Clinical Endocrinology (1976) 5, 159-166.
MATERNAL THYROID FUNCTION, IODINE DEFICIENCY A N D FETAL DEVELOPMENT P . 0. D. P H A R O A H , S H E I L A M . E L L I S , R O G E R P . E K I N S AND E D W A R D S. WILLIAMS Department of Public Health, Papua New Guinea, and Institute of Nuclear Medicine, Middlesex Hospital, London (Accepted for publication 9 September 1975)
SUMMARY
In an area of New Guinea where there is dietary iodine deficiency, measurements of thyroid function have been made on women of child-bearing age, several of whom were pregnant at the time. The outcome of these pregnancies, and also of those occurring in the four preceding years, were examined in relation to indices of thyroid function. More stillbirths, infant deaths and endemic cretins occurred among the offspring of women who showed biochemical evidence of iodine deficiency, without clinical evidence of hypothyroidism. This situation differs from that of untreated myxoedema or congenital hypothyroidism in women, which is usually associated with altered menstrual function, infertility or repeated abortion. Mechanisms that may account for these differences and the possible implications are discussed. The syndrome of endemic cretinism prevails in areas where dietary iodine deficiency and endemic goitre are found (Querido, 1971;Trotter, 1960; McCarrison, 1908). In New Guinea the salient features are deaf-mutism, mental deficiency, cerebral diplegia and strabismus. These abnormalities may exist in the same patient, though deafness, mutism and mental retardation may be observed in the absence of conspicuous neurological signs. Clinical hypothyroidism is not evident (Pharoah, 1972). Previous authors have noted that endemic cretinism is congenital (Eggenberger & Messerli, 1938; McCullagh, 1963). The prenatal origin of the syndrome was confirmed when a clinical trial of intramuscular iodized oil demonstrated that prevention was successful only if iodine was given before conception (Pharoah et al., 1971). Circumstantial evidence on the importance of iodine was also obtained when it was observed that the withdrawal of a rich source of dietary iodine precipitated a local epidemic of the disease (Pharoah & Hornabrook, 1974). Iodine deficiency, thus, is strongly implicated in the pathogenesis of the syndrome, and it exerts its effect before birth or even, possibly, before conception. Functionally, iodine is important because of its role in the synthesis of thyroid hormones Correspondence: Dr Peter 0.D. Pharoah, Department of Community Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WClE 7HT.
159
160
P . 0. D. Pharoah et al.
and it has been postulated that hypothyroidism, either maternal or fetal, as a consequence of iodine deficiency is important in the pathogenesis of endemic cretinism (Stanbury, 1970; Konig, 1969). This paper records maternal thyroid function when iodine deficiency exists and relates it to the outcome of pregnancy. METHODS The Jimi river valley is an isolated area in the highlands of New Guinea. A census of the area was carried out during August and September 1966. Subsequently numerous patrols were made and on each occasion the census records up-dated. Any woman who was pregnant was noted, and all infants born since 1966 were identified and their birth dates obtained from mission and official records. In 1970 and 1971, during visits to eight villages, blood samples were taken from 106 women aged 20-50 years. At the time of sampling, sixty-six of the 106 women were pregnant. The records of all the women were examined for the four years that preceded sampling and the outcome of any pregnancy during this period was noted. Stillbirths were included with infant deaths as the history often did not distinguish between them. Further visits to the villages were made on two occasions in 1972 and once in 1974. On each visit, the surviving children of the 106 women were examined for evidence of motor retardation ; this was diagnosed if the milestones of sitting unsupported and walking unaided had not been achieved by 12 and 24 months respectively. The parents were questioned about the child’s hearing and speech; formal assessment of deafness was attempted by noting any response of the child to a tuning fork, or, if this was negative, to a handclap. Strabismus, if present, was also noted. The clinical diagnosis of endemic cretinism was accepted if the child was a deaf-mute, or if motor retardation was present in addition to deafness and/or strabismus. Serum was frozen as soon as possible after collection and within 36 h in all cases. It was maintained frozen until laboratory analysis was performed. In order to allow for possible discrepancies induced by climatic conditions, control samples of sera were taken and assayed for thyroxine in London and sent to New Guinea where they were subjected to the same environmental conditions as the test sera. Repeat thyroxine assay in London showed no significant changes from the original values. Serum total thyroxine (TT4) was measured by the method of Ekins et al. (1969), normal range 45-1 15 ng/ml. Serum total triiodothyronine (TT3) was measured by the radioimmunoassay method of Brown et al. (1971), normal range 850-1760 pg/ml. Serum thyroid stimulating hormone (TSH) was measured by a modification of the double antibody technique (Ode11 et al., 1965; Utiger, 1965) using NPS anti-HTSH antiserum and the MRC A standard TSH preparation. The normal serum TSH concentration is < 5.0 ,uu/ml. Serum free thyroxine (FT4), and free triiodothyronine (FT3) were directly measured by radioimmunoassay in serum dialysates (Ellis & Ekins, 1974). Normal ranges are 20-40 pg/ml and 4-8 pg/ml respectively. RESULTS Serum samples were taken in 1970 and 1971 from 106 women, sixty-six of whom were
161
Maternal thyroid function and the fetus
pregnant at the time. In the period under review (1966-71), 149 children were born; sixtyfour women gave birth to one child, forty-one had two and one had three. There was one set of twins. The period of follow-up of those infants born to women pregnant at the time of sampling is limited. Although forty-four (83%) of the fifty-three survivors were examined during their first year of life, only seven (13%) have been seen after their second birthday. Seven (13%) have never been clinically examined; that they are still living has been ascertained from mission records and, for analysis, they have been classified as normal. Follow-up is longer for those who were born before the maternal blood samples were taken. The survivors, of whom there are sixty-seven, have been clinically examined at least once. Fifty-four (81%) of them have been examined since their second birthday and fortyone (61%) since their third birthday. There are 147 children for whom the mothers’ TT4 is known. The normal range for TT4 being 45-115 ng/ml, a ‘very low’ level has been arbitarily defined with an upper limit of 25 ng/ml. The outcome of pregnancy among these two categories of maternal TT4, i.e. ‘very low’ and ‘others’, is shown in Table 1. TABLE1. Maternal total thyroxine (TT4) and outcome of pregnancy Maternal TT4 (normal range 45-115 ng/ml) Sample taken
Normal During pregnancy Less than 2 years after birth of child 2-4 years after birth of child Total
Others (over 25 ng/ml)
Very low (less than 25 ng/ml) Cretins Deaths Total
Normal
Cretins Deaths Total
4
0
4
8
48
1
9
58
5
3
2
10
14
1
7
22
1 10
3 6
3 9
7 25
32 94
6 8
4 20
42 122
The offspring of those mothers with a ‘very low’ TT4 during the pregnancy had a high mortality (four out of eight). These numbers are insufficient to attain statistical significance when comparison is made with the group of maternal TT4 over 25 ng/ml (nine out of fifty-eight). However, within the ‘very low’ group, the mothers of the four survivors had TT4 levels in the range 13-25 ng/ml but, for the four that died, the values of maternal TT4 were all less than 13 ng/ml. The inclusion of infants born up to 4 years before sampling confirmed the high pregnancy wastage if maternal TT4 was ‘very low’, and there was a greater proportion of cretins among the survivors. In all, there were twenty-five infants born in the ‘very low’ group, nine died and six were cretins. The mortality is significantly higher when maternal TT4 is ‘very low’ ( x : ~= ~5-03, P0.01). The proportion of cretins among the survivors is also greater though the difference is not statistically significant (x& = 1-98). TABLE2. Maternal free thyroxine (FT4) and outcome of pregnancy Maternal FT4 (normal range 20-40 pg/ml) Sample taken
During pregnancy Less than 2 years after birth of child 2-4 years after birth of child Total
Very low (less than 10 pg/ml) Normal Cretins Deaths Total
Others (over 10 pg/ml) Normal
Cretins Deaths Total
6
0
4
10
30
1
5
36
4
3
3
10
4
0
1
5
3 13
2
2 9
7 27
20 54
7 8
2 8
29 70
5
Previous investigators have found that, when iodine deficiency is present, the serum T3 remains at normal levels or may be raised while T4 falls (Pharoah et al., 1973; Delange et al., 1972; Greer et al., 1968; Chopra et al., 1975). Thus euthyroidism is maintained in the presence of a reduced iodine supply because T3 contains less iodine weight for weight and is metabolically more active than T4. It is only when iodine deficiency is extreme that the T3 level also falls and low levels of T3 (total or free) are infrequently observed. The women have been grouped into those with normal T3 and those whose T3 is below normal. The total T3 comprises free and bound moieties and is subject to the same changes in pregnancy as occur with total T4. Table 3 relates the outcome of pregnancy to maternal TABLE3. Maternal total tri-iodothyronine (TT3) and outcome of pregnancy Maternal TT3 (normal range 850-1760 pg/ml) Sample taken
Below normal (less than 850 pg/ml) Normal
During pregnancy Less than 2 years after birth of child 2 4 years after birth of child Total
Cretins Deaths Total
Normal (over 850 pg/ml) Normal
Cretins Deaths Total
2
0
4
6
33
1
5
39
1
0
1
2
17
4
4
25
2
0
0 5
8 13
5
0
2 10
26
5
14
39 103
76
Maternal thyroid function and the fetus
163
TABLE4. Maternal free tri-iodothyronine (FT3) and outcome of pregnancy Maternal free T3 (normal range 4-8 pg/ml) Sample taken
Below normal (less than 4 pg/ml) Normal
During pregnancy Less than 2 years after birth of child 2-4 years after birth of child Total
Cretins Deaths Total
Normal (over 4 pg/ml) Normal
Cretins Deaths Total
1
0
3
4
36
1
6
43
0
0
0
0
9
3
4
16
1
1 1
0 3
2
23
6
4
33
6
68
10
14
92
2
TT3 and Table 4 to maternal FT3. The numbers in the below normal group in both Tables are too small for valid statistical analysis; nevertheless, pregnancy wastage appears to be high when maternal T3 is reduced. The feedback mechanism that exists between the thyroid and pituitary glands is characterized by an elevation in the level of the thyroid-stimulating hormone from the pituitary when the thyroid hormones are themselves reduced. As might be expected from this inverse relationship, an elevated maternal TSH is accompanied by a high mortality among the offspring (Table 5). If maternal TSH is grouped into 0-4-9, 5-9.9, 10-49.9 and 50+ pu/ml, mortality within these groups is linearly related to the level of TSH (&, for linear trend = 7.94, P
MATERNAL THYROID FUNCTION, IODINE DEFICIENCY A N D FETAL DEVELOPMENT P . 0. D. P H A R O A H , S H E I L A M . E L L I S , R O G E R P . E K I N S AND E D W A R D S. WILLIAMS Department of Public Health, Papua New Guinea, and Institute of Nuclear Medicine, Middlesex Hospital, London (Accepted for publication 9 September 1975)
SUMMARY
In an area of New Guinea where there is dietary iodine deficiency, measurements of thyroid function have been made on women of child-bearing age, several of whom were pregnant at the time. The outcome of these pregnancies, and also of those occurring in the four preceding years, were examined in relation to indices of thyroid function. More stillbirths, infant deaths and endemic cretins occurred among the offspring of women who showed biochemical evidence of iodine deficiency, without clinical evidence of hypothyroidism. This situation differs from that of untreated myxoedema or congenital hypothyroidism in women, which is usually associated with altered menstrual function, infertility or repeated abortion. Mechanisms that may account for these differences and the possible implications are discussed. The syndrome of endemic cretinism prevails in areas where dietary iodine deficiency and endemic goitre are found (Querido, 1971;Trotter, 1960; McCarrison, 1908). In New Guinea the salient features are deaf-mutism, mental deficiency, cerebral diplegia and strabismus. These abnormalities may exist in the same patient, though deafness, mutism and mental retardation may be observed in the absence of conspicuous neurological signs. Clinical hypothyroidism is not evident (Pharoah, 1972). Previous authors have noted that endemic cretinism is congenital (Eggenberger & Messerli, 1938; McCullagh, 1963). The prenatal origin of the syndrome was confirmed when a clinical trial of intramuscular iodized oil demonstrated that prevention was successful only if iodine was given before conception (Pharoah et al., 1971). Circumstantial evidence on the importance of iodine was also obtained when it was observed that the withdrawal of a rich source of dietary iodine precipitated a local epidemic of the disease (Pharoah & Hornabrook, 1974). Iodine deficiency, thus, is strongly implicated in the pathogenesis of the syndrome, and it exerts its effect before birth or even, possibly, before conception. Functionally, iodine is important because of its role in the synthesis of thyroid hormones Correspondence: Dr Peter 0.D. Pharoah, Department of Community Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WClE 7HT.
159
160
P . 0. D. Pharoah et al.
and it has been postulated that hypothyroidism, either maternal or fetal, as a consequence of iodine deficiency is important in the pathogenesis of endemic cretinism (Stanbury, 1970; Konig, 1969). This paper records maternal thyroid function when iodine deficiency exists and relates it to the outcome of pregnancy. METHODS The Jimi river valley is an isolated area in the highlands of New Guinea. A census of the area was carried out during August and September 1966. Subsequently numerous patrols were made and on each occasion the census records up-dated. Any woman who was pregnant was noted, and all infants born since 1966 were identified and their birth dates obtained from mission and official records. In 1970 and 1971, during visits to eight villages, blood samples were taken from 106 women aged 20-50 years. At the time of sampling, sixty-six of the 106 women were pregnant. The records of all the women were examined for the four years that preceded sampling and the outcome of any pregnancy during this period was noted. Stillbirths were included with infant deaths as the history often did not distinguish between them. Further visits to the villages were made on two occasions in 1972 and once in 1974. On each visit, the surviving children of the 106 women were examined for evidence of motor retardation ; this was diagnosed if the milestones of sitting unsupported and walking unaided had not been achieved by 12 and 24 months respectively. The parents were questioned about the child’s hearing and speech; formal assessment of deafness was attempted by noting any response of the child to a tuning fork, or, if this was negative, to a handclap. Strabismus, if present, was also noted. The clinical diagnosis of endemic cretinism was accepted if the child was a deaf-mute, or if motor retardation was present in addition to deafness and/or strabismus. Serum was frozen as soon as possible after collection and within 36 h in all cases. It was maintained frozen until laboratory analysis was performed. In order to allow for possible discrepancies induced by climatic conditions, control samples of sera were taken and assayed for thyroxine in London and sent to New Guinea where they were subjected to the same environmental conditions as the test sera. Repeat thyroxine assay in London showed no significant changes from the original values. Serum total thyroxine (TT4) was measured by the method of Ekins et al. (1969), normal range 45-1 15 ng/ml. Serum total triiodothyronine (TT3) was measured by the radioimmunoassay method of Brown et al. (1971), normal range 850-1760 pg/ml. Serum thyroid stimulating hormone (TSH) was measured by a modification of the double antibody technique (Ode11 et al., 1965; Utiger, 1965) using NPS anti-HTSH antiserum and the MRC A standard TSH preparation. The normal serum TSH concentration is < 5.0 ,uu/ml. Serum free thyroxine (FT4), and free triiodothyronine (FT3) were directly measured by radioimmunoassay in serum dialysates (Ellis & Ekins, 1974). Normal ranges are 20-40 pg/ml and 4-8 pg/ml respectively. RESULTS Serum samples were taken in 1970 and 1971 from 106 women, sixty-six of whom were
161
Maternal thyroid function and the fetus
pregnant at the time. In the period under review (1966-71), 149 children were born; sixtyfour women gave birth to one child, forty-one had two and one had three. There was one set of twins. The period of follow-up of those infants born to women pregnant at the time of sampling is limited. Although forty-four (83%) of the fifty-three survivors were examined during their first year of life, only seven (13%) have been seen after their second birthday. Seven (13%) have never been clinically examined; that they are still living has been ascertained from mission records and, for analysis, they have been classified as normal. Follow-up is longer for those who were born before the maternal blood samples were taken. The survivors, of whom there are sixty-seven, have been clinically examined at least once. Fifty-four (81%) of them have been examined since their second birthday and fortyone (61%) since their third birthday. There are 147 children for whom the mothers’ TT4 is known. The normal range for TT4 being 45-115 ng/ml, a ‘very low’ level has been arbitarily defined with an upper limit of 25 ng/ml. The outcome of pregnancy among these two categories of maternal TT4, i.e. ‘very low’ and ‘others’, is shown in Table 1. TABLE1. Maternal total thyroxine (TT4) and outcome of pregnancy Maternal TT4 (normal range 45-115 ng/ml) Sample taken
Normal During pregnancy Less than 2 years after birth of child 2-4 years after birth of child Total
Others (over 25 ng/ml)
Very low (less than 25 ng/ml) Cretins Deaths Total
Normal
Cretins Deaths Total
4
0
4
8
48
1
9
58
5
3
2
10
14
1
7
22
1 10
3 6
3 9
7 25
32 94
6 8
4 20
42 122
The offspring of those mothers with a ‘very low’ TT4 during the pregnancy had a high mortality (four out of eight). These numbers are insufficient to attain statistical significance when comparison is made with the group of maternal TT4 over 25 ng/ml (nine out of fifty-eight). However, within the ‘very low’ group, the mothers of the four survivors had TT4 levels in the range 13-25 ng/ml but, for the four that died, the values of maternal TT4 were all less than 13 ng/ml. The inclusion of infants born up to 4 years before sampling confirmed the high pregnancy wastage if maternal TT4 was ‘very low’, and there was a greater proportion of cretins among the survivors. In all, there were twenty-five infants born in the ‘very low’ group, nine died and six were cretins. The mortality is significantly higher when maternal TT4 is ‘very low’ ( x : ~= ~5-03, P0.01). The proportion of cretins among the survivors is also greater though the difference is not statistically significant (x& = 1-98). TABLE2. Maternal free thyroxine (FT4) and outcome of pregnancy Maternal FT4 (normal range 20-40 pg/ml) Sample taken
During pregnancy Less than 2 years after birth of child 2-4 years after birth of child Total
Very low (less than 10 pg/ml) Normal Cretins Deaths Total
Others (over 10 pg/ml) Normal
Cretins Deaths Total
6
0
4
10
30
1
5
36
4
3
3
10
4
0
1
5
3 13
2
2 9
7 27
20 54
7 8
2 8
29 70
5
Previous investigators have found that, when iodine deficiency is present, the serum T3 remains at normal levels or may be raised while T4 falls (Pharoah et al., 1973; Delange et al., 1972; Greer et al., 1968; Chopra et al., 1975). Thus euthyroidism is maintained in the presence of a reduced iodine supply because T3 contains less iodine weight for weight and is metabolically more active than T4. It is only when iodine deficiency is extreme that the T3 level also falls and low levels of T3 (total or free) are infrequently observed. The women have been grouped into those with normal T3 and those whose T3 is below normal. The total T3 comprises free and bound moieties and is subject to the same changes in pregnancy as occur with total T4. Table 3 relates the outcome of pregnancy to maternal TABLE3. Maternal total tri-iodothyronine (TT3) and outcome of pregnancy Maternal TT3 (normal range 850-1760 pg/ml) Sample taken
Below normal (less than 850 pg/ml) Normal
During pregnancy Less than 2 years after birth of child 2 4 years after birth of child Total
Cretins Deaths Total
Normal (over 850 pg/ml) Normal
Cretins Deaths Total
2
0
4
6
33
1
5
39
1
0
1
2
17
4
4
25
2
0
0 5
8 13
5
0
2 10
26
5
14
39 103
76
Maternal thyroid function and the fetus
163
TABLE4. Maternal free tri-iodothyronine (FT3) and outcome of pregnancy Maternal free T3 (normal range 4-8 pg/ml) Sample taken
Below normal (less than 4 pg/ml) Normal
During pregnancy Less than 2 years after birth of child 2-4 years after birth of child Total
Cretins Deaths Total
Normal (over 4 pg/ml) Normal
Cretins Deaths Total
1
0
3
4
36
1
6
43
0
0
0
0
9
3
4
16
1
1 1
0 3
2
23
6
4
33
6
68
10
14
92
2
TT3 and Table 4 to maternal FT3. The numbers in the below normal group in both Tables are too small for valid statistical analysis; nevertheless, pregnancy wastage appears to be high when maternal T3 is reduced. The feedback mechanism that exists between the thyroid and pituitary glands is characterized by an elevation in the level of the thyroid-stimulating hormone from the pituitary when the thyroid hormones are themselves reduced. As might be expected from this inverse relationship, an elevated maternal TSH is accompanied by a high mortality among the offspring (Table 5). If maternal TSH is grouped into 0-4-9, 5-9.9, 10-49.9 and 50+ pu/ml, mortality within these groups is linearly related to the level of TSH (&, for linear trend = 7.94, P
