1. O Intra-Uterine Growth Restriction diagnosis and management

2. Small fetus should get our attention: Increased Perinatal Mortality Stillbirth – 54 % of preterm stillbirths – 26 % of term stillbirths Neonatal Death – 2-3 fold increased risk Gardosi J, Mul T, Mongelli M, et al. Br J Obstet Gynaecol 1998 Bernstein IM, Horbar JD, Badger GJ, et al. Am J Obstet Gynecol 2000

3. Small fetus should get our attention: Morbidity Short term – Neonatal encephalopathy – Necrotizing enterocolitis – Respiratory distress Long term – Cerebral palsy, chronic lung disease, developmental – delay, cardio-vascular problems Programming for adult diseases – Diabetes – Hypertension

4. Stillbirth rates in relation to fetal growth restriction and whether it was detected antenatally

5. Risk of intrauterine death in SGA fetus Pilliod, Am J Obstet Gynecol. 2012

6. 1.Identify small fetus 2.SGA vs. FGR 3.Early vs. Late 4.Management

7. Definition of SGA Abdominal Circumference – Liver size Liver is the largest intra-abdominal organ that is most affected by aberrant growth Growth restriction and macrosomia – AC 95% Most sensitive Most scientifically applicable

8. Estimated fetal weight Most frequently used formula in ultrasound machines is by Hadlock But, there are more than 50 others in the literature

9. US fetal weight standards (in utero) 392 white women Certain menstrual dates Estimated fetal weight : BPD, HC, AC, FL Log10EFW (g) = 1.3596 – 0.00387 (AC) ´ FL + 0.0064 (HC) + 0.00061 (BPD) ´ AC + 0.0424 (AC) + 0.174 (FL) Hadlock FP, Harris RB, Martinez-Poyer J. In utero analysis of fetal growth: a sonographic weight standard. Radiology 1991; 181(1): 129-133 Note: lack of flattening at term

10. Customized formulas and serial measurements Different populations have different growth standards – customized growth Each fetus has it´s own individual growth curve – serial measurements An intra-uterine reduction in growth velocity in term appropriately sized babies is not associated with demonstrable poor perinatal outcomes (Tan,KL 2016)

11. SGA versus FGR What happens in utero to a growth retarded fetus? How can we minimize life-long effect on the fetus/newborn?

12. Classification of FGR

14. FGR – the pathophysiology Placenta The fetal circulation The heart The brain

15. FGR – affected vessels Umbilical arteries Middle cerebral arteries Ductus venosus Umbilical vein Myocardial function

16. Umbilical artery wave forms an early sign of FGR window into the circulation on the fetal side of the placenta Normal Abnormal – high resistance Abnormal – Absent EDF

17. Umbilical Artery Reverse End Diastolic Flow (REDF) is associated with obliteration of >70% of the placental arteries Kingdom JC, et al. Ultrasound Obstet Gynecol 1997 Morrow RJ, et al. Am J Obstet Gynecol 1989

18. The middle cerbral artery Blood flow through the MCA is dependent upon the pO2 of the fetus auto-regulation occurs when the fetus tries to protect the cortex normal abnormal

19. Middle cerebral artery (MCA) brainsparing associated with: Increased cesarean section rate for distress Combined adverse neonatal outcomes Neonatal neurological outcome Adverse neurodevelopment at 2 years of age Cruz-Martinez R, et al. Obstet Gynecol 2011 Flood K, Unterscheider J, Daly S, et al; PORTO Study. Am J Obstet Gynecol 2014 Oros D, Figueras F, Cruz- Martinez R, et al. Ultrasound Obstet Gynecol 2010 Eixarch E, Meier E, Iraola A, et al. Ultrasound Obstet Gynecol 2008

20. Cerebro-Placental Index

21. Intra- and Inter-observer reproducibility of MCA PI measured in the third trimester is POOR Clinical impact may be limited Repetition of measurements to confirm abnormality before clinical decisions are taken is mandatory Marchi L et al. 2016 Reproducibility

22. The venous system The ductus indirectly reflects the efficiency of the fetal heart and seems to correlate with the presence or absence of metabolic acidosis. This may be due to shunting away from the right lobe of the liver with less delivery of necessary substrates.

23. Ductus venosus in early FGR Average 6 days from A/R flow in the ductus to stillbirth (compared to average 19 days from abnormal MCA to stillbirth) Every day of ARDV flow doubles the rate of stillbirth If some flow in the “a” wave of ductus, risk of stillbirth is low, but morbidity rate is 50%. Turan S, Turan OM, Miller J, et al. Ultrasound Obstet Gynecol 2011

24. The umbilical vein Decrease in volume flow and pulsations have different meanings in FGR

25. Umbilical vein Normal Abnormal (pulsation)

26. Umbilical vein blood flow Correlates well with placental mass Decrease occurs earlier than A/R flow in umbilical artery Excellent correlation with need for emergency CS and neonatal acidosis Galan 1999, Rigano 2001, Parra-Saavedra 2014

27. FGR and the heart In most cases the peripheral vessels tell some of the story, but somewhere along the way the heart starts to flag in FGR in an unpredictable way. Measures of cardiac function: – Myocardial performance index (MPI) – Tricuspid and mitral annular plane systolic excursion (MAPSE and TAPSE) – Sphericity index

28. Tei index (Myocardial performance index) Stamilio, DM et al. AJOG, 2010

29. Figure 2 Cruz-Lemini, American Journal of Obstetrics & Gynecology 2014) Fetal cardiovascular score to predict infant hypertension and arterial remodeling in FGR TAPSE, tricuspid annular-plane systolic excursion IVRT, isovolumic relaxation time Sphericity index C/P ratio TAPSE IVRT

30. Management of FGR

31. Early FGR

32. Ensure accurate dating Consider deriving a customized centile Asses anatomy / placenta/amniotic fluid volume Perform UA Doppler Unterscheider et al. BMC Pregnancy and Childbirth 2014 Abbrevations: EFW estimated fetal weight (Hadlock-4) UA umbilical artery EDFend-diastolic flow AEDFabsent end-diastolic flow REDFreversed end-diastolic flow AFIamniotic fluid index AREDFabsent or reversed end-diastolic flow in UA CTG cardiotocograph MCAmiddle cerebral artery GAgestational age Clinical suspicion/ risk factors Sonographic assessment of fetal weight (EFW Hadlock-4) EFW >10th centile EFW < 10th centile Routine care, consider follow up scan in 4 weeks Diagnostics and management of early FGR

33. Ensure accurate dating Consider deriving a customized centile Asses anatomy / placenta/amniotic fluid volume Perform UA Doppler EFW < 10th centile Normal UA UA Doppler (PI>95 th, + EDF) UA AEDF AU REDF Repeat sonogram in 2-weekly intervals Assess biometry, UA and AFI Consider delivery at 37 weeks and no later than 40 weeks if good Repeat sonogram in weekly intervals or more frequently as necessary Assess UA, AFI; (MCA optional), 2-weekly biometry assessment, timed corticosteroids < 34 weeks Consider delivery at 37 weeks, or earlier if poor interval growth Admit, repeat sonogram in twice weekly intervals or more frequently as necessary Assess UA, AFI; (MCA optional), Timed corticosteroids, MgSO4 <32 weeks Deliver no later than 34 weeks Admit, repeat sonogram in thrice weekly intervals or more frequently as necessary Assess UA, AFI; (MCA optional), Timed corticosteroids, MgSO4 <32 weeks Deliver no later than 30 weeks Unterscheider et al. BMC Pregnancy and Childbirth 2014 Diagnostics and management of early FGR

34. In all cases, delivery is also indicated by abnormal CTG, ideally based on short term variation CTG if fetus deemed viable (ie GA>24 weeks and EFW>500grams) Send placenta for histopathology Obtain arterial and venous cord pH Offer follow up appointment to women with FGR <3rd centile and delivery <34 weeks Review of placental histology Consider thrombophilia screening Modification of risk factors Prevention with Aspirin/ LMWH Unterscheider et al. BMC Pregnancy and Childbirth 2014 In cases of AREDF, consider the opinion of a fetal medicine specialist regarding timing of delivery Diagnostics and management of early FGR

35. Management of Late FGR

36. LATE FGR This different type of growth restriction kept out of sight for many years because the umbilical artery wave forms are often normal. Major features: Slow incremental growth only late in pregnancy Normal umbilical artery but abnormal MCA Redistribution of cardiac output

37. Brain sparing in late FGR with normal Doppler in umbilical arteries Higher rate of: Infant morbidity 2-yr neuro-behavioral abnormalities C/S for non-reassuring FHR in labor Childhood Hypertension and Cardiac dysfunction with high fetal cardiovascular score Deeper Sylvian fissures, cingulate sulci, and smaller brain volumes on MRI Oros 2010, PORTO study 2014, Eixarch 2008, Cruz-Martinez 2011, Cruz-Lemli 2014, Egana-Urvinovi 2013)

38. Induction versus expectant monitoring for FGR at term N= 650 SGA > 37 wks Randomised equivalence trial (DIGITAT) BMJ 2011

39. Induction versus expectant monitoring for FGR at term N= 292 24-months SGA > 37 wks Randomised equivalence trial (DIGITAT) AJOG 2014 Admission to intermediate care + severe FGR impact on abnormal neurodevelopment

40. Late FGR in fetuses, that develop intrapartum distress, there is a pre-labour redistribution of cardiac output right to left cardiac output ratio is superior to cerebro-placental ratio in predicting fetal distress this might be a useful test in stratifying patients for intensity of monitoring during labour Paramasivam G, 2016, FMF World congress

41. FGR – when to deliver Still up for grabs based on what we know (or don´t know) A comprehensive longitudinal study with careful neurological short and long term follow up is needed to help answer this question

42. Key points 1.In diagnosing FGR pay attention to the abdominal circumference 2.Early signs of FGR in SGA fetuses involve the umbilical arteries and MCA 3.Late signs of compromise involve the DV 4.Up until 30 weeks, gestational age plays the biggest part in outcome 5.After 30 weeks, the Dopplers correlate best with outcome (especially the DV)

43. Key points (cont) 6.In early FGR, the umbilical artery is the first to become abnormal. 7.In late FGR, the MCA often is the first to become abnormal 8.Timing of delivery is critical to outcome 9.Functional heart examintion might contribute to the clinical diagnosis in Late FGR in the future

44. Thank you for your attention

46. Management of FGR There is no accepted way of “treating” FGR Best outcome is now dependent upon our interpreting a variety of fetal „messages“ We have to choose the best time to save the baby from an inhospitable environment. J.C.Hobbins, 2014

47. Management of SGA Standard methods: 1.FHR testing and BPP 2.Dopplers of the umbilical arteries Other (non-standard) methods: 1.MCA Dopplers 2.Cerebroplacental index 3.Ductus venosus 4.Umbilical vein flow 5.Various assessment of fetal cardiac function

48. Standard testing for fetal condition NST- can avoid fetal demise, but may be too late to alter neonatal morbidity Biophysical profile - Can be complimentary because it adds another element to the testing mix (the CNS)

49. Early FGR – what is known Often abnormal uterine arteries Sometimes accompanied by hypertension Early plateauing of fetal growth High risk for perinatal death and disability

50. Timeline in early FGR Decreased EDF in umbilical artery cerebroplacental ratio falls off MCA shows brain sparing Absent EDF in umbilical artery Ductus - decreased flow during atrial contraction Biophysical profile < 6 or non-reacting NST Absent or reversed flow in ductus venosus

51. Timing of delivery in early FGR Up until 27 weeks gestational age is the best predictor of survival At 29 weeks the DV is the best predictor of intact survival “Brain sparing” does not necessarily protect the brain It is unclear how long can a fetus have signs of brain sparing before the damage is done. Baschat AA, Cosmi E, Bilardo CM, et al. Obstet Gynecol 2007

52. Timeline in late FGR MCA shows brain sparing Umbilical artery is normal or shows modestly decreased EDF BPP may be completely normal, as well as the NST before labor Often abnormal FHR patterns in labor requiring cesarean section

53. Timing of delivery in late FGR conflicting data Randomised control trial showing that expectant management after 36 weeks did not increase perinatal morbidity or mortality (DIGITAT) Other study showing upswing in perinatal death after 37 weeks

54. DIGITAT study: Fetal and maternal outcomes after induction of labour are equivalent to those with expectant monitoring in women with suspected intrauterine growth restriction at term Induction is not associated with any increase in operative and instrumental delivery rates

55. DIGITAT study: Infants with suspected growth restriction are more likely to be admitted to an intermediate level of care after induction of labour than after expectant monitoring, possibly as a result of complications of late prematurity It is rational to choose induction in patients with intrauterine growth restriction near term to prevent possible neonatal morbidity and stillbirth, and future studies should focus on the optimal timing of induction

56. Figueras, Ultrasound Obstet Gynecol 2014 Classification criteria of late-onset FGR versus SGA

57. Figueras, F. Ultrasound Obstet Gynecol 2014

58. Cardiovascular Measures and outcome Cardiovascular score as a predictor of : – hypertension at 6 months – arterial remodeling (thickness of aortic wall) 40% of FGRs had diastolic and 2% had systolic hypertension Cardiovascualar score was highly predictive (90% sens, 63% PPV) Cruz-Lemli et al, Am J Obstet Gynecol 2014