First trimester determination of adverse pregnancy outcome

Transcription

1 First trimester determination of adverse pregnancy outcome Prof. Gordon C S Smith, MD, PhD Department of Obstetrics & Gynaecology, Cambridge University

2 In the first half of pregnancy, genetic control is dominant and gives rise to relatively narrow limits of variability of patterns of fetal growth Gluckman PD & Liggins GC. In Fetal Physiology and Medicine

3 Early model of human fetal growth Genetically programmed early on Variability greatest in third trimester Bulk of weight gain in third trimester Implied a key role for maternal nutrition in the last third of pregnancy Led to multiple trials of dietary supplementation in late pregnancy

4 Low birth weight anomaly Women with poor diet are at increased risk of a low birth weight baby Dietary supplementation during the presumed phase of maximum fetal growth has a minimal effect on birth weight, except in conditions of starvation Susser, Am J Clin Nutr 1991;53:

5 Hypothesis The intra-uterine conditions in early pregnancy determine, at least in part, the eventual birth weight

6 Prediction Measurements of fetal growth or placental function in early pregnancy may be predictive of eventual outcome

7 QMH cohort study All women attending for antenatal care at The Queen Mother s Hospital Glasgow Included women had a scan in the first 12 weeks actual size Excluded women who had used oral contraception in last 3 months, irregular or non- 28 day menstrual cycle and not certain of date of LMP expected size Study group of 4229

8 Outcomes studied Examined both absolute birth weights, relative weights and gestational age Low birth weight (<2500g) Low birth weight at term (<2500g at or after 37 weeks gestation) Birth weight <5 th percentile for gestational age Preterm birth Extreme (24-32 weeks) Moderate (33-36 weeks)

9 Smith GCS et al, NEJM 1998;339:

10 Smith GCS et al, NEJM 1998;339:

11 Interpretation of results Poor growth of the fetus in the first trimester associated with increased risk of adverse outcome Could also indicate over-estimation of the age of the fetus i.e. ovulation occurred later than assumed Unlikely given restriction of women to those with a regular 28 day cycle

12 Alternative hypothesis Could be due to delayed ovulation Prolonged menstruation to conception interval associated with adverse outcome Based on second trimester US measurements Expected size of fetus based on LMP alone, no information on cycle duration, certainty of recall or hormonal contraception Gardosi & Francis, BJOG. 2000;107:228-37

13 Follow-up study Data from FASTER trial Large scale, multi-center, prospective cohort study of Down syndrome screening >30,000 women, 976 eligible women conceived using assisted reproductive technology method known date of conception with CRL measurement Repeated analysis and replicated result Bukowski, et al for FASTER consortium, Unpublished data

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15 Smith GCS et al, NEJM 1998;339:

16 Predictions from hypothesis Trophoblast function in the first trimester of pregnancy will differ comparing babies ultimately born of low birth weight with those of normal birth weight Potential for testing the hypothesis as maternal blood contains many trophoblast derived proteins which are minimally produced by other maternal tissues

17 CUBS Study Non-interventional, prospective cohort study designed to evaluate predictors of Down s syndrome Measured PAPP-A and free subunit of human chorionic gonadotrophin at weeks using the Kryptor immunoassay analyzer Total cohort of approximately 13,000 women Study group of 8839 women with outcome data

18 Aims of analysis To relate risk of subsequent adverse obstetric outcomes to levels of PAPP-A and F hcg at weeks

19 Methods PAPP-A and F hcg expressed as multiples of median (MOM) for gestation MOMs adjusted for maternal weight and smoking Outcomes related to deciles of PAPP-A and F hcg to establish trend Strength of association between lowest 5 th percentile and adverse outcomes

20 Statistics Outcome across deciles of PAPP-A and F hcg tested by chi squared test for trend Univariate and multivariate analysis of lowest 5 th percentile by logistic regression

21 PAPP-A levels in early pregnancy and the risk of adverse obstetric outcome Smith GCS et al JCEM 2002;87:1762-7

22 Free beta-hcg levels in early pregnancy and the risk of adverse obstetric outcome Smith GCS et al JCEM 2002;87:1762-7

23 Multivariate analysis PAPP-A F hcg Outcome OR* (95%CI) P= OR* (95%CI) P= BW <5 th percentile 2.9 ( ) < ( ) 0.15 Delivery weeks 2.9 ( ) ( ) 0.77 Delivery weeks 2.4 ( ) < ( ) 0.04 Pre-eclampsia 2.3 ( ) < ( ) 0.64 *Adjusted for: BMI, height, smoking status, ethnicity, parity, maternal age, gestational age at the time of sampling, PAPP-A and F hcg Smith GCS et al JCEM 2002;87:1762-7

24 Summary of results No independent predictive effect of F hcg PAPP-A associated with all adverse outcomes F hcg was significantly associated with some outcomes but not independently of PAPP-A Different patterns of association between PAPP-A and different outcomes

25 PAPP-A and normal pregnancy Further analysis of cases where sampling wholly within first trimester Excluded all complicated pregnancies and confined analysis to term births Regression analysis (linear, logistic and proportional hazards) to determine associations between absolute birth weight, low birth weight and onset of labour

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27 Risk of low birth weight at term Risk of a low birth weight baby at term explored using PAPP-A as a continuous variable (logistic regression) Odds ratio 0.2 (95% CI ) Indicates that across the range of PAPP-A from the 1 st - 99 th percentile, risk of a low birth weight baby decreases by 80% Smith GCS et al, Nature 2002; 417:916.

28 Significance of fetal growth Poor fetal growth is a risk factor for antepartum stillbirth Poor fetal growth may be predictive of disease in later life

29 Antepartum stillbirth Most common cause of perinatal death Majority have no direct cause, but are associated with impaired growth Associations with second trimester biophysical measurements msafp and uterine artery Doppler Postulated may be due to impaired second wave of trophoblast invasion

30 Methods 1 Record linked CUBS study database with Scottish Morbidity Record 2 (SMR2, national database maternity hospital discharge data) and the 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 weeks gestation Independent ascertainment of exposures and events Smith GCS et al, JAMA. 2004;292:

31 Methods 2 PAPP-A and F hcg, expressed as MoMs Low defined as 5 th percentile (<0.4 MoM for PAPP-A) Smith GCS et al, JAMA. 2004;292:

32 Results 1 No association between low PAPP-A ( 5 th 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) Smith GCS et al, JAMA. 2004;292:

33 Smith GCS et al, JAMA. 2004;292:

34 Smith GCS et al, JAMA. 2004;292:

35 Smith GCS et al, JAMA. 2004;292:

36 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 F hcg No relationship with other causes of stillbirth Smith GCS et al, JAMA. 2004;292:

37 PAPP-A Produced in syncytiotrophoblast PAPP-A has protease activity on IGFBP-4 Low levels of PAPP-A lead to low levels of IGFBP-4 and likely decrease placental effects of IGF-II which would adversely affect growth Role supported by studies in mice: PAPP- A null mutants exhibit severe early onset IUGR (Conover et al, Development 2004;131: )

38 Further studies on 1 st trimester trophoblast & obstetric outcome Follow-up studies using stored samples from cohort linked to Scottish maternity and perinatal death databases Nested-case control study of 1000 complicated pregnancies and 1000 controls Measured s-flt1, PlGF, IGF-1, IGF-2, IGFBP-1, IGFBP-3, Leptin and MMP-9

39 Relationship between first and second trimester predictors Elevated AFP and hcg associated with increased risk of stillbirth How does this relate to association with PAPP-A?

40 Interaction: P=0.03 Interaction: P=0.14 Smith et al, Obstet Gynecol 2006;107:

41 Conclusions Fetal growth and risk of stillbirth determined in first trimester Synergistically predictive with second trimester markers Potential for sequential screening for stillbirth risk, comparable to Down s syndrome screening

42 Acknowledgements Dr Jill Pell, Consultant in Public Health, Greater Glasgow Health Board Information & Statistics Division of the NHS Scotland (James Boyd, David Walsh, Richard Dobbie), SMR2 & SMR1 data. Dr Jenny Crossley & Dr David Aitken, Department of Medical Genetics, Yorkhill, Glasgow (CUBS study) Mr John Fleming & Dr Margaret McNay, Department of Ultrasound, The Queen Mother s Hospital, Glasgow, Ultrasound database study