Intrauterine growth restriction Intrauterine growth restriction

Intrauterine growth restriction

1. Intrauterine Growth Restriction Pathogenesis & interventions to improve outcome Dr. Praman Kushwah Neonatology Resident NICE Hospital, Hyderabad

2. Objectives Definition Health Burden Classification Aetiology Pathophysiology Screening Prevention Diagnosis Intervention & Management

3. Intoduction “Fetus who does not achieve the expected in utero growth potential due to genetic or environmental factors” Shrunken or "wizened" appearance of an infant with intrauterine growth restriction

4. Definitions IUGR / (Fetal growth Restriction) F etus who does not achieve the expected in utero growth potential due to genetic or environmental factors ( Brodsky and Christou, 2004 ) A n estimated fetal weight <10 th   percentile Moderate FGR BW 3 rd  to 10 th   percentile S evere FGR BW < 3 rd   percentile

5. Small-for-gestational age (SGA ) Majority are constitutionally small and healthy 10–15 % of SGA infants are growth restricted, i.e., with slow growth velocity in utero ( Alberry and Soothill , 2007)

6. Health Burden 10 % of live-born are IUGR 2 nd leading cause - perinatal morbidity and mortality 1.5% risk of fetal death

7. Classification

8. The Ponderal index [birth weight in grams ×100 ]/[length in centimeters] 3 the weight-to-length ratio may be U sed to categorize growth-retarded infants. Those with asymmetric growth retardation have low Ponderal index. Ponderal index for symmetric IUGR may be normal

9. Etiology

10. Fetal Etiologies Chromosomal etiologies classically, trisomies more common ( 5 - 20 % ) C ongenital birth defects (e.g. gastroschisis )

11. Maternal Etiologies Factors affecting Health & reproductive potential maternal age, parity, or last pregnancy interval maternal health conditions prior to pregnancy hypertension and diabetes, either pre-existing or gestational, pulmonary and renal disease, autoimmune disease, thrombophilic disorders congenital heart disease. M other’s own diet and access to nutrition image distortion disorders such as bulimia, anorexia or hyperemesis gravidarum .

12. Environmental E tiologies Infections in early pregnancy (5-10%) Malaria, rubella, cytomegalovirus, Toxoplasma gondii , syphilis (malaria represents the largest portion of global burden of IUGR secondary to infectious etiologies .) Substance Abuse Alcohol, Cocaine, heroin, and narcotic use during pregnancy Teratogens, maternal medications, or maternal substance abuse antiepileptic medications ( valproic acid), antithrombotic agents (e.g., warfarin) chemotherapeutic/ antineoplastic agents (e.g., cyclophosphamide). Location High altitude versus near sea level developed versus developing nations.

13. Placental Etiologies (m/c) P lacental disorders chronic placental abruption, infarction, circumvallate shape, chorioangioma Umbilical cord abnormalities velamentous or marginal cord M ultiple gestation A/w both SGA and prematurity risk of SGA 25 % in twin pregnancies, 60 % for triplet and quadruplet monochorionicity at higher risk of SGA and IUGR (unequal placental sharing, twin-to-twin transfusion) S mall size placentas and histopathologically hypovascular villi, fibrin deposition, and/ or trophoblast degeneration Poor nutrient and oxygen provision to the fetus on a physiologic level

14. Pathophysiology

15. Placental insufficiency M ajority of IUGR neonates ( idiopathic IUGR). D isruption in normal early vascularization of the placenta I ncomplete spiral artery remodelling  shallow placental vasculature F ailure of these vessels to appropriately become low-resistance vessels L imiting blood flow to the fetus L imiting nutrient/oxygen provision to the fetus and placenta itself.

16. Cont. Hormones - Insulin , thyroid hormones, adrenal hormones, pituitary hormones Insulin control cell number via direct mitogenic effects on cellular development, regulate glucose uptake and consumption in somatic tissues regulate other metabolic pathways, such as protein breakdown. IGF-1, IGF-2, IGFBP-2 and - 3 implicated in the pathophysiology of IUGR in experimental models Chromosomal abnormalities D ecreased numbers of fetal cells and poor cellular growth  IUGR

17. Screening M aternal and family history  identify presence of etiologic risk factors Accurate gestational dating  True SGA from wrong dates Recurrence risk risk of recurrent SGA 20% risk of recurrent IUGR is estimated at ~20%- 50% Detailed maternal physical exam including Fundal height measurement

18. Evaluation Fetal ultrasound : Biometric parameters (1 ) biparietal diameter, (2) head circumference, (3) abdominal circumference, and (4) femur length T o distinguish symmetric from asymmetric IUGR A bdominal circumference - best “stand-alone” with specificity and a negative predictive value of almost 90% for diagnosing IUGR

19. If EFW < 10th percentile for gestational age detailed evaluation - Doppler & Amniotic fluid Evaluation of fetal anatomy structural and genetic abnormalities ( a/w chromosomal disorders or infections) ACOG suggest every 3-4 weeks assessment to minimize false-positive rates

20. Doppler velocimetry, (esp. umbilical artery) S everity of fetal growth restriction R eflection of maternal circulation P lacental insufficiency ,  resistance will increase, diastolic flow will decrease, absent or reversed end-diastolic flow in the umbilical artery absent or reversed end-diastolic flow  poor prognostic factor  a/w increased perinatal Mortality

21. Timing of delivery Based on U nderlying etiology E stimated gestational age Early delivery of an IUGR fetus A neuploidy or congenital infection no improved outcomes P lacental insufficiency - antenatal surveillance helpful

22. RECOMMENDATION (ACOG) In Isolated fetal growth restriction D elivery at 38 0/7 to 39 6/7 weeks in cases of, and IUGR fetuses with additional risk factors for poor prognosis delivery at 34 0/7 to 37 0/7 weeks Risk Factors - oligohydramnios , abnormal umbilical artery Doppler velocimetry D elivery ideally should be performed at a center with both high-risk maternal fetal medicine teams and a neonatal intensive care unit.

23. Prevention V ery few “preventative” strategies A ltering modifiable risk factors can help. (e.g. C igarette smoking, diet, malarial prophylaxis in high-risk areas) No role - Nutritional and dietary supplementation regimens Not recommended - Bed rest New Modality – Aspirin E fficient in mitigating severe IUGR with abnormal Dopplers Increased birth weight at delivery Prolonging gestation Decreased need for NICU admission very less existing studies  NOT ROUTINELY INDICATED

24. Postnatal Diagnosis of IUGR Problematic (lack of clarity in definition) History Prenatal history Prenatal pattern of growth Prenatal condition - Placental and F etal structural abnormalities, abnormal genetic testing, family and previous maternal pregnancy history, and pregnancy infections Evaluation Histopathologic evaluation of the placenta - structural abnormalities, and large infarctions .

25. Examination Anthropometric measurements at birth Examination of the infant Stigmata of “ malnourishment” Features of aneuploidies - dysmorphic facies , congenital anomalies stigmata congenital infections - microcephaly, petechiae and “blueberry muffin” rashes Cardiac murmur – a/w CHD

26. Stigmata of “ M alnourishment” L arge and wide anterior fontanelle, A bsent buccal fat S mall and scaphoid abdomen T hin umbilical cord, D ecreased skeletal muscle & subcutaneous fat, D isproportionately large hands and feet, L oose and dry skin (axilla &gluteal regions) L arge head compared to the body (Asymmetric IUGR)

27. Stigmata of “congenital infections”

28. Interventions to improve OUTCOME High risk of stillbirth, neonatal death, and prematurity 5 to 30-fold increase in morbidity and mortality 2.5 times more likely to be born premature Chances of needing more perinatal intervention like caesarean delivery, exposure to antenatal steroids, and admission to NICU

29. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY MANAGEMENT RECOMMENDATIONS Perinatal distress / asphyxia IUGR infants, compared to AGA, have a 5-30x increase in morbidity and mortality, even when born at term 2.5x more likely to be born premature. Increased risk for stillbirth and prematurity makes the delivery of an IUGR neonate high risk. Increased risk of perinatal distress given in the setting of chronic poor blood flow and hypoxia. Attendance at delivery by a skilled team that can resuscitate a low birth weight or premature infant, ideally at a center with a neonatal intensive care unit

30. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY MANAGEMENT RECOMMENDATIONS Hypoglycemia <2.6 mmol /L OR < 46 mg/ dL 1/3 of infants with a birth weight <10% have severe, recurrent, and/or prolonged hypoglycemia. Due to suboptimal glycogen stores, impaired gluconeogenesis. Decreased fat, increased sensitivity to insulin. May be exacerbated by polycythemia or hypothermia. Serial monitoring for hypoglycemia soon after birth. If persistent, prolonged, or severe: Formula supplementation, gavage feeding, provision of dextrose-containing intravenous fluids.

31. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY MANAGEMENT RECOMMENDATIONS Respiratory complications Poor in utero growth and concomitant risk for prematurity put IUGR infants at risk for respiratory distress syndrome in the short term and chronic lung disease in the long term. IUGR infants exhibit evidence of pulmonary vascular remodeling, which may result in increased risk of pulmonary hypertension. Supportive care and respiratory support, as necessary.

32. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY MANAGEMENT RECOMMENDATIONS Hypothermia Decreased brown fat deposition in utero. Temperature monitoring, initiated soon after birth. Provision of an exogenous heat source or incubator may be required Necrotizing enterocolitis / feeding intolerance Severe cases of IUGR (UA Dopplers ), with concomitant prematurity, may have increased susceptibility to NEC and/or feeding intolerance. Breastmilk provision and avoidance of formula. Early initiation of trophic or small volume feeding.

33. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY MANAGEMENT RECOMMENDATIONS Intraventricular hemorrhage Due to cerebral vascular remodeling , cerebral autoregulatory mechanisms, and overall hemodynamic instability in IUGR. Surveillance with head ultrasound. Avoiding fluctuations in cerebral oxygenation using continuous monitoring such as near infrared spectroscopy. Electrolyte abnormalities Hyperglycemia and hypocalcemia Monitor for and correct abnormalities Polycythemia/jaundice May occur as a response to long-standing hypoxia in utero. Check for underlying hematologic abnormalities, and treat when clinically indicated.

34. POSTNATAL CONCERN OVERALL RISK & ETIOLOGY MANAGEMENT RECOMMENDATIONS Abnormal innate and humoral immunity Due to bone marrow suppression secondary to chronic hypoxia. Check for underlying abnormalities with a complete blood count and differential. Low threshold for infectious work-up and aggressive management of infection

35. Potential targets for therapy Malhotra A, Allison BJ, Castillo-Melendez M, Jenkin G, Polglase GR, Miller SL. Neonatal morbidities of fetal growth restriction: pathophysiology and impact. Frontiers in endocrinology. 2019 Feb 7;10:55.

36. Complications

37. Neonatal morbidities in IUGR

38. Long Term Outcomes Neurodevelopmental consequences increased risk for cerebral palsy lower scores across multiple neurocognitive domains including cognition, attention, mood, and social skills decreased brain volume, gray matter, and hippocampal volumes asymmetric IUGR - brain-sparing appears to be regional, not global “Optimized postnatal growth seems to portend better neurocognitive outcomes ”

39. C ardiometabolic consequences   Phenomenon of – “Developmental programming” B ased on epidemiologic studies showing that maternal gestation during periods of famine results in IUGR offspring that are at increased risk for cardio-metabolic disease during adulthood. Examples - obesity, cardiovascular disease, and diabetes

40. Other Long term Outcomes Propensity toward cancer, schizophrenia , Alzheimer’s disease, polycystic ovarian syndrome, shorter life span immune dysfunction

41. What's New Behavioral interventions and SGA (December 2021 ) P articipants were randomly assigned to a structured Mediterranean diet, mindfulness-based stress reduction, OR usual care from 20 weeks of gestation to delivery. The rate of SGA births was significantly lower for both structured diet (14 percent) and stress reduction (16 percent) compared with usual care (22 percent ) Timing of delivery in fetal growth restriction (August 2021 )   Infants who were severely small for gestational age (SGA, birth weight <3rd percentile) and delivered early for suspected FGR had poorer school outcomes in grades 3, 5, and 7 compared with infants with the same degree of SGA who were not suspected of having FGR (mean gestational age at birth: 37.9 versus 39.4 weeks)

42. Take Home Message IUGR is due to fetal growth less than its genetic potential. To diagnose, prevent, and develop therapies for intrauterine growth restriction – A challenge Broad Aetiologies are: F etal , Maternal , Environmental and P lacental Prenatal screening largely depends on serial USG & Doppler - still debate as to how these s hould be used to dictate prenatal care and delivery planning IUGR has significant short- and long-term consequences for the neonate

43. Thank You

44. Fanaroff and martin's neonatal-perinatal medicine www.UpToDate.com