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Assessing and quantifying placental dysfunction in relation to pregnancy outcome in pregnancies complicated by reduced fetal movements.
[Thesis]. Manchester, UK: The University of Manchester; 2015.
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Abstract
Currently there is no test to accurately predict stillbirth. It is proposed that better identification of placental disease in utero may aid stillbirth prediction and prevention. Pregnancies complicated by reduced fetal movement (RFM) have increased risk of stillbirth. We hypothesised that RFM is a symptom of placental dysfunction associated with adverse pregnancy outcome (APO) and that this placental abnormality can be detected antenatally and used to identify fetuses at highest-risk of APO. We tested this hypothesis by: 1) comparison of ex vivo placental structure and function between APO RFM pregnancies and their normal outcome RFM counterparts, 2) comparison of in utero estimates of placental size, vascularity, vascular and endocrine functions obtained from placental ultrasound, Doppler waveform analysis and maternal circulating placentally-derived hormone concentrations, to their ex vivo correlates and 3) examination of the predictive potential of placental biomarkers at the time of RFM.Ex vivo placentas from APO RFM pregnancies, compared to normal outcome RFM counterparts, were smaller (diameter, area, weight and volume, p<0.0001), less vascular (vessel number and density, p≤0.002), with arteries that were less responsive to sodium nitroprusside (p<0.05), and with aberrant endocrine function (reduced tissue content and/or release of human chorionic gonadotrophin (hCG), human placental lactogen (hPL) and soluble fms-like Tyrosine Kinase-1 (sFlt-1), p<0.03). Placental volume (PV) ex vivo correlated with sonographic estimated PV (p<0.004), hPL, hCG and placental growth factor (PlGF) concentrations in the maternal circulation (p<0.03). Ex vivo villous vessel number and density correlated with Doppler impedance at the umbilical artery free-loop (UAD-F, p=0.02) and intraplacental arteries (p<0.0001) respectively, whilst UAD-F impedance correlated with arterial thromboxane sensitivity (p<0.04). Examination of placental structure and function at the time of presentation with RFM identified 15 independently-predictive biomarkers. Three potential predictive models, incorporating measures of placental size (PlGF), endocrine function (sFlt-1), arterial thromboxane sensitivity and villous vascularity (UAD-F), were proposed. Using these models, sensitivity for APO was improved from 8.9% with baseline care (assessment of fetal size and gestation) to up to 37.5% at a fixed specificity of 99% (p<0.05). This series of studies shows that antenatal placental examination is possible and improves identification of pregnancies at highest risk of stillbirth in a high-risk population by up to 29%. Therefore such tests merit further development to prospectively assess their ability to predict and prevent stillbirth itself.
Layman's Abstract
Stillbirth (the death of an infant before birth) occurs in one in every 250-300 pregnancies after 28 weeks of pregnancy in high-income countries. There is currently no good test to predict and prevent this. Stillbirth is associated with disease of the placenta (afterbirth) in six in every ten cases. It is proposed that better identification of placental disease before birth can improve the prediction, and prevention, of stillbirth. Pregnancies where there is a reduction in the baby’s movements (RFM) are two to three times more likely to experience stillbirth. We asked whether examination of the placenta before birth is possible, and whether it can help identify pregnancies at highest risk of adverse outcome (APO) after RFM. We answered this question by comparing the placentas of APO RFM pregnancies to those of their normal outcome counterparts after delivery to identify differences that may form the basis of useful tests. Ultrasound measurement of the placenta and its blood flow, and placental hormone concentrations in the mother’s blood were compared to direct measurements obtained from the same placentas after birth. Finally, we added antenatal placental examination to the assessment of pregnancies at the time of RFM and examined their ability to predict subsequent APO.Placentas from APO RFM pregnancies were smaller (length, width, area, volume and weight), with poorer blood supply (reduced number and density of blood vessels), and abnormal function (reduced relaxation of placental arteries, and altered production and release of placental hormones). A number of these placental features were reflected in examination of the placenta before birth. Placental size was related to ultrasound estimation of its volume, length and width, but also to the level of some hormones arising from the placenta in the maternal blood. Placental blood supply was related to assessment of blood flow resistance between the baby and placenta and within the placenta itself, whilst resistance to blood flow from baby to placenta reflected how sensitive the placental arteries were to chemicals that cause arteries to tighten. Using these placental tests, in a group of 300 pregnancies affected by RFM, three more pregnancies out of every 10 that resulted in APO could be predicted by the additional measurement of two placental hormones (placental growth factor and soluble fms-like tyrosine Kinase-1) and three measures of placental blood flow resistance between baby and the placenta, in addition to normal care.This series of studies shows that examination of the placenta before birth is possible and that it improves the ability to identify pregnancies that are at the highest risk of stillbirth following RFM. These tests should be further developed to assess their ability to predict and prevent stillbirth itself.
Keyword(s)
Adverse pregnancy outcome; Biomarker; Doppler; Fetal growth restriction; Placenta; Reduced fetal movement; Stillbirth; Ultrasound