Background:

Over recent years, we have witnessed a great improvement in population-based screening methods for fetal abnormalities as a result of technological developments in ultrasound, biochemical screening and molecular genetics. However, the methods for screening the low risk population for other complications of pregnancy such as fetal growth restriction, preeclampsia and stillbirth have remained largely unchanged for the past 20-30 years. The National Institute for Clinical Excellence (NICE) has highlighted a number of research priorities in their guidelines for pregnancy care, which focus on the ability to screen apparently healthy low risk women and identify those at high risk of complications. This area has been a major focus for research in the Department of Obstetrics and Gynaecology for many years.

Origins:

In 2007, Cambridge received funding from NIHR to establish a comprehensive Biomedical Research Centre (BRC). The Cambridge BRC Women’s Health theme focuses on tackling the origins, treatment and prevention of many of the health issues that affect women during their reproductive years. The bulk of the Cambridge BRC funding for Women’s Health supports a prospective cohort study called the Pregnancy Outcome Prediction study (POPs) (Pasupathy et al 2008, Gaccioli et al 2016).

 

Design and Aims:

The POPs study included 4,512 nulliparous women with a viable singleton pregnancy attending The Rosie Hospital (Cambridge, UK) for their dating ultrasound scan between 2008 and 2012 (Pasupathy et al 2008, Gaccioli et al 2016). Women were serially scanned through the pregnancy and had blood obtained at recruitment, 20, 28 and 36 weeks gestational age. DNA samples and height/weight measurements of the partners were also collected. After delivery, biopsies of the placenta, placental membranes, umbilical cord, and cord blood were collected (visual placental sampling demonstration). Thorough design of POPs and careful sample collection allowed us to create an extensive, optimally phenotyped biobank of complicated pregnancies and controls, including approximately 230,000 blood and tissue samples stored in -80°C freezers, 24,000 formalin fixed placental biopsies, and 4,000 paternal DNA samples. The rationale behind our focus on the placenta is that placental dysfunction is implicated in several major complications of pregnancy associated with adverse maternal and infant outcome, such as preeclampsia, fetal growth restriction and stillbirth. Yet, despite years of intensive research, screening for these complications is still largely based upon clinical grounds rather than ultrasonic and/or biochemical assessment of placental function.

Therefore the projects based on POPs samples have the following aims: (i) understanding the mechanisms leading to placentally-related complications, (ii) studying the association between pregnancy complications and the presence of infectious agents in the placenta, (iii) evaluating the performance of known biomarkers and serial ultrasonography in assessing maternal and fetal well-being, and iv) discovering novel, placentally-derived circulating biomarkers which reflect the underlying pathology and are highly sensitive and specific in predicting the associated disease.

Multiple projects based on the clinical records, measurements, and samples collected during the POPs study have been started and the analysis of this extremely valuable resource of data/specimens is currently ongoing. Some of our studies include:

• Assessment of altered fetal growth using ultrasonographic fetal biometry and the association between fetal growth abnormalities and adverse pregnancy outcomes (Sovio et al 2015, Partap et al 2016, Sovio et al 2016);
• Analysis of placental morphometry and its relationship with prenatal ultrasonic measurements (Salavati et al 2016);
• Histopathological analysis of placental biopsies (focusing on samples from pregnancies complicated by preeclampsia and fetal growth restriction) to study inflammatory markers in these specimens;
• Automated immunoassay analysis of maternal serum samples to study circulating proteins which have shown associations with placental function, i.e. alpha fetoprotein (AFP), chorionic gonadotropin (hCG), Pregnancy Associated Plasma Protein A (PAPP-A), PlGF (Placental Growth Factor), and soluble fms-like tyrosine kinase 1 (sFlt-1) (Sovio et al 2017);
• Next Generation Sequencing (NGS) applied on placental biopsies, with a focus both on the transcriptome and the epigenome (small RNAs, DNA methylation and histone modifications).

These projects received funding from the Medical Research Council, the NIHR, the Wellcome Trust, the British Heart Foundation, and the Stillbirth and Neonatal Death Society (Sands). We have also benefited from industry, with GE Healthcare providing two ultrasound systems and Roche providing equipment and reagents for ~80,000 assays of placental proteins. Some of these studies involve collaborations with the Cambridge University School of Biological Sciences (in particular, the Centre for Trophoblast Research with whom we have extremely close links) as well as the CRUK Cambridge Institute and the Wellcome Trust Sanger Institute. These associations reflect one of the key approaches in our research, namely, to use the incredible technical innovations that have been achieved in sequencing to study our placental samples.

Publications:

1. The RNA landscape of the human placenta in health and disease.  Gong, S., Gaccioli, F., Dopierala, J. et al.  Nat Commun 12, 2639 (2021).
2. A maternal serum metabolite ratio predicts large for gestational age infants at term: a prospective cohort study.  Sovio U, Goulding N, McBride N, Cook E, Gaccioli F, Charnock-Jones DS, Lawlor DA, Smith GCS. The Journal of Clinical Endocrinology & Metabolism, 2021.
3. Abnormal placental CD8+ T‐cell infiltration is a feature of fetal growth restriction and pre‐eclampsia.  Lager S, Sovio U, Eddershaw E, van der Linden MW, Yazar C, Cook E, Happerfield L, Jessop FA, Sebire NJ, Charnock-Jones DS, Smith GCS.  J Physiol 2020.
4. Comparison of estimated fetal weight percentiles near term for predicting extremes of birthweight percentile. Sovio U, Smith GCS.Am J Obstet Gynecol 2020.
5. Independent influences of maternal obesity and fetal sex on maternal cardiovascular adaptation to pregnancy: a prospective cohort study. Teulings NEWD, Wood AM, Sovio U, Ozanne SE, Smith GCS, Aiken CE.  Int J Obes 2020.
6. Fetal inheritance of chromosomally integrated human herpesvirus 6 predisposes the mother to pre-eclampsia.  Gaccioli F, Lager S, de Goffau MC, Sovio U, Dopierala J, Gong S, Cook E, Sharkey A, Moffett A, Lee WK et al. Nat Microbiol 2020;5:901-908.
7. A maternal serum metabolite ratio predicts fetal growth restriction at term. Sovio U, Goulding N, McBride N, Cook E, Gaccioli F, Charnock-Jones DS, Lawlor DA, Smith GCS. Nature Medicine 2020;26:348-353.
8. Human placenta has no microbiome but can contain potential pathogens. de Goffau MC, Lager S, Sovio U, Gaccioli F, Cook E, Peacock SJ, Parkhill J, Charnock-Jones DS, Smith GCS. Nature 2019.
9. The association between first trimester AFP to PAPP-A ratio and placentally-related adverse pregnancy outcome. Hughes AE, Sovio U, Gaccioli F, Cook E, Charnock-Jones DS, Smith GCS. Placenta 2019;81:25-31.
10. 4-Hydroxyglutamate is a novel predictor of pre-eclampsia. Sovio U, McBride N, Wood AM, Masconi KL, Cook E, Gaccioli F, Charnock-Jones DS, Lawlor DA, Smith GCS.  Int J Epidemiol 2020;49(1):301-311.
11. Screening for breech presentation using universal late pregnancy ultrasonography: A prospective cohort study and cost-effectiveness analysis. Wastlund D, Moraitis AA, Dacey A, Sovio U, Wilson ECF, Smith GCS. PLOS Med 2019;16(4):e1002778.
12. Evaluation of a simple risk score to predict preterm preeclampsia using maternal characteristics: a prospective cohort study. Sovio U, Smith GCS. BJOG 2019.
13. A lower maternal cortisol-to-cortisone ratio precedes clinical diagnosis of preterm and term preeclampsia by many weeks. Jayasuriya NA, Hughes AE, Sovio U, Cook E, Charnock-Jones DS, Smith GCS. J Clin Endocrinol Metab 2019;104(6):2355-2366.
14. Detecting eukaryotic microbiota with single-cell sensitivity in human tissue. Lager S, de Goffau MC, Sovio U, Peacock SJ, Parkhill J, Charnock-Jones DS, Smith GCS.  Microbiome 2018;6(1):151.
15. Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia.  Gong S, Sovio U, Aye ILMH, Gaccioli F, Dopierala J, Johnson MD, Wood AM, Cook E, Jenkins BJ, Koulman A, Casero Jr RA, Constância M, Charnock-Jones DS, Smith GCS. JCI Insight. 2018.
16. Screening for fetal growth restriction using ultrasound and the sFLT1/PlGF ratio in nulliparous women: a prospective cohort study.  Gaccioli F, Sovio U, Cook E, Hund M, Charnock-Jones DS, Smith GCS. Lancet Child & Adol Health. 2018.
17. Genome-wide oxidative bisulfite sequencing identifies sex-specific methylation differences in the human placenta. Gong S, Johnson MD, Dopierala J, Gaccioli F, Sovio U, Constancia M, Smith GCS, Charnock-Jones DS. Epigenetics. 2018. 
18. Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers. Gaccioli F, Aye ILMH, Sovio U, Charnock-Jones DS, Smith GCS. Am J Obstet Gynecol. 2017.
19. The effect of customization and use of a fetal growth standard on the association between birthweight percentile and adverse perinatal outcome.  Sovio U, Smith GCS.  Am J Obstet Gynecol. 2017.
20. Birth weight to placenta weight ratio and its relationship to ultrasonic measurements, maternal and neonatal morbidity: A prospective cohort study of nulliparous women. Salavati N, Gordijn SJ, Sovio U, Zill-E-Huma R, Gebril A, Charnock-Jones DS, Scherjon SA, Smith GCS. Placenta. 2017.
21. Blinded ultrasonic fetal biometry at 36 weeks and the risk of emergency caesarean delivery: a prospective cohort study of 3,047 low risk nulliparous women. Sovio U, Smith GCS. Ultrasound Obstet Gynecol. 2017.
22. Universal versus selective ultrasonography to screen for large for gestational age infants and associated morbidity. Sovio U, Moraitis AA, Wong HS, Smith GCS. Ultrasound Obstet Gynecol. 2017.
23. The pregnancy outcome prediction (POP) study: Investigating the relationship between serial prenatal ultrasonography, biomarkers, placental phenotype and adverse pregnancy outcomes. Gaccioli F, Lager S, Sovio U, Charnock-Jones DS, Smith GCS. Placenta 2017;59(Suppl 1):S17-S25.
24. Prediction of Preeclampsia Using the Soluble Fms-Like Tyrosine Kinase 1:Placental Growth Factor Ratio. A Prospective Cohort Study of Unselected Nulliparous Women. Sovio U, Gaccioli F, Cook E, Hund M, Charnock-Jones DS, Smith GCS. Hypertension 2017;69:731-738.
25. Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction. Cleaton MA, Dent CL, Howard M, Corish JA, Gutteridge I, Sovio U, Gaccioli F, Takahashi N, Bauer SR, Charnock-Jones DS, Powell TL, Smith GC, Ferguson-Smith AC, Charalambous M. Nat Genet 2016 Dec;48(12):1473-1480.
26. Fetal Growth and the Risk of Spontaneous Preterm Birth in a Prospective Cohort Study of Nulliparous Women. Partap U, Sovio U, Smith GC. Am J Epidemiol. 2016 Jul 15;184(2):110-119.
27. Accelerated Fetal Growth Prior to Diagnosis of Gestational Diabetes Mellitus: A Prospective Cohort Study of Nulliparous Women. Sovio U, Murphy HR, Smith GC. Diabetes Care 2016 Jun;39(6):982-987.
28. The relationship between human placental morphometry and ultrasonic measurements of utero-placental blood flow and fetal growth. Salavati N, Sovio U, Mayo RP, Charnock-Jones DS, Smith GC. Placenta 2016 Feb;38:41-48.
29. Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study. Sovio U, White IR, Dacey A, Pasupathy D, Smith GC. Lancet 2015 Nov 21;386(10008):2089-2097.
30. Study protocol. A prospective cohort study of unselected primiparous women: the pregnancy outcome prediction study. Pasupathy D, Dacey A, Cook E, Charnock-Jones DS, White IR, Smith GC. BMC Pregnancy Childbirth 2008, 8:51.