1. Iodine in Pregnancy in the UK Margaret P Rayman Department of Nutritional Sciences University of Surrey UK

2. Iodine Deficiency in the UK - Historical  Iodine deficiency used to be widespread in Britain with high rates of goitre and even of cretinism in some areas  Goitre was still present in many areas until the 1960s e.g. Sheffield & S.Wales Areas of endemic goitre in the past Phillips D 1997; Lee S et al. 1994 Derbyshire neck

3.  Iodine supplementation of livestock to improve reproductive performance and lactation was begun in the 1930s.  Iodophor disinfectants were used for teat dipping and cleaning of dairy equipment.  Milk became an excellent iodine source. Phillips D 1997; Wenlock et al. 1982 How did iodine deficiency disappear in the UK?  Milk consumption increased owing to free school milk and advertising by the Milk Marketing Board.  A three-fold increase in iodine intake occurred between the 1950s and the 1980s.

4. The Current UK Iodine Situation

5. Recent Studies of UK Iodine Status 1. Vanderpump 2011; 2. Lampropoulou et al 2012; 3. Bath et al. 2014; 4.Barnett et al. 2002; 5.Kibirige et al. 2004; 6. Pearce et al 2010; 7. Bath et al. 2013; 8. Bath et al. 2014; 9. Bath et al. 2015. Recent UK studies have shown deficiency in: Women of childbearing age 1-3 Pregnant women 4-9

6. Measurement Adult women Pregnant women Iodine intake (WHO) 1 150 µg/d250 µg/d Urinary iodine concentration (UIC) 2 100 µg/L150 µg/L Urinary iodine:creatinine ratio*110 µg/g183 µg/g 1.WHO et al. 1996; 2. WHO et al. 2007; 3. Knudsen et al. 2000 Minimal Iodine Requirements for Adult & Pregnant Women by Different Measurement Criteria *based on excretion of 1.23 g creatinine/24 hr in women of childbearing age 3

7. First national survey since the 1940s Urinary iodine concentration measured in 737 adolescent girls aged 14-15 years Nine centres across the UK Median urinary iodine concentration 80.1 µg/L Iodine excretion indicated mild deficiency in the cohort This raised concern that iodine deficiency may be widespread in the UK Iodine status of UK schoolgirls* *Vanderpump et al. Lancet 2011

8. Iodine Intake of Surrey Women of Childbearing Age Bath, Sleeth, McKenna, Walter, Taylor, Rayman. Br J Nutr. 2014 Nov 28;112(10):1715-23. Requirement for pregnancy/lactation (77% do not meet) * WHO adult requirement (40% do not meet) * Subject took I 2 -containing supplement *WHO (2007) A substantial proportion of UK women may be entering pregnancy with low iodine stores Iodine intake extrapolated from 24 h urinary excretion (µg/d) Median intake 167  g/d

9. Studies of Iodine in Pregnancy in the UK 1. Barnett et al. 2002; 2. Kibirige MS et al. 2004; 3. Pearce et al 2010 Avon (n=1023): UIC 91 μg/L Iodine/creatinine 110 μg/g Cardiff (n=480) 3 : UIC 117 μg/L Middlesborough (n=227) 2 : 40% had UIC below 100 μg/L Tayside (n=433) 1 : UIC 137 μg/L 40% had intake < ½ recommended Oxford 2009-2011 (n=229): UIC 56 μg/L Iodine/creatinine 116 μg/g Surrey 2009 (n=229): UIC 85 μg/L Iodine/creatinine 123 μg/g

10. Longitudinal study in 1991-1992 in “Avon” area of UK Total of 14,541 pregnant women enrolled Urine samples collected and stored Urinary iodine and creatinine measured in spot-urine samples ALSPAC (Avon Longitudinal Study of Parents & Children)

11. Iodine status of ALSPAC pregnant women 1 The women were classified as mildly-to-moderately iodine deficient 1,2 Median urinary iodine concentration = 91.1 µg/L Median iodine:creatinine ratio = 110 µg/g creatinine None of the women reported taking iodine-containing supplements or seaweed during pregnancy. However, these are data from 1991-1992. 1. Bath et al. Lancet. 2013; 382(9889):331-7; 2. WHO et al. 2007 Adequate range for population median iodine concentration in pregnancy 2 Urinary iodine concentration (μg/L) Urinary iodine-to- creatinine ratio (μg/g) Adequate iodine- to-creatinine ratio

12. 100 pregnant women recruited at 12 weeks of gestation Recruited July-September 2009 (i.e. summer) Spot-urine sample provided for measurement of iodine & creatinine Questionnaires completed – including whether or not an iodine- containing supplement was used Iodine status of Surrey pregnant women

13. Iodine status of Surrey pregnant women 1 Median urinary iodine concentration (UIC) was 85.3 µg/L and iodine:creatinine was 122 µg/g classifying the group as mildly-to- moderately iodine deficient 2 Supplement users had significantly better iodine status, p=0.001 1. Bath et al. Br J Nutr. 2014; 111:1622-31. 2. WHO et al. 2007 Adequate range for population median iodine concentration in pregnancy 2 Urinary iodine concentration (μg/L) Urinary iodine-to- creatinine ratio (μg/g) Adequate iodine- to-creatinine ratio

14. Iodine status of Oxford pregnant women 1 230 primiparous UK women recruited from 2009-2011 at 12 weeks gestation in the ultra-sound clinic at the John Radcliffe Hospital, Oxford, to the Selenium in Pregnancy Intervention Trial (SPRINT) Blood and urine samples were taken at 12, 20 and 35 weeks Spot urinary iodine and creatinine were measured and thyroid parameters, including thyroglobulin (Tg) and thyroid antibodies were measured in serum The intervention with selenium had no effect on iodine status Only 3% of women took supplements containing iodine Bath et al. AJCN 2015; 101:1180-7

15. Adequate range for population median urinary iodine concentration in pregnancy 2 Overall median UIC of 56.8 μg/L and iodine:creatinine ratio of 116 μg/g classified the group as mildly-to-moderately iodine deficient throughout gestation 1,2 The large difference between UIC and iodine:creatinine is because women are told to have full bladders for the ultrasound scan so the urine is quite dilute UIC and iodine:creatinine ratio increased with advancing gestation Iodine status of Oxford pregnant women 1 1. Bath et al. AJCN 2015; 101:1180-7; 2. WHO et al. 2007 Urinary iodine concentration (μg/L) Urinary iodine-to- creatinine ratio (μg/g) Adequate iodine- to-creatinine ratio

16. P=0.006 P=0.001 P=0.03 UIC:Cr Serum Tg in Oxford Pregnant Women Bath et al (submitted, JCEM) Serum Tg measured in SPRINT women at 12, 20 and 35 weeks Tg and TPO antibodies also measured and women with Tg-Ab > 115 U/ml and/or TPO-Ab > 35 U/ml were excluded Tg was significantly different by category of UIC:Cr in all trimesters Tg < 13 µg/L adequate in pregnancy? (Ma & Skeaff, 2014) Data are unadjusted & cross-sectional

17. Serum Tg in Oxford Pregnant Women Bath et al (submitted, JCEM) a: significantly higher than 150- 249 (p<0·001) and ≥250 μg/g group (p<0·001) b: significantly higher (p=0·005) than 150-249 and ≥250 μg/g group (p=0·002) Results were computed by back transformation of estimated marginal means from a linear mixed model (on log- transformed data), controlling for the effects of gestational week, season (winter/summer), BMI (<25 vs. ≥25 kg/m 2 ), smoking status (never vs. ex- smoker), ethnicity (Caucasian vs. other) and maternal age. Adjusted geometric mean Tg concentration by iodine status Low iodine status in pregnancy is associated with higher serum Tg, suggesting that iodine deficiency increases thyroid volume. Tg shows promise as a functional marker of iodine deficiency in a mildly-to- moderately iodine-deficient pregnant population. p <0.005 p <0.001

18. Serum TSH in Oxford Pregnant Women Bath et al (submitted, JCEM) Results were computed by back transformation of estimated marginal means from a linear mixed model (on log- transformed data), controlling for the effects of gestational week, season (winter/summer), BMI (<25 vs. ≥25 kg/m 2 ), smoking status (never vs. ex- smoker), ethnicity (Caucasian vs. other) and maternal age. Adjusted geometric mean TSH concentration by iodine status By contrast, there was no difference in TSH concentration between the four iodine-status groups (p=0·25) Clearly Tg is a more sensitive biomarker of iodine status in pregnancy than is TSH.

19. Graph based on Linear Mixed Models with an interaction term between gestational week and the iodine group variable. The interaction was significant (P=0.012). Iodine:creatinine < 150 µg/g Iodine:creatinine ≥ 150 µg/g Change in thyroglobulin (Tg) with gestational age according to iodine status (deficient/sufficient) Bath et al (unpublished data)

20. What are the implications of the current mild-to-moderate level of iodine deficiency in UK pregnant women and the borderline deficiency in women of childbearing age?

21. Urinary iodine concentration (μg/L) Urinary iodine-to- creatinine ratio (μg/g) Adequate iodine- to-creatinine ratio Adequate range for population median urinary iodine concentration in pregnancy 2 The level of deficiency recently seen in UK Surrey and Oxford pregnant women is similar to that in the UK ALSPAC cohort (Avon/Bristol) which was associated with poorer brain development in their children as shown by: significantly lower verbal IQ at age 8* significantly lower reading accuracy and comprehension at age 9* *Bath et al. Lancet 2013; 382(9889): 331-7

22. Verbal IQ (p=0.002) Total IQ (p=0.04) Reading comprehension (p=0.04) Effect of Degree of Iodine Deficiency in ALSPAC Verbal IQ Total IQ Reading accuracy Reading comprehension Maternal iodine-to-creatinine ratio (µg/g) in the first trimester Deficient category was subdivided into mildly-to-moderately deficient (50-150 µg/g) and severely deficient (<50 µg/g) categories Bath et al. Lancet 2013; 382(9889): 331-7

23. As iodine status in early gestation is very important for fetal brain development UK women planning pregnancy and, ideally, all UK women of childbearing age should be made aware of the need for sufficient iodine intake so they enter pregnancy with adequate iodine stores Supplementing once pregnancy is confirmed may be less effective or may even have adverse consequences 1,2 Murcia et al. 2011; Rebagliato et al. 2013

24. What We Really Need An RCT of iodine in pregnancy is needed in a country like the UK where there is: mild-to-moderate iodine deficiency no programme of salt iodisation This is important because there are some indications of adverse effects on: psychomotor development index 1,2 TSH 3,4 FT4 4 when supplementation at  150 µg/d is started in pregnancy. The trial needs to start at as early in gestation as possible as having an adequate iodine intake in the first trimester is crucial. 1.Murcia et al. 2011; 2. Rabagliato et al. 2013; 3. Moleti et al. 2011; 4. Rabagliato et al. 2010

25. Acknowledgements Collaborators ALSPAC Executive Prof Jean Golding Colin Steer Dr Pauline Emmett Dr John Wright Prof Victor Pop Analysts Dr Christine Sieniawska Dr Andrew Taylor Alan Walter Dr Maarten Broeren Colleague Dr Sarah Bath