Women’s health and paediatrics
Key areas of focus
- Predictors of Pregnancy Outcome
- Identification of neonatal neurodevelopmental disorders and brain injury in the “Neuro-NICU.”
- Metabolic Disease and Cancer
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 overall strategy is to build a collaborative group of clinical and lab-based investigators who provide expertise in basic, translational and clinical Maternal-Fetal and Paediatric research. Our Aims are to develop knowledge on basic biological determinants of health and disease in women, neonates and children and to better predict and detect disease to aid in prevention and intervention. The overarching goal of our theme is the development of measurable improvements and treatments with a positive effect on the health of women and their newborn babies.
Predictors of Pregnancy Outcome. 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). The 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. 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.
Thorough design of the POPs and careful samples 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, 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 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 (Sovio et al 2015, Partap et al 2015, Sovio et al 2016);
- Analysis of placental morphometry to investigate its relation 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);
- 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. We have also benefited from Industry, with GE Healthcare providing two ultrasound systems and Roche providing equipment and reagents for about 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.
Over recent years, we 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.
Early detection and diagnosis/stratification of neonatal brain disorders
The prevalence of cerebral palsy is rising in the UK because of increased survival of vulnerable extremely low birth weight (ELBW) preterm infants. We will develop the “Neural Net”, a collaborative of East of England regional NICUs attuned to diagnosis of neurological problems using imaging, EEG metabolic and biomarker studies. Neonatal rare neurological disorders present with seizures, encephalopathy and extremis. We will collect samples for genomic analysis to build on the Decipher project for rare neurodevelopmental disorders to investigate genetic and phenotypic diversity and use iPSC and organoids to model these disorders.
Paediatric solid cancers: Detection and personalised medicine. Solid tumours are the leading cause of cancer-related death in children. Cambridge leads international clinical and biological cancer studies in children, including biomarker studies of solid tumors (germ cell tumours, lymphoma and neuroblastoma).
Metabolic disease and Type-1 Diabetes (T1D). We can achieve significant progress in understanding the mechanisms in babies that progress to full blown T1D. Prof David Dunger studies young people with T1D with detailed immune phenotyping moving towards targeted mechanistic intervention studies in collaboration Oxford and Guys London BRCs. We developed a computer program communicating with commercially available insulin pumps and continuous glucose monitoring devices to create the Artificial Pancreas (NEJM 2015) and application of this method will be further studied in children and pregnant women.
Challenges and Precision Medicine
Paediatric illness has a collective impact on children, their families and society at large. Cutting-edge challenges are to identify individuals at risk and provide new therapies that can treat acute disease as well as adverse developmental effects that can have life-long consequences. The prevalence of rare/genetic disorders in Paediatrics argues for routine application of Precision Medicine to better understand the pathobiological sequence and tailor therapies to the individual patient.