Iodine in Pregnancy in the UK

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

2. Areas of endemic goitre in the past Derbyshire neck 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 Phillips D 1997; Lee S et al. 1994

3. How did iodine deficiency disappear in the UK? • 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. • 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. Phillips D 1997; Wenlock et al. 1982

4. The Current UK Iodine Situation

5. Recent Studies of UK Iodine Status • Recent UK studies have shown deficiency in: • Women of childbearing age1-3 • Pregnant women4-9 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.

6. Minimal Iodine Requirements for Adult & PregnantWomen by Different Measurement Criteria *based on excretion of 1.23 g creatinine/24 hr in women of childbearing age3 1.WHO et al. 1996; 2. WHO et al. 2007; 3. Knudsen et al. 2000

7. Iodine status of UK schoolgirls* • 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 *Vanderpump et al. Lancet 2011

8. Iodine Intake of Surrey Women of Childbearing AgeBath, 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 I2-containing supplement Median intake 167 g/d Iodine intake extrapolated from 24 h urinary excretion (µg/d) *WHO (2007) • A substantial proportion of UK women may be entering pregnancy with low iodine stores

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

10. ALSPAC(Avon Longitudinal Study of Parents & Children) • 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

11. Iodine status of ALSPAC pregnant women1 Adequate range for population median iodine concentration in pregnancy2 Urinary iodine-to-creatinine ratio (μg/g) Adequate iodine-to-creatinine ratio Urinary iodine concentration (μg/L) • The women were classified as mildly-to-moderately iodine deficient1,2Median 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

12. Iodine status of Surrey pregnant women • 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

13. Iodine status of Surrey pregnant women1 Adequate range for population median iodine concentration in pregnancy2 Urinary iodine-to-creatinine ratio (μg/g) Adequate iodine-to-creatinine ratio Urinary iodine concentration (μg/L) • 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 deficient2 • 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

14. Iodine status of Oxford pregnant women1 • 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. Iodine status of Oxford pregnant women1 Adequate range for population median urinary iodine concentration in pregnancy2 Urinary iodine-to-creatinine ratio (μg/g) Adequate iodine-to-creatinine ratio Urinary iodine concentration (μg/L) • 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 gestation1,2 • 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 1. Bath et al. AJCN 2015; 101:1180-7; 2. WHO et al. 2007

16. 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 P=0.001 P=0.006 P=0.03 Tg < 13 µg/L adequate in pregnancy? (Ma & Skeaff, 2014) UIC:Cr Data are unadjusted & cross-sectional

17. Serum Tg in Oxford Pregnant Women Bath et al (submitted, JCEM) Adjusted geometric mean Tg concentration by iodine status 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/m2), smoking status (never vs. ex-smoker), ethnicity (Caucasian vs. other) and maternal age. p <0.001 p <0.005 • 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.

18. Serum TSH in Oxford Pregnant Women Bath et al (submitted, JCEM) Adjusted geometric mean TSH concentration by iodine status 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/m2), smoking status (never vs. ex-smoker), ethnicity (Caucasian vs. other) and maternal age. • 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. Change in thyroglobulin (Tg) with gestational age according to iodine status (deficient/sufficient) Iodine:creatinine< 150 µg/g Iodine:creatinine≥ 150 µg/g 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). 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. 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* Adequate range for population median urinary iodine concentration in pregnancy2 Urinary iodine-to-creatinine ratio (μg/g) Adequate iodine-to-creatinine ratio Urinary iodine concentration (μg/L) *Bath et al. Lancet 2013; 382(9889): 331-7

22. Effect of Degree of Iodine Deficiency in ALSPAC Deficient category was subdivided into mildly-to-moderately deficient (50-150 µg/g) and severely deficient (<50 µg/g) categories Total IQ Verbal IQ • Verbal IQ (p=0.002) • Total IQ (p=0.04) • Reading comprehension (p=0.04) Reading accuracy Reading comprehension Maternal iodine-to-creatinine ratio (µg/g) in the first trimester Maternal iodine-to-creatinine ratio (µg/g) in the first trimester 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 consequences1,2 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 index1,2 • TSH3,4 • FT44 • 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 Colleague • Dr Sarah Bath 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