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Stephanie Cooper, MD FRCSC

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

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Stephanie Cooper, MD FRCSC

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

  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 GuidelinesPrenatal Screening for Aneuploidy (2007)

  4. 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 BirthsCanada 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

  13. What is PAPP-A?

  14. 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

  15. PAPP-A PAPP-A levels in the first trimester of pregnancy are predictive of a range of adverse outcomes* “Additional monitoring should occur in such circumstance*” “Screening reports should highlight such cases with increased risk*” *Smith et al. JAMA 2004: 2249-2252, Dugoff et al. Am J ObstetGynecol 2004; 191:1446-51, Krantz et al. Am J ObstetGynecol 2004; 191:1446-51, Spencer et al. PrenatDiagn 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

  16. Uterine Artery Doppler • 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

  17. Uterine Artery Doppler Abnormal Normal

  18. Uterine Artery Doppler 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. PrenatDiagn 2005: 25:949-953

  19. 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

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

  21. PURPOSE A: To assess the diagnostic accuracy of maternal serum PAPP-A <0.4 MOM (<5th %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.

  22. 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 NORMALS “Normal” PAPP-A (> 0.4 MOM) Matched by independent reviewer to cases (2:1) for ethnicity, age, FTS date Followed to pregnancy outcome Low PAPP-A (< 0.4 MOM’s) No interventions specific to low PAPP-A (patients and physicians ‘blinded’) Followed to pregnancy outcome

  23. 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 Additional surveillance & management as clinically indicated

  24. 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-eclampsia1 (PIH) • Small for gestational age (SGA) (< 10th%ile) • SOGC Clinical Practice Guidelines. Diagnosis, evaluation and management • of hypertension in pregnancy. JOGC March 2008

  25. 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

  26. 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)

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

  28. RESULTS: Part A PAPP-A as a predictor of adverse outcomes

  29. RESULTS : Part A PAPP-A: Test performance for adverse outcomes

  30. RESULTS PAPP-A: Test performance for any adverse outcome using cut-offs 0.2 MOM- 0.4 MOM

  31. CONCLUSIONS- Part A Low PAPP-A is a significant predictor of adverse obstetrical outcomes This association would support pregnancy monitoring and surveillance 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 Further study is needed to determine if adjunctive biochemical and ultrasound markers can better identify risk

  32. 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%)

  33. RESULTS Uterine artery Doppler as a predictor of adverse outcomes in low PAPP-A patients + uterine artery Doppler = PI > 1.45

  34. RESULTS 22 Week Uterine Artery Doppler: test performance for adverse outcomes

  35. RESULTS 18 Week Uterine Artery Doppler: test performance for adverse outcomes

  36. 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 notPIH

  37. 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

  38. 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

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

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