Gestational weight gain in a UK cohort: patterns, risk factors and associations with later mother and offspring health Debbie A Lawlor (d.a.lawlor@bristol.ac.uk)

Background Importance Inform policy on the ideal GWG for supporting both short and long-term optimal health in offspring and mother 2009 IOM guidelines; NICE guidelines Should weight be measured in pregnancy? Science Scant evidence of associations of GWG with long term outcomes in both mothers and offspring. Even with short-term outcomes often based on just two measures (with one or both retrospectively reported) Will screening identify women at risk and provide an opportunity to intervene

Aims and Objectives To examine the associations of pre-pregnancy weight and GWG with long term outcomes in mothers and offspring Determinants of GWG Cardiovascular risk factors in offspring at age 9 Asthma in offspring at age 7.5 BMI, WC and BP in mothers 16 years post-pregnancy Future plans

Participants Mothers and offspring enrolled in the Avon Longitudinal Study of Parents and Children, a population-based birth cohort study that recruited 14,541 pregnant women resident in Avon, UK with expected dates of delivery 1st April 1991 to 31st December 1992 Gestational weight available for 12,484 mothers; of which 12,449 had a term pregnancy and offspring who survived 1 year.

Statistical methods Categorise women according to IOM categories; using pre-pregnancy BMI and highest gestational weight Use all of the available repeat ANC weight measurements Median (IQR): 10 (8, 11) MLwiN - linear spline random effects model with two knots (fractional polynomials to identify position of knots)

Mean rate of weight gain in 2nd and 3rd trimesters in kg/week IOM recommendations ALSPAC Pre-pregnancy BMI Absolute weight gain in kg Mean rate of weight gain in 2nd and 3rd trimesters in kg/week Mean (range) absolute weight gain in kg* Mean rate (SD) of weight gain in 2nd and 3rd trimesters in kg/week Underweight (<18.5kg/m2) 12.5-18 0.51 12.9 (-2.0, 30.5) 0.54 (0.14) Normal weight (18.5-24.9kg/m2) 11.5-16 0.42 12.8 (-2.2, 37.8) 0.53 (0.14) Overweight (25-29.9kg/m2) 7-11.5 0.28 11.9 (-3.0, 33.5) 0.49 (0.17) Obese (>=30kg/m2) 5-9 0.22 9.5 (-6.9, 30.9) 0.41 (0.20) Overweight and obese gain too much

Results: Descriptive IOM categories Less than adequate: 35% More than adequate: 27% ---- 18 weeks ----- 28 weeks

Determinants of gwg

Maternal Education

Maternal age

Number of previous pregnancies

Maternal smoking Never Stopped during pg Smoked throughout Pre-pg wt -0.77 (0.53) -0.66 (0.36) GWG 0-18 wks 0.08 (0.01) 0.00 (0.01) GWG 18-28 wks 0.03 (0.01) -0.03 (0.01) GWG 28+ wks 0.02 (0.01) -0.05 (0.01)

Genetic variants and GWG Variants known to be robustly associated with greater adiposity Both maternal and fetal variants FTO MC4R TMEM18 GNPDA2

FTO MC4R TMEM18 and Mean difference per additional maternal risk allele adjusted for offspring risk score

Association of GWG with offspring CVD risk factors Previous studies showing +ve associations with offspring BMI / fat mass Varied results with BP All used two measurements of weight only (one or both retrospectively reported) None looked at risk factors beyond adiposity & BP Our findings published (Circulation 2010)

Association of GWG with offspring CVD risk factors Offspring of women with higher than IOM recommended GWG were more adipose and had more adverse CVD risk factor levels; those with lower than IOM recommended GWG were less adipose but had similar CVD risk factor levels to those with recommended IOM GWG. Offspring of women with greater GWG up to 28 weeks were more adipose and had more adverse CVD risk factor levels The associations of greater GWG with more adverse offspring CVD risk factor levels were largely mediate by associations with offspring adiposity Non-linear associations of GWG with outcomes

With offspring Asthma Using IOM categories: Using spline estimates: OR of childhood asthma (vs. =recommended GWG): < recommended GWG – 1.10 (95%CI: 0.99, 1.26) > Recommended GWG – 1.05 (95%CI: 0.91, 1.22) When adjusting for potential confounders Using spline estimates: Pre-pregnancy - 1.004 (1.00, 1.01) No strong assoc. of GWG in 1st and 2nd period with childhood asthma In late pregnancy - 1.20 (1.10, 1.30)

Associations with maternal outcomes Expectation for positive association with adiposity, but few studies examined this beyond early postnatal period Other CVD outcomes not studied Used ‘opportunistic data’ from mothers attending 15+ clinic with their offspring SBP, DBP (N ~ 2000) BMI, WC (N = 1000-1500)

IOM categories

Is pre-pregnancy weight driving associations. i. e Is pre-pregnancy weight driving associations? i.e. heavier women more likely to exceed recommended weight gain (which is lower for them), and therefore account for the observed association. In order to examine this we used the splines and stratified by pre-pregnancy overweight

Pre-pregnancy 0-18 weeks 18-28 weeks 29+ weeks BMI (kg/m2) 0.34 Pre-preg BMI <25kg/m2 Pre-preg BMI ≥25kg/m2 BMI (kg/m2) 0.34 (0.32, 0.36) 1.43 (0.97, 1.89) 1.58 (1.07, 2.09) 0.16 (-1.46, 1.78) (-0.10, 0.41) 1.33 (0.47, 2.19) WC (cm) 0.73 (0.68, 0.78) 3.55 (2.20, 4.90) 4.05 (2.55, 5.56) 1.49 (-3.19, 6.19) -0.005 (-0.74, 0.73) 2.66 (0.40, 4.91 SBP (mmHg) 0.36 (0.31, 0.42) 0.27 (-1.21, 1.75) 2.29 (0.46, 4.11) -1.99 (-6.19, 2.21) 0.44 (-0.41, 1.28) DBP (mmHg) 0.17 (0.14, 0.20) -0.08 (-1.00, 0.85) 1.38 (0.22, 2.53) -2.39 (-4.82, -0.04) 0.05 (-0.48, 0.57) In mid preg it is the normal weight women in which we see associations. positive associations of pre-pregnancy weight with all outcomes. WG in early pregnancy (0-18 weeks) positively associated with BMI and WC. Mid pregnancy GWG (19-28 weeks) positively associated with BMI, WC in normal weight prior to pregnancy. LAte pregnancy GWG (29+ weeks) positively associated with BMI, WC in overweight prior to pregnancy.

Conclusions Using repeat measurements of weight suggests a much more complex picture than when IOM categories used Maternal education, age, parity and smoking related to patterns of GWG, but neither maternal nor fetal ‘fat-related’ genetic variants are. Greater pre-pregnancy BMI and GWG associated with greater offspring and maternal adiposity in later life and via this with adverse lipids, inflammatory markers and blood pressure in offspring May be a U-shaped association with offspring asthma

Future plans Associations of GWG with: Cognition in offspring at age 4 and educational achievements at age 15-16 – Suzi Gage, PhD student. Cardiovascular risk factors in offspring at age 15, including fasting insulin and glucose – Sumaiya Patel, Post-doc. Maternal cIMT, DXA determined fat mass, fasting insulin, glucose, and lipids in mothers 17 years post pregnancy – Abi Fraser MRC research fellow Joint modelling of trajectories of BP and GWG during pregnancy – Corrie MacDonald-Wallis, PhD student. GWAS to identify genetic variants associated with GWG that could be used to improve causal inference (through MR).

Papers Fraser A, Tilling K, Macdonald-wallis C, Sattar N, Brion M-J, Benfield L, Ness A, Deanfield J, Hingorani A, Nelson SM, Davey Smith G, Lawlor DA. Association of maternal weight gain in pregnancy with offspring obesity and metabolic and vascular traits in childhood. Circulation 2010;121:2557-2564 Fraser A, Tilling K, Macdonald-Wallis C, Sattar N, Nelson SM, Lawlor DA. Associations of pre-pregnancy weight and gestational weight gain with mothers’ BMI, waist circumference and blood pressure measured 16 years post-pregnancy: the Avon Longitudinal Study of Parents and Children. Submitted to American Journal of Clinical Nutrition 2011 in press Lawlor DA, Fraser A, MacDonald-Wallis, Palmer T, Davey Smith G, Tilling K. Maternal and offspring adiposity related genetic variants and gestational weight gain. American Journal of Clinical Nutrition 2011 in press Fraser A, Tilling K, Henderson J, Grannell R, MacDonald-Wallis C, Lawlor DA. The association of gestational weight gain and offspring asthma. Thorax Submitted February 2011 (under review) Gage S, Lawlor DA, Tilling K, MacDonald-Wallis C, Fraser A. Gestational weight gain and offspring intelligence: findings from the Avon Longitudinal Study of Parents and Children. Pediatrics Submitted April 2011

Acknowledgements Kate Tilling Abigail Fraser Corrie MacDonald-Wallis US NIH Wellcome Trust MRC British Heart Foundation