J. Perinat. Med. 2017; aop Pippa Staps*, Marije Hogeveen, Joris Fuijkschot, Joris van Drongelen and Michèl A.A.P. Willemsen Understanding fetal factors that contribute to preterm birth: Sjögren-Larsson syndrome as a model https://doi.org/10.1515/jpm-2017-0187 Received June 7, 2017. Accepted July 25, 2017. Abstract Aim: Preterm birth is the world’s leading cause of neona- tal death. Unfortunately, the pathophysiology of preterm birth remains poorly understood. Sjögren-Larsson syn- drome is a rare, neurometabolic disorder caused by a fatty aldehyde dehydrogenase deficiency. A majority of patients with Sjögren-Larsson syndrome is born preterm. Methods: Data of all known Dutch patients with Sjögren- Larsson syndrome and all cases reported in literature were analyzed to learn from preterm birth in context of this rare disease. Results: Exact gestational age was known in 33 Dutch patients; 24 (73%) of them were born preterm, with a median gestational age of 36 weeks. The literature search confirmed our findings: 13 (59%) of 22 cases was born preterm. Conclusions: Preterm birth is a hallmark of Sjögren- Larsson syndrome, presumably caused by the abnormal lipid metabolism of the fetus. At least five additional rare genetic disorders (namely Ehlers-Danlos syndrome, ichthyosis prematurity syndrome, congenital analbu- minemia, osteogenesis imperfecta type II and restrictive dermopathy) were found in literature that lead to preterm birth of the affected fetus. These disorders are in fact “experiments of nature” and as such they shed new lights on the mechanisms causing preterm birth. Keywords: Genetics; genetic diseases; inborn; physiopa- thology; preterm birth; Sjögren-Larsson syndrome. Introduction Preterm birth, defined as birth before 37 weeks of gesta- tion, is the most important cause of neonatal death and the second largest direct cause of child deaths in chil- dren younger than 5 years [1, 2]. According to the World Health Organization (WHO), preterm birth occurs in 11% of all live births worldwide, ranging from 5% in European countries to 18% in some African countries [1]. Altogether, an estimated 15 million neonates are born preterm every year, of which approximately 1 million die due to the complications of preterm birth [2]. Among the children who survive, there are substantial short- and long-term morbidities. The best way to improve child healthcare, compromised by complications of preterm birth, would be to prevent preterm birth. Therefore, more knowledge about parturition and causes of preterm birth is necessary. There are multiple maternal risk factors known in relation to preterm birth. However, fetal factors contributing to preterm birth are poorly understood. Labor is a complex process of consecutive events, the so-called common pathway of labor, involving the inter- play of increased uterine contractility, rupture of the cho- rioamniotic membranes, and weakening of the uterine cervix [3]. Important mechanisms to activate this common pathway are thought to be hormonal [hypothalamic- pituitary-adrenal axis (HPA axis)], inflammatory (pros- taglandins) and mechanical (weakening of membranes and contraction of myometrium). Timing of birth and how these mechanisms act together still remain unclear [4]. Preterm birth may occur after the “spontaneous” onset of labor or medically indicated due to maternal or fetal complications, such as preeclampsia or intrauterine growth restriction [5]. Several disease mechanisms have been described that may result in activation of the common *Corresponding author: Pippa Staps, MD, Department of Pediatric Neurology, Radboud University Medical Center, Donders Institute for Brain Cognition and Behaviour, PO Box 9101, 6500 HB Nijmegen, The Netherlands, Tel.: +31 24 3614430, E-mail: pippa.staps@radboudumc.nl. http://orcid.org/0000-0002-0238-1412 Marije Hogeveen and Joris Fuijkschot: Department of Pediatrics, Radboud University Medical Center, Amalia Children’s Hospital, Nijmegen, The Netherlands Joris van Drongelen: Department of Obstetrics, Radboud University Medical Center, Nijmegen, The Netherlands Michèl A.A.P. Willemsen: Department of Pediatric Neurology, Radboud University Medical Center, Donders Institute for Brain Cognition and Behaviour, Nijmegen, The Netherlands