Fetal MBL2 haplotypes combined with viral exposure are associated with adverse pregnancy outcomes CATHERINE S. GIBSON 1,2 , ALASTAIR H. MACLENNAN 1 , ERIC A. HAAN 3,4 , KEVIN PRIEST 5 ,& GUSTAAF A. DEKKER 1 ; WRITING FOR THE SOUTH AUSTRALIAN CEREBRAL PALSY RESEARCH GROUP 1 Discipline of Obstetrics and Gynaecology, The University of Adelaide, South Australia, 2 South Australian Birth Defects Register, Women’s and Children’s Hospital, Adelaide, South Australia, 3 Discipline of Paediatrics, The University of Adelaide, South Australia, 4 South Australian Clinical Genetics Service, SA Pathology, Adelaide, South Australia, and 5 Epidemiology Branch, SA Health, Adelaide, South Australia (Received 5 August 2010; accepted 22 September 2010) Abstract Objective. To investigate the roles of inherited polymorphisms in the MBL2 gene and exposure to viral infection in the development of a range of adverse pregnancy outcomes, including birthweight 510th percentile (small-for-gestational age, SGA), antepartum hemorrhage (APH), pregnancy-induced hypertensive disorders (PIHD), and preterm birth (PTB). Methods. This was a case–control study using DNA from newborn screening cards of 717 cases (babies with at least one of the adverse pregnancy outcomes listed above) and 609 controls, to screen for six polymorphisms within the MBL2 gene. These combine to create haplotypes with high (HYPA), intermediate (LYQA, LYPA), low (LXPA), and defective (HYPD, LYQC, LYPB) circulating MBL2 levels. Results. Significant associations were found between variant MBL2 haplotypes and SGA (LYPA 532 weeks OR 5.37, 95% CI 1.50–17.27), antepartum hemorrhage (LYPA 537 weeks OR 2.29, 95% CI 1.25–4.18), and PIHD (LYQC 532 weeks (OR 17.89, 95% CI 2.20–139.57). Evidence of exposure to infection increased the effect of these associations, (SGA OR 17.00, 95% CI 1.03–252.48; APH OR 5.67, 95% CI 1.73–18.84; PIHD OR 23.80, 95% CI 1.08–1414.76), while no evidence of exposure to infection demonstrated no associations. PTB was significantly associated with the defective HYPD haplotype with evidence of exposure to infection (OR 6.14, 95% CI 1.21–29.89). Conclusions. This research suggests that the combination of fetal MBL2 haplotypes and exposure to in utero viral infection increases the risk of adverse pregnancy outcomes, including PTB, antepartum hemorrhage, small-for-gestational age and PIHD. Keywords: Fetal MBL2 haplotype, preterm birth, small-for-gestational age, pregnancy-induced hypertension, antepartum hemorrhage Introduction Obstetric complications leading to adverse pregnancy outcomes, such as severe preeclampsia, intrauterine growth restriction requiring delivery before 34 weeks gestation, and early preterm delivery (532 weeks gesta- tion) occur in up to 5% of pregnant women [1]. Mannose binding lectin (MBL2) is a serum protein involved in the activation of the complement system of the innate immune system and is involved in the fetal inflammatory response to injury and infec- tion [2]. MBL2 has been detected in amniotic fluid [3]. The MBL2 pathway of the complement system is activated when MBL2 recognizes and binds to carbohy- drates, such as mannose- and N-acetyl-glucosamine-rich oligosaccharides, present on a wide range of bacteria, viruses, fungi, and parasites [4,5]. Polymorphisms within the MBL2 gene alter the immune response to infection by reducing the amount of MBL2 circulating in the body. The human MBL2 gene on chromosome 10 has six known polymorphic sites [6], three within the promoter region of exon 1, and 3 within exon 1. These promoter and structural polymorphisms are found in various cis combi- nations, resulting in haplotypes associated with high, intermediate, and low levels of MBL2 [7]. A haplotype is defined as being a group of closely linked alleles along a chromosome. Seven different haplotypes have been identi- fied in a range of populations and in order of decreasing levels of MBL2 are: HYPA, LYQA, LYPA, LXPA, HYPD, LYQC, and LYPB. The HYPD, LYQC, and LYPB haplotypes are considered defective haplotypes because they are associated with virtually undetectable concentrations of MBL2 [8]. Subclinical maternal viral infection is a common event [9,10]. Viral infection may increase the risk of Correspondence: Dr Catherine S. Gibson, Discipline of Obstetrics and Gynaecology, The University of Adelaide, 1 st Floor Queen Victoria Building, Women’s and Children’s Hospital, 72 King William Road, North Adelaide 5006, Adelaide, South Australia. Tel: þ61-8-8161-7616. Fax: þ61-8-8161-7652. E-mail: catherine.s.gibson@adelaide.edu.au Other Authors and Members of the South Australian Cerebral Palsy Research Group: Gai L. McMichael 1 , Phillipa van Essen 2 , Heather Scott 2 , Annabelle Chan 5 , William M. Hague 1 , T. Yee Khong 7 , Zbigniew Rudzki 6 , Graeme Casey 6 , & Enzo Ranieri 8 ( 6 Division of Molecular Pathology, SA Pathology, Adelaide, South Australia, 7 Department of Histopathology, SA Pathology, Adelaide, South Australia, 8 SA Neonatal Screening Centre, SA Pathology, Adelaide, South Australia). The Journal of Maternal-Fetal and Neonatal Medicine, June 2011; 24(6): 847–854 ISSN 1476-7058 print/ISSN 1476-4954 online Ó 2011 Informa UK, Ltd. DOI: 10.3109/14767058.2010.531324