Disclosure No commercial interests related to topics Intrauterine - PowerPoint PPT Presentation

Disclosure • No commercial interests related to topics Intrauterine Growth Restriction presented How Small Is Too Small? Danny Wu, MBChB Kaiser Permanente Perinatology 6/2017 Outline In-utero Growth Restriction • ACOG defined IUGR as EFW < 10 th percentile • Definition • Implications of IUGR • 4 million births per year -- 400,000 babies are • Etiology IUGR • Diagnosis • Consequences – Percentile – At birth and in infancy – Growth curves – Childhood and adult life : Barker Hypothesis – Doppler • Risk of hypertension, hypercholesterolemia, coronary heart • Management disease, impaired glucose tolerance and diabetes • Enormous burden 1

Perinatal Mortality and Morbidity Perinatal Morbidity • Increased risk of spontaneous or induced preterm births – Preterm infants: NEC, need for respiratory support • Neonatal Complications: – Neonatal asphyxia – Meconium aspiration – Hypoglycemia – Metabolic abnormalities – Polycythemia Long Term Sequelae Barker Hypothesis • Low et al • Barker et al found an increased risk of cardiovascular disease and low – 218 “high risk neonates” followed up age 11 birthweight in UK – 77 (35%) learning difficulties • Insulin resistance, obesity – IUGR independent risk factor (30/77) • Blair et al • Others have reported association with bone density, schizophrenia, breast – Strong association of CP and IUGR among neonates >33 weeks cancer and asthma Barker DJP, Robinson RJ, ed. Fetal and Infant Origins of Adult Disease, London: British Medical Journal; 1992. Low JA, Handley-Derry MH, Burke SO, et al Am J Obstet Gynecol 1992; 167:1499. Gluckman PD, Hanson MA, ed. Developmental Origins of Health and Disease, Blair E, Stanley F: Cambridge: Cambridge University Press; 2007. Am J Obstet Gynecol 1990; 162:229. 2

Etiology Not All IUGR Are the Same • Maternal – Chronic disease ( eg cHTN, DM, SLE, APLS ) • Small for gestational age (SGA) – Pregnancy related hypertension – Smoking and substance abuse ( eg alcohol, cocaine ) – “constitutionally small” – Malnutrition • Pathologically small – Teratogens (eg anticonvulsants) • Fetal – Maternal illness present – Genetic disorder: chromosomal ( eg T13,T18 T21), genetic – Fetal pathology present syndromes – No obvious reason – Structural ( eg gastroschisis, CHD ) – Infection: eg CMV, toxo, rubella , zika ( <5% of all IUGR ) – Multiple ( more common in mo/di than di/di ) • Placental – Chorangioma, Confined placental mosaicism – Abruption PORTO Study Porto Study • Prospective cohort study in Ireland • Mean GA enrolment 30.1 weeks • 1200 consecutive singleton pregnancies • Mean GA at delivery 37.8 weeks with EFW < 10 th percentile recruited • Only Doppler UA and EFW < 3 rd percentile • 24 0/7 to 36 6/7 are associated with adverse outcome • USS every 2 weeks with Doppler • Oligohydramnios, EFW < 5 th or < 10 th are NOT associated with adverse outcome • All of the 8 deaths occurred in the group EFW < 3 rd percentile Unterscheider J, Daly S, Geary MP et al. PORTO study AJOG2013 ;208: 290. e1-6 3

Growth Curve Which one should we use? Pilliod RA, Cheng YW, Snowden JM et al 2012 Growth Curves: Population Ultrasound Derived Curve • Many USS curves published since 1980s • In the last few years, large prospective studies were published aiming to provide fetal growth standards 1) INTERGROWTH-21 st Project • Lancet. 2014;384(9946):869. 2) NICHD Fetal Growth Study Am J Obstet Gynecol . 2015 October ; 213(4): 449.e1–449.e41. doi:10.1016/j.ajog.2015.08.032 • 3) WHO Fetal Growth Charts • Kiserud T, Piaggio G, Carroli G, Widmer M, Carvalho J, Neerup Jensen L, et al. (2017) PLoS Med 14(1): e1002220. doi:10.1371/ 4

Customized Growth Curve Racial/Ethnic Difference • Gardosi et al – proposed standards according to individual growth potential calculated for each pregnancy – Standard are adjusted according to maternal characteristics ( ht, wt, parity, ethnic origin ) are considered – Pathological process are excluded ( eg DM, smoking and prematurity ) Buck Louis et al Racial/Ethnic Standards for Fetal Growth, the NICHD Fetal Growth Studies Am J Obstet Gynecol . 2015 Gardosi J, Francis A. Adverse pregnancy outcome and association with October ; 213(4): 449.e1–449.e41 smallness for gestational age by customised and population based birthweight percentiles .AmJ Obstet Gynecol 2009;201:28.e1-8. Customized Growth Curve Customized Growth Curve • Other studies do not find it beneficial – Hutcheon et al 1 • Cohort of 783303 births • Use of customized curve showed no advantage – Grobman et al 2013 2 • Secondary analysis of the BEAM study • Individualized growth curve does not improve the association or prediction of CP or death by age 2 1. J. A. Hutcheon et al “Customised birthweight percentiles: does adjusting for maternal characteristics matter?” Gardosi J, Francis A. Adverse pregnancy outcome and association with International Journal of Obstetrics and Gynaecology, vol. 115, no. 11, pp. 1397–1404, 2008 smallness for gestational age by customised and population based 2. Grobman et al. The association of cerebral palsy and death with small-for-gestational-age birthweight in preterm birthweight percentiles .AmJ Obstet Gynecol 2009;201:28.e1-8. neonates by individualized and population-based percentiles. Am J Obstet Gynecol 2013;209:340.e1-5. 5

Multiple Gestation • In the first and second trimesters – the growth rate of twins is not significantly different from that of singletons • In the third trimester, – especially after 30-32 weeks, most studies have described slower fetal growth – Near term, up to 40% will be labelled as small Grantz KL, Grewal J, Albert PS, et al. Dichorionic twin trajectories: the NICHD Fetal Growth Studies. Am J Obstet Gynecol 2016;215:221.e1-16. Twin Growth Curve Screening for IUGR • Is that a normal adaptive process or is it • All pregnant patients should be screened associated with adverse outcome? for risk factors • More information is needed • Fundal heights after 24 weeks – Sensitivity 27-86% specificity 80-90% • Most physicians use the singleton standard – Limitations with obesity, multiple gestation, fibroid • Consider USS if risk factors present ACOG Technical Bulletin No. 134 May 2013 6

POP Study Screening for IUGR • Prospective cohort study • Routine 3 rd trimester USS • 4512 nulliparous women with singleton – For low risk unselected populations does not pregnancy enrolled confer benefit on mother or baby • They all get research ultrasounds at 28 – 8 trials recruiting 27024 women were included and 36 weeks. Results were not disclosed – Screened group has a higher C-section rate, • Women will get ultrasound in 3 rd trimester but not statistically different if clinically indicated – Not recommended Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study. Lancet vol 386 Nov, 2015 Bricker et al Cochran Database Syst Review 2008 Result Other Screening Strategies SGA Severe SGA • Serum analytes • Low PAPP-A ( under 5 th percentile ) Selective Universal Selective Universal • Birth weight under 10 th percentile OR 2.8 Sensitivity 20% 57% 32% 77% • Positive predictive value of 16% • Doppler of uterine artery Specificity 98% 90% 97% 87% • High impedance in flow is associated with adverse obstetric outcomes False 2% 10% 3% 13% • Pooled likelihood ratio 3.7 / 0.8 if normal result positive • Not recommended 1. Dugoff et al : AJOG vol191 issue4, Oct 2004 Pg 1446-1451 Adapted from Savio et al . Lancet vol 386 2015 2. Papgeorghiou et al : Best practice & Research Clinical Obstet Gynae vol19 Issue 3 2004 Pg 383-396 7

Confirm EDC GA Method Discrepancy to support re-dating ≤ 8 6/7 CRL >5d Doppler 9 0/7 to 13 6/7 CRL >7d 14 0/7 to 15 6/7 BPD, HC, AC, FL >7d 16 0/7 to 21 6/7 BPD, HC, AC, FL >10d Umbilical Artery (UA) Middle Cerebral Artery (MCA) 22 0/7 to 27 6/7 BPD, HC, AC, FL >14d Ductus Venosus (DV) 28 0/7 + BPD, HC, AC, FL >21d ACOG Committee Opinion 611 Fetal Circulation Dopplers Venous Arterial Umbilical Vein Umbilical Artery Ductus Venosus MCA placenta Uterine artery 8

Doppler Waveform Analysis Umbilical Artery Doppler Doppler waveform represents downstream impedance to flow Umbilical Artery Doppler Absent End Diastolic Flow • As placental insufficiency worsens, diastolic flow progressively decreases Decreased Absent Reversed Abnormal 30% 70% Vasculature Morrow RJ; Adamson SL; Bull SB; Ritchie JW SO Am J Obstet Gynecol 1989 Oct;161(4):1055-60. 9

Reversed End Diastolic Flow Perinatal Outcomes • Absent or reversed flow is associated with adverse perinatal outcome • It may be present for weeks before additional sign of fetal compromise occurs PORTO Study Classic Model for Progression of Doppler Changes • “Classic Model” exists but no more frequent than any Physiological Doppler Changes other pattern Changes Increased placental • With UA Doppler alone, it UA S/D increases vascular resistance captures 86% of all adverse outcomes Shunting to vital organs MCA P/I decreases “Brain-sparing” Impaired cardiac Abnormal Unterscheider J, Daly S, Geary MP, et al. Predictable progressive Doppler deterioration in functions venous flow IUGR: does it really exist? Am J Obstet Gynecol 2013;209:539.e1-7 10