1. Stephanie Cooper, MD FRCSC Beyond Aneuploidy- Prediction of Adverse Obstetrical Outcomes with First Trimester Screening: PAPP-A Prediction of Adverse Obstetrical Outcomes with First Trimester Screening: PAPP-A

2. Prenatal Screening Sensitive and accessible prenatal screening for aneuploidy and open neural tube defects is a standard recognized in the 2007 SOGC Clinical Practice Guidelines on Prenatal Screening for Fetal Aneuploidy

3. “All pregnant women in Canada, regardless of age, should be offered, through an informed consent process, a prenatal screening test for the most common clinically significant aneuploidies” SOGC- Clinical Practice Guidelines Prenatal Screening for Aneuploidy (2007)

4. FTS Quad Test Integrated Test (IPS) Serum IPS IPS without inhibin Triple Screen (MSS) MA + NT + free ß-hCG + PAPP-A at 11-14 weeks DR 84%, FPR 5% MA + AFP + uE3 + ß-hCG (or total hCG) and Inhibin-A DR 77%, FPR 5.2% MA + NT + PAPP-A (11-14 weeks) + quad test (15-17 weeks) DR 87%, FPR 1.9% MA + PAPP-A (11-14 weeks) + quad test (15-17 weeks) DR 85%, FPR 4.4% MA+ NT + PAPP-A + triple screen DR 88%, FPR 3% MA + AFP + uE3 + ß-hCG (or total hCG) DR 71%, FPR 7.2 %- MA= Maternal age, NT= nuchal translucency Current Screening Combinations in Canada

5. BEYOND ANEUPLOIDY

6. Why is early prediction of adverse outcomes important? Alberta has highest rate of preterm birth and low birth weight in Canada Preeclampsia is the 2nd most common cause of maternal death worldwide and most common cause of iatrogenic prematurity Strategies to identify risk factors and interventions that may improve pregnancy outcome in this group is a priority

7. Low Birth Weight - Province of Alberta

8. Preterm Births Canada vs Alberta

9. Where it all starts The pathologic changes of preeclampsia, IUGR (and in some cases of preterm labour) occur as early as the first trimester, long before clinical manifestations are observed

10. Where it all starts Early placental cells invade maternal spiral arteries transforming them from small muscular arterioles to large vessels of low resistance.

11. Where it all starts In pregnancies destined for preeclampsia and IUGR, the cytotrophoblasts infiltrate the decidual portion of the spiral arteries, not the myometrial portion. The vessels remain narrow leading to hypoperfusion

12. A detectable maternal humeral response to inadequate placentation might predict those pregnancies at risk

14. What is PAPP-A?

15. PAPP-A PAPP-A is a protease for IGFBP-4 IGF binding proteins inhibit the action of IGFs, which play a key role in regulating fetal growth and trophoblastic invasion of the decidua

16. PAPP-A “Additional monitoring should occur in such circumstance*” “Screening reports should highlight such cases with increased risk*” PAPP-A levels in the first trimester of pregnancy are predictive of a range of adverse outcomes* PAPP-A levels in the first trimester of pregnancy are predictive of a range of adverse outcomes* * Smith et al. JAMA 2004: 2249-2252, Dugoff et al. Am J Obstet Gynecol 2004; 191:1446-51, Krantz et al. Am J Obstet Gynecol 2004; 191:1446-51, Spencer et al. Prenat Diagn 2005: 25:949-953 However, as prospective data assessing PAPP-A as a screening tool in a low risk population is limited, the finding of low PAPP-A in women undergoing FTS presents a clinical management dilemma

17. Impaired trophoblastic invasion of maternal spiral arteries is associated with increased impedance to flow in uterine arteries Uterine artery Doppler ultrasound can assess blood flow for adequate or reduced perfusion Uterine Artery Doppler

18. Normal Abnormal Uterine Artery Doppler

19. Combining uterine artery Doppler at 22-24 weeks with low PAPP-A (10-14 weeks) improves detection of hypertension than by either marker in isolation. Combining uterine artery Doppler at 22-24 weeks with low PAPP-A (10-14 weeks) improves detection of hypertension than by either marker in isolation. Spencer et al. Prenat Diagn 2005: 25:949-953

20. SOGC Clinical Practice Guideline “Uterine artery Doppler may be performed at the time of the 17-22 weeks...in women with the following risk factors”: Previous early onset gestational hypertension Placental abruption IUGR Stillbirth Pre-existing hypertension Gestational hypertension Pre-existing renal disease Long standing IDDM with end organ involvement Abnormal maternal serum screening (hCG or AFP >2.0 MOM) Low PAPP-A Fetal Health Surveillance: Antepartum and Intrapartum Consensus Guidelines. JOCG Sept 2007

21. Association between first trimester maternal serum pregnancy associated plasma protein-A (PAPP-A) and adverse pregnancy outcome Division of Maternal Fetal Medicine Department of Obstetrics and Gynecology University of Calgary Calgary Laboratory Services Cooper S, Johnson JM, Metcalfe A, Connors G, Pollard J, Simrose R, Jones D Roggensack A, Krause R, Lange I

22. PURPOSE A: To assess the diagnostic accuracy of maternal serum PAPP-A <0.4 MOM (<5 th %ile) at 11-13 +6 weeks gestation in detecting adverse obstetrical outcomes in a low risk population. B: To determine if the addition of UA Doppler pulsatility index (PI) at 18 and 22 weeks gestation improves the predictive accuracy of low first trimester PAPP-A in the detection of adverse obstetrical outcomes.

23. METHODS- Part A TYPE OF STUDY Prospective, non-intervention, matched cohort study INCLUSION CRITERIA All pregnant women attending for FTS at single site with: –Live singleton gestations at 11-13 +6 weeks –Able to provide informed consent EXCLUSION CRITERIA Pregnancies with chromosomal or structural abnormalities Low PAPP-A (< 0.4 MOM’s) No interventions specific to low PAPP-A (patients and physicians ‘blinded’) Followed to pregnancy outcome “Normal” PAPP-A (> 0.4 MOM) Matched by independent reviewer to cases (2:1) for ethnicity, age, FTS date Followed to pregnancy outcome

24. METHODS: Part B TYPE OF STUDY Prospective cohort study INCLUSION CRITERIA All pregnant women attending FTS February- Oct 2007 with: –Live singleton gestations at 11-13 +6 weeks –PAPP-A < 0.4 MOM –Agreeing to additional pregnancy surveillance –Provided informed consent EXCLUSION CRITERIA Pregnancies with chromosomal or structural abnormalities PAPP-A < 0.4 MOM: counseled and consented Uterine artery Doppler 18 weeks ( + = PI > 1.45) Uterine artery Doppler 22 weeks( + = PI > 1.45) Followed to pregnancy outcome Additional surveillance & management as clinically indicated

25. Primary Outcomes PRIMARY OUTCOMES ( A&B) Manual in-patient chart review at 3 hospital sites Low Birth Weight (LBW) (<2500 grams) Preterm Delivery (PTB) (< 37 weeks gestation) Pre-eclampsia 1 (PIH) Small for gestational age (SGA) (< 10 th %ile ) 1.SOGC Clinical Practice Guidelines. Diagnosis, evaluation and management of hypertension in pregnancy. JOGC March 2008

26. Statistical Analysis Part A: –Chi square tests were used to compare outcomes (LBW, PTB, PIH and SGA) between groups –Logistic regression was used to determine if low PAPP-A predicts negative outcomes Part B : –Logistic regression analysis was used to compare outcomes in low PAPP-A patients with positive and negative UA Doppler at both gestational age groups

27. RESULTS: Part A March 2006 – December 2006: –3815 women completed FTS –Low PAPP-A (< 0.4 MOM) n= 198 (5.6%) –Eligible patients with complete obstetrical outcomes n=150 (80%), matched to 300 controls Demographics –Low PAPP-A group representative of controls: Average Age: 32 yrs (31% ≥ 35, 4.6% > 40 yrs) 87%: High school +/- University 35%: Primiparous 18%: Non-English speaking (ESL)

28. RESULTS : Part A Incidence (%) of Adverse Outcomes

29. RESULTS: Part A OR (95% CI)P-value LBW 3.13 (1.41-6.93) 0.01 PTB 2.26 (1.11-4.62) 0.03 HTN 1.50 (0.77-2.96) 0.24 NS SGA 1.26 (0.61-2.60) 0.53 NS Cumulative 1.40 (0.87-2.24) 0.16 PAPP-A as a predictor of adverse outcomes

30. Sensitivity (95% CI) Specificity (95% CI) PPV (95% CI)NPV (95% CI) LBW 59% (0.41-0.76) 68% (0.64-0.73) 11% (0.07-0.17) 96% (0.93-0.98) PTB 52% (0.35-0.68) 68% (0.63-0.72) 12% (0.07-0.18) 95% (0.91-0.97) HTN 38% (0.24-0.55) 67% (0.62-0.71) 9% (0.05-0.14) 93% (0.89-0.95) SGA 44% (0.28-0.58) 67% (0.63-0.72) 11% (0.07-0.17) 93% (0.89-0.95) RESULTS : Part A PAPP-A: Test performance for adverse outcomes

31. 0.4 MOM0.3 MOM0.25 MOM0.2 MOM Sensitivity 66%32%18%6.7% Specificity 51%81%90%96% PAPP-A: Test performance for any adverse outcome using cut-offs 0.2 MOM- 0.4 MOM RESULTS

32. CONCLUSIONS- Part A 1.Low PAPP-A is a significant predictor of adverse obstetrical outcomes This association would support pregnancy monitoring and surveillance 2.However, the predictive value of low PAPP-A for these outcomes is weak Therefore the clinical utility of isolated low PAPP-A as a predictor of adverse obstetrical outcomes is limited 3.Further study is needed to determine if adjunctive biochemical and ultrasound markers can better identify risk

33. RESULTS- Part B January - October 2007; –5359 women completed FTS –Low PAPP-A (< 0.4 MOM) n= 289 (5.3%) –Patients consenting to ongoing surveillance, n= 229 (79%) –Complete obstetrical outcomes, n= 202 (89%)

34. + Doppler 18 weeks (n= 34) + Doppler 22 weeks (n= 11) PTB (<37 w) OR= 1.95 (0.85-4.50), NS OR= 12.6 (3.15-50.0), p= 0.001 PIH (< 2500g) OR = 1.15 ( 0.29-4.40), NS OR= 3.77 (0.91-15.0) NS SGA (< 10 th %ile) OR= 2.28 (1.03-5.10), p= 0.04 OR= 8.24 (2.27-30.0), p= 0.001 LBW (<2500 g) OR= 1.56 (0.69-3.52) NS OR= 6.85 (1.90-25.0), p=0.003 RESULTS Uterine artery Doppler as a predictor of adverse outcomes in low PAPP-A patients + uterine artery Doppler = PI > 1.45

35. SensitivitySpecificityPPVNPV PTB <37 21%98%73%83% PIH 1.7%95%27%48% SGA 18%97%64%83% LBW 16%97%64%79% At least 1 of above 91%67%15%99% RESULTS 22 Week Uterine Artery Doppler: test performance for adverse outcomes

36. SensitivitySpecificityPPVNPV PTB 31%82%31%82% PIH 23%79%83%93% SGA 33%83%36%80% LBW 26%80%31%78% At least 1 of above 27%83%50%65% RESULTS 18 Week Uterine Artery Doppler: test performance for adverse outcomes

37. RESULTS: SUMMARY A positive uterine artery Doppler (PI >1.45) at 18 weeks in low PAPP-A patients was found to significantly predict SGA but not found to significantly predict PTB, PIH or LBW A positive uterine artery Doppler (PI >1.45) at 22 weeks in low PAPP-A patients was found to significantly predict PTB, SGA and LBW but not PIH

38. CONCLUSIONS- 18 w Uterine artery Doppler at 18 weeks was found to have good specificity and a strong negative predictive value, however, there was a high rate of false positives Economic analysis is required to determine the cost effectiveness of a 2 stage uterine artery Doppler protocol

39. CONCLUSIONS- 22 w Due to small sample size, we are unable to conclude if uterine artery Doppler at 22 weeks can accurately predict the risk of adverse outcomes in low PAPP-A patients At present, clinical judgement is advised Consider third trimester ultrasound for fetal growth and well- being Future studies are required to verify our findings –Larger sample sizes –Additional ultrasound and biochemical markers should be evaluated in low PAPP-A patients

40. But most importantly, clinical assessment and judgment of the maternal-fetal unit as a whole can never be forgotten