Use of biochemical tests of placental function for improving pregnancy outcome

Alexander E P Heazell, Melissa Whitworth, Lelia Duley, Jim G Thornton
Cochrane Database of Systematic Reviews 2015 November 25, (11): CD011202

BACKGROUND: The placenta has an essential role in determining the outcome of pregnancy. Consequently, biochemical measurement of placentally-derived factors has been suggested as a means to improve fetal and maternal outcome of pregnancy.

OBJECTIVES: To assess whether clinicians' knowledge of the results of biochemical tests of placental function is associated with improvement in fetal or maternal outcome of pregnancy.

SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2015) and reference lists of retrieved studies.

SELECTION CRITERIA: Randomised, cluster-randomised or quasi-randomised controlled trials assessing the merits of the use of biochemical tests of placental function to improve pregnancy outcome.Studies were eligible if they compared women who had placental function tests and the results were available to their clinicians with women who either did not have the tests, or the tests were done but the results were not available to the clinicians. The placental function tests were any biochemical test of placental function carried out using the woman's maternal biofluid, either alone or in combination with other placental function test/s.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data and assessed trial quality. Authors of published trials were contacted for further information.

MAIN RESULTS: Three trials were included, two quasi-randomised controlled trials and one randomised controlled trial. One trial was deemed to be at low risk of bias while the other two were at high risk of bias. Different biochemical analytes were measured - oestrogen was measured in one trial and the other two measured human placental lactogen (hPL). One trial did not contribute outcome data, therefore, the results of this review are based on two trials with 740 participants.There was no evidence of a difference in the incidence of death of a baby (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.36 to 2.13, two trials, 740 participants (very low quality evidence)) or the frequency of a small-for-gestational-age infant (RR 0.44, 95% CI 0.16 to 1.19, one trial, 118 participants (low quality evidence)).In terms of this review's secondary outcomes, there was no evidence of a clear difference between women who had biochemical tests of placental function compared with standard antenatal care for the incidence of stillbirth (RR 0.56, 95% CI 0.16 to 1.88, two trials, 740 participants (very low quality evidence)) or neonatal death (RR 1.62, 95% CI 0.39 to 6.74, two trials, 740 participants, very low quality evidence)) although the directions of any potential effect were in opposing directions. There was no evidence of a difference between groups in elective delivery (RR 0.98, 95% CI 0.84 to 1.14, two trials, 740 participants (low quality evidence)), caesarean section (one trial, RR 0.48, 95% CI 0.15 to 1.52, one trial, 118 participants (low quality evidence)), change in anxiety score (mean difference -2.40, 95% CI -4.78 to -0.02, one trial, 118 participants), admissions to neonatal intensive care (RR 0.32, 95% CI 0.03 to 3.01, one trial, 118 participants), and preterm birth before 37 weeks' gestation (RR 2.90, 95% CI 0.12 to 69.81, one trial, 118 participants). One trial (118 participants) reported that there were no cases of serious neonatal morbidity. Maternal death was not reported.A number of this review's secondary outcomes relating to the baby were not reported in the included studies, namely: umbilical artery pH < 7.0, neonatal intensive care for more than seven days, very preterm birth (< 32 weeks' gestation), need for ventilation, organ failure, fetal abnormality, neurodevelopment in childhood (cerebral palsy, neurodevelopmental delay). Similarly, a number of this review's maternal secondary outcomes were not reported in the included studies (admission to intensive care, high dependency unit admission, hospital admission for > seven days, pre-eclampsia, eclampsia, and women's perception of care).

AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of biochemical tests of placental function to reduce perinatal mortality or increase identification of small-for-gestational-age infants. However, we were only able to include data from two studies that measured oestrogens and hPL. The quality of the evidence was low or very low.Two of the trials were performed in the 1970s on women with a variety of antenatal complications and this evidence cannot be generalised to women at low-risk of complications or groups of women with specific pregnancy complications (e.g. fetal growth restriction). Furthermore, outcomes described in the 1970s may not reflect what would be expected at present. For example, neonatal mortality rates have fallen substantially, such that an infant delivered at 28 weeks would have a greater chance of survival were those studies repeated; this may affect the primary outcome of the meta-analysis.With data from just two studies (740 women), this review is underpowered to detect a difference in the incidence of death of a baby or the frequency of a small-for-gestational-age infant as these have a background incidence of approximately 0.75% and 10% of pregnancies respectively. Similarly, this review is underpowered to detect differences between serious and/or rare adverse events such as severe neonatal morbidity. Two of the three included studies were quasi-randomised, with significant risk of bias from group allocation. Additionally, there may be performance bias as in one of the two studies contributing data, participants receiving standard care did not have venepuncture, so clinicians treating participants could identify which arm of the study they were in. Future studies should consider more robust randomisation methods and concealment of group allocation and should be adequately powered to detect differences in rare adverse events.The studies identified in this review examined two different analytes: oestrogens and hPL. There are many other placental products that could be employed as surrogates of placental function, including: placental growth factor (PlGF), human chorionic gonadotrophin (hCG), plasma protein A (PAPP-A), placental protein 13 (PP-13), pregnancy-specific glycoproteins and progesterone metabolites and further studies should be encouraged to investigate these other placental products. Future randomised controlled trials should test analytes identified as having the best predictive reliability for placental dysfunction leading to small-for-gestational-age infants and perinatal mortality.

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