Molecular biological changes in human placenta in relation to maternal, foetal and neonatal characteristics

The intrauterine environment influences the possibility for the fetus to reach its genetically determined growth potential. An adverse intrauterine environment can lead to fetal growth restriction and changes in the structure and function of developing organs and tissues in accordance with the theory of fetal programming. Fetal growth restriction can lead to the birth of a small-for-gestational age infant and is associated with an increased risk for diseases and complications both in the neonatal period and later in life. In this research group, we study molecular biological changes in the placenta – the important organ that influences the physiology of the pregnant woman to maintain the pregnancy, supplies the fetus with nutrients and oxygen, and transports waste products away from the fetus. We study these placental changes in relation to maternal characteristics like obesity, fetal exposures like cigarette smoking, and in relation to neonatal characteristics like abnormal birth size to increase our knowledge on the pathogenesis of pregnancy complications and to enable improvements of the fetal period. Our material originates from a large sample collection of placental tissues and cord blood at Örebro University Hospital.

The placenta and cord blood sample collection at Örebro University Hospital, Örebro, Sweden

Aims, principal investigators and ethical approvals

Professor emeritus Jens Schollin, former head of the Department of Paediatrics, Örebro University Hospital, and vice-chancellor at Örebro University, initiated the collection of placental tissue and cord blood samples aiming at studying associations between inflammation in these tissues and preterm birth and the later risk for development of cerebral palsy in the offspring. The project was approved by the Research Ethics Committee at Örebro University Hospital in December 2003 (D-nr 340/03).

Schollin transmitted the responsibility for the project and the sample collection to Ph.D. and consultant in paediatrics Maria Björkqvist, who broadened the research questions to also include foetal and postnatal growth. These changes were approved by the Regional Board of Ethics, Uppsala, Sweden, in June 2010 (D-nr 2010/189). Later on, the responsibility for the study and the sample collection were transferred to Ph.D. and consultant in paediatrics Maria Lodefalk, who further broadened the purpose of the study to include epigenetic, gene expression and protein expression changes in relation to pregnancy complications, intrauterine exposures and maternal and foetal characteristics. This alteration was approved by the Regional Board of Ethics, Uppsala, in September 2016 (D-nr 2010/189-1).   

Methods and materials

After written informed consent was received from each pregnant woman, placental tissue and cord blood samples were collected immediately after the delivery at the Department of Women’s Health, Örebro University Hospital, during 2004–2012. In total, approximately 10,000 samples have been collected.

After removal of the membranes, two pieces (approximately 1 cm³ each) were taken from the maternal side of the placenta. The samples were rinsed in cold phosphate buffered saline to remove blood and then stored frozen (-80°C) in 3 mL RNAlater. Before April 2009, 30 mL tubes were used for the storage of the placenta samples and after that time point, 5 mL tubes were used.

A cord venous blood sample was collected from each child at the time of delivery in 10 mL clot activator tubes (BD Vacutainer, Plymouth, UK). Each sample was centrifuged at 2000 x g for 7 min and the serum was stored frozen (-80°C) in separate aliquots (2 mL tubes).

For the capture of data on the pregnant woman, the pregnancy, the delivery and the newborn infant, a background data form was used during 2004–2007. At the beginning of 2008, electronic medical records (Obstetrix®) were introduced at the Department of Women’s Health and from then, the background data on each mother-infant pair was collected from these records.

The data collected during 2004–2007 lacked some information (for example the height of the woman, the birth length of the infant, and Apgar score at 5 min of age). This missing data was collected from the Swedish Medical Birth Register at the National Board of Health and Welfare in October 2017.  

Birth weight, length and head circumference of the infants have been transformed to z-scores using Swedish reference data (Niklasson A et al, BMC Pediatrics, 2008).

Publications, dissertations and on-going projects as for November 2020

Allbrand M, Bjorkqvist M, Nilsson K, Ostlund I, Aman J. Placental gene expression of inflammatory markers and growth factors - a case control study of obese and normal weight women. J Perinat Med. 2015; 43: 159-64. PMID: 25014513. DOI: 10.1515/jpm-2013-0343

Allbrand M, Aman J, Lodefalk M. Placental ghrelin and leptin expression and cord blood ghrelin, adiponectin, leptin, and C-peptide levels in severe maternal obesity. J Matern Fetal Neonatal Med. 2018; 31: 2839-46. PMID: 28783996. DOI: 10.1080/14767058.2017.1358262

Allbrand M, Aman J, Nilsson K, Cao Y, Lodefalk M. Expression of genes involved in inflammation and growth - does sampling site in human full-term placenta matter? J Perinat Med. 2019; 47: 539-46. PMID: 30920955. DOI: 10.1515/jpm-2018-0290

Ostling H, Kruse R, Helenius G, Lodefalk M. Placental expression of microRNAs in infants born small for gestational age. Placenta. 2019; 81: 46-53. PMID: 31138431. DOI: 10.1016/j.placenta.2019.05.001

Allbrand, M. (2020). Gene expression of inflammatory markers and growth factors in placenta in relation to maternal obesity and foetal and postnatal growth. Örebro: Örebro University. Dissertation.

Lodefalk M, Allbrand M, Montgomery S. Duration of the pushing phase of labour is inversely associated with the expression of TNF, IL6, IGF1 and IGF2 in human placenta. The Journal of Maternal-Fetal & Neonatal HealthThe Journal of Maternal-Fetal & Neonatal Health, https://doi.org/10.1080/14767058.2021.1916459

Roxenlund F, Kruse R, Östling H, Lodefalk M. Differential microRNA expression in placentas of small-for-gestational age neonates with and without exposure to poor maternal gestational weight gain. https://doi.org/10.1515/jpm-2020-0597

Allbrand M, Eklund D, Cao Y, Nilsson K, Lodefalk M. Gene expression of leptin, leptin receptor isoforms, and inflammatory cytokines in placentas of obese women – associations to birth weight and foetal sex. https://doi.org/10.1016/j.placenta.2021.10.002

Proteome expression in human placenta exposed to maternal smoking during the pregnancy

Lodefalk, M. , Chelslín, F. , Patriksson Karlsson, J. & Hansson, S. R. (2023). Placental Changes and Neuropsychological Development in Children-A Systematic Review. Cells, 12 (3).

Östling, H. , Lodefalk, M. , Backman, H. & Kruse, R. (2022). Global microRNA and protein expression in human term placenta. Frontiers in Medicine, 9.