Esther Briganti. Fetal And Maternal Health Beyond the Womb: hot topics in endocrinology and pregnancy. Endocrinologist and Clinician Researcher

Transcription

1 Fetal And Maternal Health Beyond the Womb: hot topics in endocrinology and pregnancy Esther Briganti Endocrinologist and Clinician Researcher Director, Melbourne Endocrine Associates Associate Professor, Monash University, Department of Epidemiology and Preventive Medicine Senior Research Officer, Baker Heart and Diabetes Institute, Clinical Diabetes Services Melbourne Endocrine Associates specialising in diabetes and endocrinology

2 Objectives 1. Overview of Developmental Origins of Health and Disease also known as the Baker Hypothesis 2. Relevance to specific endocrine disorders a. osteoporosis in adulthood b. thyroxine replacement in pregnancy

3 Overview Barker Hypothesis Professor David Barker ( ) - UK clinician and epidemiologist Barker hypothesis originating in 1989 low birth and infant weight have a causal relationship to the origins of hypertension, type 2 diabetes and coronary heart disease in adults events during early development have life-long influences on health outcomes

4 Overview Barker Hypothesis Professor David Barker ( ) - UK clinician and epidemiologist

5 Overview Barker Hypothesis Ethel Margaret Burnside ( ) - midwife Hertfordshire s first chief health visitor and lady inspector of midwives. In 1911, she set up an army of trained nurses to attend women in childbirth and to advise mothers on how to keep their infants healthy after birth. origin of modern time Maternal and Child Health programs

6 Overview Barker Hypothesis Ethel Margaret Burnside ( ) - midwife Barker hypothesis based on records from Hertfordshire between established by E Margaret Burnside and found by David Barker in 1986

7 Overview Barker Hypothesis

8 Development of Barker hypothesis Barker Hypothesis 1. exposure: undernutrition 2. outcome: type 2 diabetes, hypertension, and coronary heart disease Fetal Origin of Adult Disease Developmental Origins of Health and Disease expansion of the hypothesis to INCLUDE: 1. exposure: overnutrition as well as undernutrition 2. outcome: non-metabolic disorders including immunological, mental health and reproductive disorders; renal failure; cancers expansion of the hypothesis to INCLUDE: 1. exposure: chemicals and drugs as well as over and under nutrition 2. outcome: neurodevelopmental, neurobehavioural and learning disabilities

9 Development of Barker hypothesis

10 Development of Barker hypothesis???????

11 Mechanisms adverse influences in early development permanent changes in physiology and development increased risk of disease in adulthood hypothesised mechanisms: 1. programming via exposure to nutritional/chemicals/drugs factors at a critical or sensitive period results in permanent or long term changes in structure or function (i) directly via cellular effects (ii) indirectly via epigenetic modifications adjust the expression patterns of genes in a site and tissue specific manner as an adaptive response to insults 2. traditional (i) genetic predisposition (ii) environmental risk factors

12 Osteoporosis

13 Osteoporosis - background Pathogenesis of osteoporosis is due to lower than normal peak bone mass in childhood and/or greater than normal bone loss in adults

14 Osteoporosis background

15 Osteoporosis - background 1.6 Lumbar spine BMD over adult years peak bone mass menopause aging

16 Osteoporosis - background 1.6 Lumbar spine BMD over adult years earlier lower menopause peak bone mass

17 Osteoporosis - background 1.6 Lumbar spine BMD over a lifetime

18 Osteoporosis - background 1.6 DXA over a lifetime born normal but growth in first 5 years is not normal, but then normalises born low body weight/low bone mass but growth is normal

19 Osteoporosis review of the evidence

20 EVIDENCE BASED MEDICINE systematic reviews of randomised controlled trials randomised controlled trials controlled trials systematic reviews of cohort studies prospective cohort studies retrospective cohort studies cases reports and series personal opinions and ideas

21 Osteoporosis epidemiology bone density lower birth weight and slow growth in first year of life associated with: lower adult bone mass for women and men at years, born in Hertfordshire after adjustment for other predictors of osteoporosis and osteopenia lower birth weight in dizygotic or monozygotic co-twin associated with: lower BMC (and to a lesser degree BMD) at lumbar spine and hip women, 604 monozygotic and 1400 dizygotic twin pairs, 25 to 65 years not independent of adult weight and height height accounted for most of the association of birth weight with BMC Cooper C, Growth in infancy and bone mass in later life. Ann Rheum Dis. 1997;56: Antoniades L, Association of birth weight with osteoporosis and osteoarthritis in adult twins. Rheumatol. 2003;42:

22 Osteoporosis epidemiology bone density lower weight at 1 year old associated with: lower BMC (lumbar spine and femoral neck) for women 21 years, born in Bath independent of adult weight lower adult bone area at the lumbar spine and hip for women and men years, born in Hertfordshire Independent of genetic and lifestyle factors associated with osteoporosis risk shorter inter-trochanteric width of the femur, but not femoral neck length for women and men years, born in Hertfordshire Independent of adult weight Cooper C, Childhood growth, physical activity, and peak bone mass in women. J. Bone Miner. Res. 1995;10: Dennison EM. Birth weight and weight at 1 year: independent determinants of bone mass in 7th decade: Pediatr. Res. 2005;57: Javaid MK,Infant growth influences proximal femoral geometry in adulthood. J. Bone Miner. Res. 2006;21:

23 Osteoporosis epidemiology fracture low birth length and slow childhood growth (height, weight) is associated with: hip fracture for men and women, born in in Helsinki independent of age and gender slow childhood growth for BMI is associated with: hip fracture for women, born in in Helsinki Cooper C, Maternal height, childhood growth and risk of hip fracture in later life: Osteoporosis Int. 2001;12: Javid MK,. Growth in childhood predicts hip fracture in later life. Osteoporos Int. 2011;22:69 73.

24 EVIDENCE BASED MEDICINE evidence for in utero and infant weight effects on bone density and fractures positive association retrospective cohort studies

25 Osteoporosis? mediator of effect

26 Osteoporosis? mediator of effect

27 Osteoporosis epidemiology vitamin D maternal dietary calcium maternal vitamin D supplements maternal UVB exposure maternal healthy eating maternal serum vitamin D cord blood calcium neonatal whole body BMC childhood 9 years whole body and LS BMC BMD bone mass adulthood 20 years peak bone mass

28 Osteoporosis epidemiology vitamin D association or cause and effect?

29 Osteoporosis vitamin D: the evidence Lancet Diabetes Endocrinol 2016; 4: multicentre, double-blind, randomised, placebo-controlled trial in the UK mothers >18 years, singleton pregnancy, gestation of less than 17 weeks serum vitamin D of nmol/l at weeks gestation cholecalciferol 1000 IU/day or placebo orally, from 14-17weeks gestation until delivery. primary outcome: neonatal whole-body BMC, assessed within 2 weeks of birth by DXA secondary outcome: seasonal effects on neonatal whole-body BM

30 Osteoporosis vitamin D: the evidence

31 Osteoporosis vitamin D: the evidence

32 Osteoporosis vitamin D: the evidence treatment effect greater for winter births for: whole-body BMC whole-body bone area BMD BMC adjusted for length treatment effect not different by season for: birth length birth weight

33 EVIDENCE BASED MEDICINE randomised controlled trials evidence for maternal vitamin D supplementation on offspring bone density and fractures no effect

34 Osteoporosis the evidence more clinical trials required

35 Maternal Thyroid Dysfunction

36 Maternal Thyroid Dysfunction Professor Walsh wrote in the MJA: It is uncertain whether pregnant women with TSH values in the 2.5 and 4.0 mu/l range benefit from thyroxine treatment. American Endocrine Society guidelines recommend thyroxine treatment for all such women, but this is increasingly challenged as overly simplistic, and is likely to result in overdiagnosis of subclinical hypothyroidism and unnecessary treatment. Professor Robinson stated that treating people with TSH levels between 2.5 and 4 mu/l is a bit overzealous. Ultimately it s thyroxine that crosses the placenta and that s what is really required for the baby s brain formation in the first trimester. As long as the thyroxine levels are normal, that s the main thing that counts, That is what is required to be pointed out to people who come along very anxiously clutching a set of thyroid function tests showing a slightly elevated level of TSH, but a normal level of T4. They just need to be reassured that it s the T4 which is what gets across the placenta and is good for their baby.

37 EVIDENCE BASED MEDICINE personal opinions and ideas

38 Maternal Thyroid Dysfunction BIOLOGY During pregnancy, thyroid gland increases in: 1. size - 10% (iodine replete) to 20%-40% (iodine deficiency) 2. function - 50% increase T4 and T3 3. iodine requirement - 50% increase thyroid dysfunction can occur especially if underlying iodine deficiency (NSW, VIC, TAS) autoimmune thyroid disease (20% women TPO antibody +)

39 Iodine Deficiency PATHOLOGY impaired maternal and fetal thyroid hormone synthesis maternal and fetal goiter thyroid nodules - severe iodine deficiency NEGATIVE OUTCOMES increased pregnancy loss, stillbirth, perinatal mortality neurodevelopmental dysfunction in offspring

40 Iodine Supplementation 8 controlled trials mild to moderate iodine-deficiency; pregnant European women RESULTS consistent decrease in maternal and neonatal thyroid volumes mixed findings for positive maternal thyroid function maternal TSH decreases with supplementation 4/8 studies maternal T4 or FT4 increases 2/8 studies mixed findings for neurodevelopmental outcomes in children improved (early supplementation) 2/3 studies no improvement (late supplementation) 1/3 studies timing of supplementation likely to be critical no beneficial effects if supplementation started after 1 st trimester

41 Iodine Supplementation BUT lack of high-quality evidence in relation to these outcomes? ethical to perform randomized clinical trials of iodine supplementation in pregnancy in regions that are mildly to moderately iodine deficient? feasible where iodine supplementation is common Taylor PN, Therapy of endocrine disease: impact of iodine supplementation in mild-to-moderate iodine deficiency: systematic review and meta-analysis. Eur J Endocrinol; 2013; 170: R1 R15.

42 EVIDENCE BASED MEDICINE randomised controlled trials controlled trials evidence for maternal iodine supplementation on pregnancy and offspring effects positive association poor quality studies

43 Autoimmune Thyroid Disease in women with normal thyroid function THYROID ANTIBODIES ASSOCIATED WITH: sporadic spontaneous pregnancy loss recurrent spontaneous pregnancy loss premature delivery EFFECT OF THYROXINE TREATMENT lack of high-quality evidence in relation to these outcomes 2 poor quality studies - thyroxine may decrease the risk pregnancy loss particularly in the setting of IVF 1 poor quality study - thyroxine may decrease the risk premature delivery

44 Overt Hypothyroidism in women with overt hypothyroidism DEFINITION OVERT HYPOTHYROIDISM elevated TSH and a decreased serum FT4 concentration both outside the trimester-specific reference ranges TSH is increased (above miu/l) and T 4 is low

45 Overt Hypothyroidism in women with overt hypothyroidism NEGATIVE OUTCOMES Infertility pregnancy loss premature birth low birth weight gestational hypertension detrimental effects upon fetal neurocognitive development lower offspring IQ clear evidence that thyroxine treatment prevents these outcomes

46 Subclinical Hypothyroidism in women with subclinical hypothyroidism TSH level is increased BUT T4 level remains within the normal range. no need to be treated in the absence of pregnancy? associated with infertility and pregnancy loss? associated with detrimental fetal neurocognitive effects? treatment with thyroxine in pregnancy reduces these events increased risk of adverse pregnancy complications less consistent variable cut-off used for TSH thyroid antibody status not always accounted for

47 Subclinical Hypothyroidism systematic review of overt and subclinical hypothyroidism in pregnancy - studies published between EVIDENCE fair: association between overt hypothyroidism (TSH > 4.0 miu/l) and miscarriage insufficient: association between subclinical hypothyroidism (TSH miu/l) and infertility fair: treatment with thyroxine TSH > 4.0 miu/l improved pregnancy rates and decreased pregnancy loss insufficient: treatment with thyroxine TSH 2.5 and 4 miu/l

48 EVIDENCE BASED MEDICINE systematic reviews of controlled trials and cohort studies evidence for maternal thyroxine treatment for subclinical hypothyroidism on pregnancy and offspring effects probably no effect but studies were of poor quality

49 Subclinical Hypothyroidism

50 Subclinical Hypothyroidism

51 Subclinical Hypothyroidism

52 Maternal Thyroid Dysfunction

53 EVIDENCE BASED MEDICINE randomised controlled trials evidence for maternal thyroxine treatment for subclinical hypothyroidism on pregnancy and offspring effects no effect treat only when TSH > 4 mu/l

54 Conclusions and Questions