
thyroid hormone on early brain development (71,72). How-
ever, the entire issue needs to be revisited because the find-
ings of one study question the benefit of screening and
early treatment as screening reduces but does not eliminate
neurological impairment (42). To sum it up, lack of an exper-
imental model, lack of a similar clinical picture in children of
hypothyroid mothers in non-iodine deficient countries, and
lack of a similar clinical picture in syndromes of resistance
to thyroid hormones are paradoxical and require further in-
vestigation to understand the mechanism of neurological
cretinism using a holistic approach. Until that time, present
efforts need to continue to prevent CH.
Evidence for Benefits of Iodized Salt
Even in this area the evidence from trials and other studies
is conflicting as most of the studies showed only a marginal
decrease in prevalence of goiter despite so-called universal
salt iodization. Some of the possible reasons for this lack of
effectiveness were commented by some researchers but
studied by none. These included poor implementation of
the program, iodine losses during cooking, increased goi-
trogens in environment/diet/water, decrease in goiter due
to economic development, iatrogenic goiter/anemia, etc.
There is a definite lack of cohort studies at present.
There have been very few community-based intervention
studies and two of these were conducted in the present Hima-
chal Pradesh (India) (2,73). The first one showed no evidence
of the role of iodine in goiter whereas the other has provided
the only evidence of effectiveness of iodized salt in the pre-
vention and control of goiter. The two communities provided
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9
with iodized salt showed decreased prevalence in all groups
as compared to the third community. However, the assess-
ment was not blinded and inter- and intra-observer variability
in classification of goiter was neither commented upon nor
shown in the results. Thus, subjective interpretation might
have affected grade b of the classification used in the study,
with more in this grade before iodization and less after iod-
ization in the intervention areas. Moreover, only those partic-
ipants were studied who were available at home during the
time of the survey. The prevalence of goiter among the gen-
eral population at baseline was higher in the control area as
compared to both intervention areas and this was statistically
significant. The difference among school children after 12
years of follow-up was reduced significantly (74). The resid-
ual difference was in grade b goiter, which suffers from
subjective classification.
In a trial in one of the southern states of India, the blocks
were provided with double-fortified (iodine and iron) or only
iron-fortified salt or only iodized salt. However, the blocks
were not comparable at baseline. The results of the third
arm of the intervention group, which was supplied with
iodized salt, have not been provided in the paper for reasons
best known to the investigators. The question that needs to be
answered is whether these showed any negative effects or did
not show any benefit. Although urinary iodine excretion in-
creased among the double-fortified salt (DFS) group as well
as the iodized salt group, the mean hemoglobin levels de-
creased in both groups. A significantly higher proportion of
girls ( p !0.001) showed a decrease in hemoglobin levels
in the iodized salt group as compared to the DFS group
(75). In another trial, iodine supplementation alone was
shown to raise levels of urinary iodine, T4 and iron status,
whereas iron and iodine supplementation in combination
did not lead to any significant changes in these parameters
(76). These results raise an important issue of whether
iodized salt is hampering, in any manner, the absorption or
utilization of iron. Could the present high prevalence of iron-
deficiency anemia in India be contributed to by iodine in salt?
The issue needs to be understood well before any changes are
implemented in the programs for correction of these defi-
ciencies, especially in countries with high levels of iron-
deficiency anemia. Decreased incidence of CH in one of
the northern states of India post-iodization was concluded
to demonstrate the effectiveness of USI (77) despite surveys
in UP in the 1990s, showing a high continued usage of non-
iodized salt. Was it iodized salt, iodine from other sources
(improved nutrition/dietary practices), or increased iodine
availability due to lack of goitrogens (improved water supply,
dietary) that played a role in decreased CH?
Assessment of Intervention
As with other aspects, assessment of intervention, i.e.,
iodized salt/oil also suffers from various drawbacks. We
10 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14
highlight a few: lack of temporal comparability due to use
of different classifications, methodologies, techniques and
study population; confounders not studied adequately in
available cohort studies; inadequate data on other factors
affecting absorption/utilization of iodine; and inadequate
studies on lack of correlation between iodine nutrition
and TGP.
In the U.S., a high prevalence was found in 1924, but
subsequent surveys in 1951 (consequent to iodization of ta-
ble salt in 1924) found a low prevalence of goiter, from
38.6% to 1.4%. Whereas 20% were still using uniodized salt
only, 75% of households were using iodized salt only and
4% were using both. Thus, the decrease in goiter prevalence
was largely due to iodization of table salt but changes in the
processing and distribution of food as well as in food habits,
which also occurred during the same period of time, con-
tributed to this decrease. However, from 1955 onwards,
the iodine intake increased tremendously (O600% of
U.S. RDA) due to other sources like greater utilization of
iodine in food technology, sanitation and in the chemical
industry. Still the goiter persisted! Thus a hypothesis was
generated that this persistent goiter was not related to
iodine deficiency (53).
The decision of the Indian government to implement
USI by 1990, 20 years after inception of NGCP, was se-
verely criticized by researchers presently spearheading the
campaign of USI (78,79). According to these researchers,
iodine deficiency was a place-specific problem and hence
necessitated area-specific solutions. They clearly stated that
‘‘USI besides introducing a fresh economic burden would
also magnify the already extensive chain of participating
agencies out of proportion. All this might lead to a delay
in the supply of iodated salt to hyperendemic areas. Thus,
priority should be to consolidate the existing infrastructure,
strengthen weak links and prioritize the distribution of salt.
Only after meeting the needs of endemic areas, one may
subsequently plan for USI’’. They also commented on the
methodological issues like classification of goiter, need
for uniform sampling procedures and use of median for uri-
nary iodine excretion instead of mean values due to skewed
values.
However, as the available evidence indicates, none of the
subsequent studies/surveys addressed these issues satisfac-
torily. Even when the prevalence was shown to have in-
creased after a period of iodization and banning plain salt
in a particular area, only salt iodization was being targeted
for review without making any attempt to study the situa-
tion in its entirety. None of the researchers ever thought
about whether the problem was with the program imple-
mentation or with the entire concept of salt iodization or
were there other factors operating/interfering with avail-
ability/assimilation of iodine? A detailed analysis of avail-
able studies reveals that various researchers have used
different classifications. Some have used Perez, some
WHO, others Stanbury and in one paper a new improvised
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classification of only two categories (0 and 1) was also
seen. The other major drawbacks noticed were different
age groups being studied and piecemeal evaluation of the
program. In India, salt and goiter are being targeted during
evaluations. No effort is being made to study the changes in
diets, etc. to correlate with the present prevalence. Many of
the studies have only looked at the process, i.e., proportion
of salt sample having adequate amount of iodine with utter
disregard to outcome, thus conducting a biased exercise
with predetermined notion of efficacy and effectiveness of
the intervention (80e83).
Increase in goiter post-iodination has been shown in
some northeastern states of India (84e87). However, none
of these studied possible reasons for this high prevalence
despite IDD control program. Was it failure of the program
or other factors affecting the absorption and utilization of
iodine provided by salt? A high prevalence was found
among adolescents in slums of a coastal city despite iodin-
ation of salt. Another important finding was that difference
in urinary iodine excretion levels was statistically nonsig-
nificant among various grades of goiter (88,89). Thus, rais-
ing the issue whether this high prevalence is due to excess
iodine as shown by studies from China (31,32) or some
goitrogens in water/diet are behind this high prevalence?
In another coastal area, where no survey was done ear-
lier or there was a ban on noniodized salt, survey preva-
lence included children of 6e11 years of age, whereas
the same researchers had been studying children of only
8e10 years of age for evaluation surveys in other areas.
Without any explanation being given for this differential
methodological choice, one is left wondering whether a de-
liberate effort is being made towards some unstated objec-
tive. Even then, TGP was only 2.6%, which clearly pointed
to the fact of non-existence of goiter even in the absence of
iodized salt. In fact, no further attempt was evident from
discussion to evaluate any reasons for this low prevalence
of goiter (90). A similar study in Andaman and Nicobar is-
lands (Bay of Bengal) found TGP of 16.5% despite 93%
salt samples having O15 ppm of iodine (91). The tribal
population of these islands was found to consume a great
amount of seafood, which is rich in iodine. However,
iodized salt was introduced to this island, which most
probably resulted in iodine excess goiter.
Iodine is a volatile substance and how much iodine in
salt is lost during cooking? In India, substantial losses of io-
dine during cooking have been shown (92). Countries like
the U.S. introduced iodine only in table salt (added to
cooked food) but as per the current Indian policy, iodine
is added to all types of salt, thus wasting a lot of iodine
due to the addition of salt prior to cooking. It has been
shown that iodine content of raw food was significantly
higher than that of a mixed cooked diet due to appreciable
iodine losses during cooking (range 37.4e69.7% loss) (93).
However, iodine losses during cooking have not been
adequately studied.
 A Systematic Review of Goiter and Other Iodine Deficiency Disorders
Low levels of TGP were found 7 years after the Delhi
government banned sale of non-iodized salt despite 41%
of families consuming salt with !15 ppm (94). However,
only 8- to 10-year-old children were studied instead of all
children. This kind of variance makes comparison difficult
with other studies that included children 5e15 years of age.
Moreover, during prevalence surveys that formed the basis
of USI, all children (especially 5e15 years old) were stud-
ied, including adolescents with a high probability of having
a physiological goiter, but in evaluation surveys the major-
ity of studies include only children between 8 and 10 years
of age! Other studies regarding evaluation are depicted in
Table 3 (84e86,90,91,95e100).
In a well-designed multicentric study to assess iodine-
deficiency disorders, children (6e!12 years old) from 15
districts of ten states in India were studied during
1997e2000. What the results show is really quite disturb-
ing. The prevalence of goiter in one of the districts of UP
was maximum (31.02%), though median urinary iodine ex-
cretion (UIE) value was sufficient (127 mg/L), and O82%
salt samples had adequate iodine content. The next in order
of prevalence of goiter (12.95%) was another district with
adequate median UIE value (115 mg/L) but adequate iodine
content in only 4.7% of the salt samples. A district in Bihar,
with insufficient median UIE value of 90 mg/L and only
2.9% of the salt samples having adequate iodine content,
showed prevalence of only 0.2% goiter. The investigators
just cursorily mentioned this lack of correlation between
the three parameters of iodine deficiency at the end of their
paper, without giving it due importance (101). In fact, the
findings clearly call for a revisit of the entire debate of
iodine-deficiency disorders—magnitude of the problem,
causality and control strategy. A similar lack of correlation
between adequate iodine nutrition and TGP has also been
shown by WHO in many countries worldwide, to mention
a few: Bangladesh (49.9%) and Australia (19.4%) with dif-
ferent TGPs but classified as having mild iodine deficiency,
and Eritrea (36.7%) and India (17.9) both shown as having
optimal iodine nutrition (8).
Similar results of ineffectiveness of iodized salt in the
reduction of goiter were available since 1980, raising the
hypothesis that after a certain level the prevalence of goiter
does not decrease by iodination alone due to the role of
other factors such as goitrogens in food, pollutants in water,
etc. Definite identification of the active agents and knowl-
edge of their biological and physicochemical properties
may permit public health officials to develop procedures
for eliminating these compounds at the community level
and eradicating goiter from endemic areas (102).
Harmful Effects of Iodine
Studies are available on the possible link of increased iodine
intake leading to increased hypothyroidism/hyperthyroid-
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11
ism. Many researchers have commented on toxicity of
iodine but other harmful effects, e.g., hypothyroidism, auto-
immune thyroiditis, etc. at smaller dosage have not been
studied adequately. None of the researchers have studied this
problem, especially among the higher socioeconomic group,
and what level of iodine is optimal to avoid the conse-
quences of iodine deficiency while preventing side effects.
Studies in China showed that goiter might be caused by
excess iodine intake. All subjects were clinically euthyroid
but biochemical tests suggested a spectrum of thyroid dys-
function from subclinical to overt hypothyroidism (31).
Studies showing similar results have been done in Japan
(103) and China (32,104,105). In one of these commu-
nity-based surveys in China (32) among people from all
ages in two villages, it was found that goiter due to iodine
excess affected all ages in different geographical locations.
These findings strengthen the association between iodine
excess and goiter and hypothyroidism probably due to some
autoimmune mechanism and have also been corroborated
by pioneers of research in goiter and IDDs (106).
Studies done in a few countries to analyze the current sta-
tus of morphological and functional thyroid abnormalities in
a previously iodine-deficient area have shown a number of
thyroid disorders in previously iodine-deficient regions. This
clearly points to the need for further studies to investigate the
change of thyroid disorders during iodine supplementation
programs. A study in Laos to assess the impact of salt iodin-
ation program found a higher median value of urinary iodine
but almost similar goiter prevalence after introduction of io-
dized salt as compared to an earlier period (107). A review of
IDD found that in areas with relatively high iodine intake, the
incidence rate of hypothyroidism is several fold higher than
that of hyperthyroidism (108). Even experimental studies
show that iodine appeared to have a direct toxic effect on thy-
roid epithelial cells of rats by showing that a high intake of
iodine accelerated the development of lymphocytic thyroid-
itis in BB/W rats (109,110).
Conclusions and Future Perspectives
Evidence from this scientific, systematic review of empiri-
cal studies provides enough basis to question the current
dominant paradigm and reveals that opposing research find-
ings were ignored. The studies available provide enough
evidence to start a fresh debate on evidence about iodine
as the sole factor in causality; magnitude of the problem
as a major public health problem universally; effectiveness
of universal iodization of salt as a measure that leads to
decreasing goiter and other IDDs by itself; and possible
negative impacts on health itself like increase in hyperthy-
roidism, goiter and interaction with other minerals like iron.
The problem of IDDs has increased in many parts of the
world (refer to Table1), and the use of iodization as a strategy
can at best claim to prevent further increase than present
prevalence. This review shows that wherever endemic IDD
12 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14
does exist it is a problem with socioeconomic, developmental
and ecological causes. Rarely has it been tackled successfully
through iodine supplementation alone. Iodine deficiency of
soil is related to flooding, deforestation and soil degradation.
Changes in dietary patterns could be significant factors.
Changing exposure to bacterial flora could be another issue.
Lack of food exchanges is also important in the causation of
endemic goiter. These factors could be interacting at different
levels in various regions and so local factors of significance
need to be identified. A program to combat iodine deficiency
should essentially tackle these issues for a long-term and sus-
tainable solution rather than looking at a single intervention
of iodized salt alone. Development and ecology thus should
be the key areas of focus to reduce IDD. The problem of goi-
trogens in food, water and synthetic chemicals and the role of
polluted water need to be understood and taken care of rather
than just pushing iodized salt as a panacea for the prevention
and control of IDD. The ethics of public health demands that
the possible negative consequences of interfering with iron
metabolism and thereby enhancing anemia and the increase
in goiter due to excess iodine need to be investigated under
diverse conditions before a program for universal iodization
of salt can be initiated.
We propose use of iodized salt in populations where io-
dine deficiency is convincingly found to be a major public
health problem after other causes have been ruled out, and
leaving people the choice in other regions. The proponents
of USI say a ban in just the severely affected regions has
proved unsuccessful without analyzing the reasons for this
failure. There are optional approaches available to deal with
the problem in highly affected areas. Participatory commu-
nity programs of iodization of salt or water at a local level
is one that has been tried successfully in countries such as
Thailand. Supplying subsidized iodized salt in these areas
so that it is cheaper than non-iodized salt is another option,
which directly addresses the problem without adding the
negative health consequences of the intervention and adher-
ing to the concept of ‘primum non nocere’.
Acknowledgments
The authors are extremely grateful to Dr. Monica Agrawal and
Ms. Parul for collection of various references from libraries and
organizations spread all over the vast city of New Delhi; Dr. (Lt
Col) Jyoti Kotwal for her patient reading of several drafts of this
review and providing insightful comments.
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