OUTLINE. Advanced Maternal Age Management of Pregnancy in Women over 40. I have nothing to disclose.

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1 Advanced Maternal Management of Pregnancy in Women over 40 I have nothing to disclose. Kirsten E. Salmeen, MD Assistant Professor Obstetrics, Gynecology & Reproductive Sciences Maternal-Fetal Medicine OUTLINE Maternal age statistics and trends Assisted reproductive technologies (ART) Aneuploidy & Miscarriage Risk Underlying health problems Infertility Multiple Gestations Perinatal morbidity Management Assisted Reproductive Technology Medical Co-Morbidities 1

2 MATERNAL AGE STATISTICS AND TRENDS What percent of births in the United States would you estimate are in women over age 40? A. < 5% B. 5 10% C % D. > 15% 39% 28% 22% 11% < 5 % % % > 1 5 % 12% 10% 8% 6% 4% 2% 0% US Birth Rates Among Women 35 12% Deliveries to Women Years Deliveries to Women 40 Years 3% CDC, National Center for Health Statistics, National Vital Statistics System. 2

3 Total # of Births in US 3,880,894 3,932, Years # of Births (%) 93% 76,084 (2) 109,484 (2.8) Years # of Births (%) 3,333 (0.09) 7,495 (0.19) 50 Years # of Births (%) 144 (0.004) 677 (0.017) Infertility CDC, National Center for Health Statistics, National Vital Statistics System. and Fertility and Fertility At age 30, a woman s chance of conception is ~ 20% per cycle Data from multiple non-contracepting communities over many decades Practice Committee Committee Opinion No 589 Fertil Steril 2014 By age 40 it is ~ 5% per cycle Maternal Births Resulting from ART Procedures National Vital Statistics Data 2011 Number of Births Number of Known ART-Births Percent < 35 2,273,953 19, ,392 7, ,937 5, ,299 2, ,717 1, ,247 1, National Vital Statistics Reports, Vol. 63, No. 8, December

4 RISKS ASSOCIATED WITH ASSISTED REPRODUCTIVE TECHNOLOGIES Assisted Reproductive Technology Infertility ART & Multiple Gestation 25 30% of ART pregnancies are twins 1.5 3% of ART pregnancies are triplets or more Monozygotic twinning: % (vs 0.5%) Infertility Multiple Gestations Assisted Reproductive Technology Kanter et al Trends and correlates of monozygotic twinning after single embryo transfer Ob Gyn 2015; cdc.gov Assisted Reproductive Technology (ART) National Summary Report

5 ART is an independent risk factor for which of ART & Birth Defects the following? A. Birth defects 89% 301 Infants 837 Infants B. Cesarean section C. Placenta previa 4,000 Infants D. Pre-eclampsia E. All of the above 4% 2% 1% B i r t h d e f e c t s C e s a r e a n s e c t i o n 3% P l a c e n t a p r e v i a P r e - e c l a m p s i a A l l o f t h e a b o v e Figure 1. Cumulative prevalence of diagnosed major birth defects in singleton infants, according to age at diagnosis Hansen et al. NEJM 346:725-30, 2002 ART & Birth Defects Assisted Conception (N = 4333) Singleton Births Spontaneous Conception (N = 295,220) Adjusted Odds Ratio Any Defect 361 (8.3) 16,989 (5.8) 1.30 ( ) Multiple Defects 95 (2.2) 4,690 (1.6) 1.24 ( ) Cardiovascular 78 (1.8) 3,472 (1.2) 1.36 ( ) Musculoskeletal 130 (3.0) 4,776 (1.6) 1.50 ( ) Urogenital 95 (2.2) 4,872 (1.7) 1.25 ( ) Gastrointestinal 34 (0.8) 1832 (0.6) 1.18 ( ) Central nervous system 22 (0.5) 1,104 (0.4) 1.34 ( ) Cerebral Palsy 17 (0.4) 496 (0.2) 2.22 ( ) Adjusted for age, parity, fetal sex, year, race/ethnicity, country of birth, maternal conditions in pregnancy, maternal smoking during pregnancy, socioeconomic status and maternal and paternal occupation Davies et al. NEJM 366: , 2012 ART & Birth Defects Assisted Conception (N = 1,830) Multiple Births Spontaneous Conception (N = 7,591) Adjusted Odds Ratio Any Defect 152 (8.3) 557 (7.3) 1.16 ( ) Multiple Defects 55 (3.0) 188 (2.5) 1.10 ( ) Cardiovascular 30 (1.6) 142 (1.9) 0.99 ( ) Musculoskeletal 25 (1.4) 102 (1.3) 0.92 ( ) Urogenital 50 (2.7) 173 (2.3) 1.10 ( ) Gastrointestinal 23 (1.3) 88 (1.2) 1.13 ( ) Central nervous system 10 (0.5) 42 (0.6) 1.08 ( ) Cerebral Palsy 16 (0.9) 50 (0.7) 1.39 ( ) Adjusted for age, parity, fetal sex, year, race/ethnicity, country of birth, maternal conditions in pregnancy, maternal smoking during pregnancy, socioeconomic status and maternal and paternal occupation Davies et al. NEJM 366: ,

6 ART & Perinatal Risk ANEUPLOIDY & MISCARRIAGE RISK Reddy et al. Infertility, assisted reproductive technology, and adverse pregnancy outcomes. Ob Gyn Maternal at Delivery (years) Risk of Chromosomal Abnormalities Risk at Live Birth, According to Maternal Risk of Down Syndrome Risk of Any Chromosomal Abnormality 20 1/1667 1/ /378 1/ /106 1/ /30 1/21 Miscarriage Risk Risk of Spontaneous Abortion According to Maternal at Conception Risk of Spontaneous Abortion (%) 80% 40% Maternal at Conception (Years) Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA 1983;249: Nybo Anderson AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320:

7 ART Modifies Miscarriage Risk Donor Oocytes Further Modify SAB Risk ~ 65% ~ 30% ~ 50% cdc.gov Assisted Reproductive Technology (ART) National Summary Report 2010 cdc.gov Assisted Reproductive Technology (ART) National Summary Report 2010 UNDERLYING HEALTH PROBLEMS Infertility Multiple Gestations Assisted Reproductive Technology Medical Co-Morbidities 7

8 Risk of Death Increases with Percent of US Women With Obesity (BMI > 30) 2007 Number of Deaths/100,000 US Females Years 35% 30% 25% 20% 15% 10% 5% 0% yrs yrs yrs yrs CDC, National Center for Health Statistics, National Vital Statistics System. cdc.gov NHANES Percent of US Females With Hypertension NHANES Diabetes & Prediabetes Women 18, % 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% aor = 3.3 ( ) aor = 8.2 ( ) Adjusted for: race/ethnicity, diabetes, chronic kidney disease, alcohol use, OCP use, BMI Total 10.6% 39.7% Yrs 3.1% 39.7% Yrs 11.1% 51.1% 0% 10% 20% 30% 40% 50% 60% Diabetes Prediabetes Bateman et al. Hypertension in Women of Reproductive in the United States: NHANES PLoS ONE 2012 cdc.gov NHANES

9 Chance of Being Diagnosed with Breast or Colon Cancer in the Next 10 Years 2.50% 2.00% 1.50% Colon Cancer Breast Cancer PERINATAL MORBIDITY 1.00% 0.50% 0.00% yrs yrs yrs Infertility Multiple Gestations 100 Perinatal 50Risk Assisted Reproductive Technology Medical Co-Morbidities (Years) 9

10 Obstetrical Risks Associated with Increased Maternal Obstetrical Risks Associated with Increased Maternal Non-Chromosomal Congenital Anomalies % Odds Ratio/Relativ e Risk Maternal Reference Reefhuis Loane Cleary-Goldman < 35 Preterm Birth Cleary-Goldman (< 37 wks) < 35 Yogev (< 34 wks) Yogev (< 34 wks) Luke (< 32 wks) Reefhuis et al. Birth Defects Research (Part A) 70: , 2004; Loane et al. BJOG 116: , 2009; Yogev et al. Am J Obstet Gynecol 203:558.e1-7, 2010; Cleary-Goldman et al. Obstet Gynecol105:983 90, 2005; Luke B et al. Hum Reprod 22(5): , 2007 Low Birth Weight % Odds Ratio/Relativ e Risk Maternal Reference Cleary-Goldman < 35 Yogev Luke NR Yogev Salihu ~ Cleary-Goldman et al. Obstet Gynecol 105:983 90, 2005; Yogev et al. Am J Obstet Gynecol 203:558.e1-7, 2010; Luke B et al. Hum Reprod 22(5): , 2007; Salihu et al. Obstet Gynecol 102: , 2003 Pre-Eclampsia Obstetrical Risks Associated with Increased Maternal % Odds Ratio/Relativ e Risk Maternal Reference Cleary-Goldman < 35 Yogev 2.4 NR N/A Yogev 10.7 NR 45 N/A Pare 13.4 aor NS > 40 < 35 Luke > Paulson 35 NR 50 N/A Cleary-Goldman et al. Obstet Gynecol105:983 90, 2005; Yogev et al. Am J Obstet Gynecol 203:558.e1-7, 2010; Luke et al. Hum Reprod 22(5): , 2007; Paulson et al. JAMA;228: , 2002 Gestational Diabetes Obstetrical Risks Associated with Increased Maternal % Odds Ratio/Relativ e Risk Maternal Reference Cleary-Goldman < 35 Placenta Previa Yogev 10.2 NR N/A Yogev 17.0 NR 45 N/A Paulson 17.5 NR 50 N/A Cleary-Goldman < 35 Yogev Yogev Jacobsson Salihu 16.7 NR 50 N/A Cleary-Goldman et al. Obstet Gynecol 105:983 90, 2005; Yogev et al. Am J Obstet Gynecol 203:558.e1-7, 2010; Paulson et al. JAMA;228: , 2002; Jacobsson et al. Obstet Gynecol 104:727 33, 2004; Salihu et al. ObstetGynecol 102: ,

11 Cesarean Section Yrs Yrs Yrs > 50 Yrs Mode of Delivery Cleary- Goldman 31.4% 40.5% (aor 2.0) Yogev 42.9% (RR 3.7) 78.5% (RR 31.8) Luke (primiparous) 43% (RR % (RR 3.14) Jacobsson 23.5% (OR 2.8) 30.3% (OR 3.8) Dulitzki 39.4% (OR 7.3) Paulson (singletons) 68% Risk Factors for Cesarean Section Cesarean Section & Oocyte Recipients Krieg: Stanford University, 40 pregnancies in oocyte recipients compared to women 38 yrs who underwent autologous IVF cycles OR for C/S in oocyte recipients: 2.78 ( ) Each 1 year increase in maternal age was associated with a 13% increase in the odds of C/S. Dulitzki et al. Effect of very advanced maternal age on pregnancy outcome and rate of cesarean delivery. Ob Gyn 1998 Krieg SA, Henne MB, Westphal LM. Obstetric outcomes in donor oocyte pregnancies compared with advanced maternal age in in vitro fertilization pregnancies. Fertil Steril 2008;90:

12 At what gestational age do you offer induction Risk of Intrauterine Fetal Demise of labor for women who are over 40 without other risk factors? A weeks B weeks 40% 28% 24% C. > 41 weeks 8% D weeks w e e k s w e e k s > 4 1 w e e k s w e e k s Risk of IUFD IUFD Risk Odds of IUFD by GA compared to women < 35 years (N = 108,547) Years aor* (95% CI) N = 13, years aor* (95% CI) N = 3, weeks 2.03 ( ) 1.73 ( ) weeks 1.20 ( ) 1.63 ( ) weeks 0.80 ( ) 2.28 ( ) * Adjusted for race/ethnicity, parity, chronic hypertension, pre-elcampsia, diabetes Hoffman et al. Pregnancy at or beyond age 40 years is associated with an increased risk of fetal death and other adverse outcomes. AJOG Bateman et al. Higher rate of stillbirth at the extremes of reproductive age: A large nationwide sample of deliveries in the United States. AJOG

13 IUFD Risk Other Reported Risks Intensive care stay Myocardial infarction Pulmonary edema Venous thromboembolism Postpartum depression Reddy et al. Maternal age and the risk of stillbirth throughout pregnancy in the United States. AJOG Other Anecdotal Risks Anxiety Difficulty with breastfeeding A BRIEF DIVERSION TO ADVANCED PATERNAL AGE 13

14 Advanced Paternal MANAGEMENT Possibly increased risk for other birth defects, autism-spectrum disorders Salmeen, Zlatnik. The oldest gravidas: a review of pregnancy risks in women over 45. Obstetrical and Gynecological Survey 2011 Preconception Work-Up for Women 40 (or 35 with risk factors) What I do Without a lot of evidence Hemoglobin A1c, fasting glucose TSH Mammogram EKG Lipids Serial BPs Cardiac Stress Test/Cardiology evaluation 14

15 First Trimester Care for Women 40 ** Aspirin Prophylaxis ** Determine mode of conception Assess fetal number, chorionicity of multiples TSH (if not recently obtained) Early glucose testing If hypertensive: baseline pre-eclampsia labs Genetic counseling (adjust for oocyte-donor age) Consideration of aspirin prophylaxis In high-risk women, aspirin prophylaxis may reduce the risk of pre-eclampsia by up to 17% I consider women over 40 to be high risk and offer aspirin Detailed fetal anatomic survey Low-threshold for fetal echocardiogram Repeat glucose tolerance testing Evaluation of fetal growth in the third trimester Antenatal testing Prenatal Care for Women 40 (or 35 with risk factors) Labor planning, counseling regarding mode of delivery Labor induction weeks TAKE HOME POINTS -related risks are actually multifactorial IUFD increases with increasing maternal age. Induction for post dates may be appropriate after weeks for women > years. nor donor-oocyte recipient status are indications for cesarean delivery. Aspirin prophylaxis is indicated for women at highrisk for pre-eclampsia, including women over

16 Questions? 16