Risk factors and predictors of stillbirth

1. Risk factors and predictors of stillbirth Gordon C S Smith, MD, PhD, MRCOG Professor of Obstetrics & Gynaecology, Cambridge University

2. Antepartum stillbirth Major cause of perinatal death Majority have no direct cause Associated with poor fetal growth

3. Risk assessment and prevention of antepartum stillbirth Primary means of prevention is elective delivery of a fetus deemed at risk Risk of antepartum stillbirth balanced against risk of elective delivery Risks of elective delivery Preterm: Morbidity and mortality related to prematurity Term: Operative delivery Interference in natural process of birth

4. Planning intervention Identify high risk groups Increased level of surveillance (fetal and placental Doppler ultrasound) Elective delivery if surveillance indicates fetal compromise or pregnancy reaches given threshold of gestation Previous SB at 38 weeks IDDM at 39 weeks Post-dates pregnancy at term + 10 days

5. Predicting risk High risk groups already identified IDDM Previous SB Connective tissue disease Problem: most stillbirths occur to “low risk” women Solution: identify factors associated with an increased risk of stillbirth

6. Where to start? Majority of stillbirths have a placental cause Abruption Pre-eclampsia IUGR In the absence of overt risk factors, may be able to identify high risk women within a low risk population by screening tests of placental function

7. Tests of placental function Assess resistance in uterine circulation by Doppler ultrasound of uterine arteries Measure circulating maternal concentrations of placentally-derived proteins

8. Uterine artery Doppler Measured at 20-23 weeks Indicates invasion of maternal circulation by placenta Increased resistance associated with increased risk of placentally-related events (fetal death, abruption, PET or IUGR delivered before 34 weeks)

9. Biochemical tests of placental function Alpha-feto protein (AFP) Pregnancy associated plasma protein A (PAPP-A) Human chorionic gonadotrophin

10. PAPP-A Derived from placenta Involved in the control of insulin-like growth factors Measured in screening for Down’s syndrome

11. CUBS Study Non-interventional, prospective cohort study in central Scotland designed to evaluate predictors of Down’s syndrome Measured PAPP-A and FbhCG 8-14 weeks Study group of 8839 women with outcome data manually retrieved Stillbirth excluded congenital abnormality but included all other causes

12. PAPP-A and stillbirth

13. Methods for follow-up study Record linked CUBS study database with Scottish Morbidity Record 2 (SMR2, national database maternity hospital discharge data) Scottish Stillbirth & Infant Death Enquiry (national register of perinatal deaths) Limited to women assayed in first 10 weeks post-conception Linked database contained first trimester biochemistry and eventual outcome for 7934 singleton births between 24-43 weeks gestation Independent ascertainment of exposures and events

14. Results 1 No association between low PAPP-A (=5th percentile) and a range of maternal characteristics Age, marital status, socio-economic deprivation, ethnicity, smoking, parity, previous abortions, height and BMI (all P>0.05)

18. Summary of results Very strong relationship between low PAPP-A and subsequent risk of stillbirth Association due to stillbirth related to placental dysfunction No placental stillbirths in upper 60% of PAPP-A Association specific Not due to maternal confounding No relationship with FbhCG No relationship with other causes of stillbirth

19. Aims of research studies To identify biological determinants of stillbirth To obtain clinically useful assessment of risk Requires analysis of multiple factors with a summary estimate of risk Gestational age dependent

20. Potential for combinations of tests

21. Gestational age

22. Current work Data source (funded by FSID) record linkage of: CUBS study (PAPP-A) West of Scotland regional biochemical screening databases (AFP and hCG), SMR2 (basic pregnancy outcome data) SSBIDE (perinatal deaths)

23. Aims of current study To assess predictive ability of combined maternal and biochemical assessment of stillbirth risk to identify high risk women To determine whether associations with maternal and biochemical factors vary according to gestational age Study cohort of >200,000 women

24. Current data (unpublished) Factors associated with stillbirth and associations similar between 24-43 weeks Maternal age, deprivation category, height, smoking, body mass index and parity Factors associated with stillbirth and associations differ between 24-43 weeks Maternal serum levels of alpha-fetoprotein and human chorionic gonadotrophin Factors not independently associated with stillbirth risk Marital status

27. Screening performance of models

28. Requirements of model for population-based screening Develop sensitive and specific methods for identifying women at increased risk of antepartum stillbirth Assess mass screening and intervention on the basis of such a test

29. Intervention Needs to be assessed in RCT Recruit population and screen all Reveal results and manage 50% per protocol and conceal results in other 50% Primary outcome: perinatal death at term Intervention would be elective delivery at 37 weeks Less potential to cause harm than preterm elective delivery

30. Sample power calculations Incidence of antepartum stillbirth at term 1.8 per 1000 Trial of a screening test which took the top 5% of predicted risk as ‘screen positive’ 50% sensitivity, trial would require 60,000 women 75% sensitivity would require 22,000 women Current method top 5% has 16.4% sensitivity for term stillbirth

31. Mass screening Key to further progress is to develop a good screening tool Large scale prospective observational study is required to evaluate integrated assessment of risk Maternal history and characteristics Biochemical interrogation of the placenta using further analysis of samples already obtained at time of booking and triple test Uterine artery Doppler at 20 weeks ?growth and umbilical artery Doppler scan in third trimester Identify women with a high absolute risk of term stillbirth

32. Conclusions Many maternal factors associated with the risk of antepartum stillbirth Tests of placental function also predictive of stillbirth risk Currently available methods are better predictors of preterm than term stillbirth Current methods to assess stillbirth risk are not sufficiently discriminative to assess population-based screening Need to evaluate whether a clinically useful model can be created by adding further tests to AFP/maternal prediction

33. Acknowledgements Foundation for the Study of Infant Deaths Richard Dobbie at ISD of NHS Scotland for record linkage CUBS study group and West of Scotland Regional Genetics service (Drs Jenny Crossley and David Aitken) Prof Jill Pell (Public Health, Glasgow) Ian White and Dr Angela Wood at MRC Biostatistics Unit, Cambridge