Marfan syndrome resulting from a rare pathogenic FBN1 variant, ascertained through a proband with IgG4-related arteriopathy.

A 57-year-old man with a family history of aortic aneurysm was found, during assessment of unexplained fever, to have an infrarenal aortic aneurysm requiring immediate repair. Dilatation of popliteal and iliac arteries was also present. Progressive aortic root dilatation with aortic regurgitation was documented from 70 years leading to valve-sparing aortic root replacement at 77 years, at which time genetic studies identified a likely pathogenic FBN1 missense variant c.6916C > T (p.Arg2306Cys) in exon 56. The proband's lenses were normally positioned and the Marfan syndrome (MFS) systemic score was 0/20. Cascade genetic testing identified 15 other family members with the FBN1 variant, several of whom had unsuspected aortic root dilatation; none had ectopia lentis or MFS systemic score ≥ 7. Segregation analysis resulted in reclassification of the FBN1 variant as pathogenic. The combination of thoracic aortic aneurysm and dissection (TAAD) and a pathogenic FBN1 variant in multiple family members allowed a diagnosis of MFS using the revised Ghent criteria. At 82 years, the proband's presenting abdominal aortic aneurysm was diagnosed retrospectively to have resulted from IgG4-related inflammatory aortopathy.

Reproductive technologies and the risk of birth defects.

BACKGROUND: The extent to which birth defects after infertility treatment may be explained by underlying parental factors is uncertain. METHODS: We linked a census of treatment with assisted reproductive technology in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of at least 400 g and registries of birth defects (including cerebral palsy and terminations for defects at any gestational period). We compared risks of birth defects (diagnosed before a child's fifth birthday) among pregnancies in women who received treatment with assisted reproductive technology, spontaneous pregnancies (i.e., without assisted conception) in women who had a previous birth with assisted conception, pregnancies in women with a record of infertility but no treatment with assisted reproductive technology, and pregnancies in women with no record of infertility. RESULTS: Of the 308,974 births, 6163 resulted from assisted conception. The unadjusted odds ratio for any birth defect in pregnancies involving assisted conception (513 defects, 8.3%) as compared with pregnancies not involving assisted conception (17,546 defects, 5.8%) was 1.47 (95% confidence interval [CI], 1.33 to 1.62); the multivariate-adjusted odds ratio was 1.28 (95% CI, 1.16 to 1.41). The corresponding odds ratios with in vitro fertilization (IVF) (165 birth defects, 7.2%) were 1.26 (95% CI, 1.07 to 1.48) and 1.07 (95% CI, 0.90 to 1.26), and the odds ratios with intracytoplasmic sperm injection (ICSI) (139 defects, 9.9%) were 1.77 (95% CI, 1.47 to 2.12) and 1.57 (95% CI, 1.30 to 1.90). A history of infertility, either with or without assisted conception, was also significantly associated with birth defects. CONCLUSIONS: The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors. The risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded. (Funded by the National Health and Medical Research Council and the Australian Research Council.).

Single-nucleotide polymorphism associations with preterm delivery: a case-control replication study and meta-analysis.

BACKGROUND: The aim of this study was to replicate single-nucleotide polymorphism (SNP) associations with preterm birth (PTB; birth at <37 completed weeks of gestation) and synthesize currently available evidence using meta-analysis. METHODS: Spontaneous PTB cases and controls were selected from an existing cohort. Candidate SNPs were taken from an existing genotype panel. A systematic review was conducted for each SNP in the panel to determine suitability as a PTB candidate. Those with significant associations previously reported in Caucasians were selected for replication. Candidate SNPs were already genotyped in cases and controls and clinical data were accessed from state perinatal and cerebral palsy databases. Association analysis was conducted between each SNP and PTB, and meta-analysis was conducted if there were ≥ 3 studies in the literature. Maternal and fetal SNPs were considered as separate candidates. RESULTS: A cohort of 170 cases and 583 controls was formed. Eight SNPs from the original panel of genotyped SNPs were selected as PTB candidates and for replication on the basis of systematic literature review results. In our cohort, fetal factor V Leiden (FVL) was significantly associated with PTB (odds ratio (OR): 2.6, 95% confidence interval (CI): 1.31-5.17), and meta-analysis confirmed this association (OR: 2.71, 95% CI: 1.15-6.4). CONCLUSION: Replication and meta-analysis support an increased risk of PTB in Caucasians with the fetal FVL mutation.

Genetic and clinical contributions to cerebral palsy: a multi-variable analysis.

AIM: This study aims to examine single nucleotide polymorphism (SNP) associations with cerebral palsy in a multi-variable analysis adjusting for potential clinical confounders and to assess SNP-SNP and SNP-maternal infection interactions as contributors to cerebral palsy. METHODS: A case control study including 587 children with cerebral palsy and 1154 control children without cerebral palsy. Thirty-nine candidate SNPs were genotyped in both mother and child. Data linkage to perinatal notes and cerebral palsy registers was performed with a supplementary maternal pregnancy questionnaire. History of known maternal infection during pregnancy was extracted from perinatal databases. RESULTS: Both maternal and fetal carriage of inducible nitric oxide synthase SNP rs1137933 were significantly negatively associated with cerebral palsy in infants born at less than 32 weeks gestation after adjustment for potential clinical confounders and correction for multiple testing (odds ratio 0.55, 95% confidence interval 0.38-0.79; odds ratio 0.57, 95% confidence interval 0.4-0.82, respectively). Analysis did not show any statistically significant SNP-SNP or SNP-maternal infection interactions after correction for multiple testing. CONCLUSIONS: Maternal and child inducible nitric oxide synthase SNPs are associated with reduced risk of cerebral palsy in infants born very preterm. There was no evidence for statistically significant SNP-SNP or SNP-maternal infection interactions as modulators of cerebral palsy risk.

Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder.

TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug-resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597-1340A>G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice-switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients' cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility.

The Australian cerebral palsy research study--protocol for a national collaborative study investigating genomic and clinical associations with cerebral palsy.

AIM: Previous studies have proposed a link between the presence of specific single nucleotide polymorphisms (SNPs) and cerebral palsy and the majority of these associations remain to be confirmed or rejected by prospective studies with sufficient statistical power. Prior studies have also given little attention to the interaction of genomic characteristics and clinical risk factors. METHODS: This paper describes the design of a prospective case-control study to test these genetic associations in conjunction with more stringent data collection in respect to clinical features associated with pregnancy, particularly maternal infection. Here we consider the ethical requirements, our hypothesis that genetic susceptibility modifies the risk of cerebral palsy in the presence of perinatal environmental triggers, a priori primary and secondary aims, power calculations, participant recruitment strategies, data linkage, sampling methods of genetic material and subsequent SNP analysis, collection of clinical data and the proposed final statistical analysis.

A new syndrome with craniosynostosis and cleft lip and palate.

Two unrelated girls with craniosynostosis and bilateral cleft lip and palate who also had developmental delay and umbilical herniae are presented. We propose that these patients have the same condition, and that their combination of features may constitute a new syndrome. Management of the patients is discussed.

Genetic susceptibility to viral exposure may increase the risk of cerebral palsy.

AIM: Cytokine polymorphisms may alter the fetal inflammatory response, increasing susceptibility to cerebral palsy (CP). This study investigates associations between selected inflammatory mediator and cytokine gene polymorphisms (Toll-like receptor-4 (TLR-4) Asp299Gly, interleukin-6 G-174C and interleukin-4 C-589T) and CP from 443 CP infants and 883 control infants. Results were correlated with viral nucleic acids in the same samples. RESULTS: At all gestational ages (GA), TLR-4 was associated with a decreased risk of developing CP (homozygous/heterozygous odds ratio (OR) 0.70, 95% confidence interval (CI) 0.50-0.98) and interleukin (IL)-6 was associated with an increased risk of developing hemiplegia (OR 1.38, 95% CI 1.05-1.83). For infants born 32-36 weeks GA, there was a tenfold increase in the risk of quadriplegic CP with homozygous/heterozygous IL-6 (OR 10.42, 95% CI 1.34-80.82). Viral exposure in combination with IL-4 in preterm infants was associated with a fourfold increased risk of quadriplegia (homozygous/heterozygous OR 4.25, 95% CI 1.21-14.95). In very preterm infants, the absence of detectable viral exposure in combination with IL-4 decreased the risk of developing CP (homozygous/heterozygous OR 0.31, 95% CI 0.13-0.76). CONCLUSION: Polymorphisms in TLR-4 may be associated with a decreased risk of CP. Polymorphisms in IL-6 or IL-4 may act as susceptibility genes, in the presence of viral exposure, for the development of hemiplegic and quadriplegic CP. These associations require confirmation but they suggest a hypothesis for CP causation due to double jeopardy from neurotropic viral exposure and genetic susceptibility to infection.

Association between Apolipoprotein E genotype and cerebral palsy is not confirmed in a Caucasian population.

Apolipoprotein E (APOE) plays a significant role in lipid metabolism and has been implicated in the growth and repair of injured neurons. Two small studies have suggested an association between APOE genotype and cerebral palsy. We investigated if APOE genotype is associated with an increased risk for cerebral palsy, influences the type of cerebral palsy or interacts with prenatal viral infection to influence risk of cerebral palsy. The population-based case-control study comprised newborn screening cards of 443 Caucasian patients with cerebral palsy and 883 Caucasian matched controls. APOE genotyping was performed on DNA extracted from dried blood spots. Allelic and genotypic frequencies did not differ between cases and controls and combined frequencies were 0.10 (epsilon2), 0.76 (epsilon3), 0.14 (epsilon4), 0.03 (epsilon2/epsilon2), 0.10 (epsilon2/epsilon3), 0.03 (epsilon2/epsilon4), 0.02 (epsilon4/epsilon4), 0.21 (epsilon3/epsilon4), 0.61 (epsilon3/epsilon3). APOE genotype was correlated with cerebral palsy, type of cerebral palsy, gestation at birth and the presence of viral nucleic acids detected in previous work. Analysis by gestational age (all gestational ages, >/=37, 32-36 and <32 weeks) and type of cerebral palsy (all types, diplegia, hemiplegia and quadriplegia) showed no association between APOE genotype and cerebral palsy in this Caucasian population. An association between prenatal viral infection, APOE genotype and cerebral palsy was not demonstrated. These results did not confirm an association between APOE genotype, cerebral palsy, type of cerebral palsy and prenatal infection in a Caucasian population. Given the low frequency of APOE epsilon2 and some of the heterozygote and homozygote combinations in this study, a larger study is assessing this further.

Self-esteem, self-concept, and quality of life in children with hemiplegic cerebral palsy.

OBJECTIVES: To investigate self-esteem, self-concept and quality of life in children with hemiplegic cerebral palsy (HCP) compared with typically developing peers. STUDY DESIGN: Cross-sectional evaluation of 86 children (3-16 years; 54 boys; mean age 9.4 +/- 3.7 years) with HCP and age and sex-matched peers. Self-esteem/concept was measured with the Self-Perception Profile for Children (age 8-16; n = 55 pairs) and the Pictorial Scale of Perceived Competence and Social Acceptance for Young Children (age 3-7 years; n = 31 pairs). Quality of life was measured with the Pediatric Quality of Life Inventory, version 4. RESULTS: Significant differences in mean scores ([95%CI] P < .05) favoring the peer group were found for physical competence (HCP 2.8 [2.5, 3.0]; peer 3.2 [3.1, 3.3]), athletic competence (HCP 2.7 [2.5, 2.9]; peer 3.1 [3.0, 3.3]), and scholastic competence (HCP 2.8 [2.6, 3.0]; peer 3.1 [3.0, 3.3]), but favored children with HCP for maternal acceptance (HCP 3.1 [2.9, 3.3]; peer 2.7 [2.5, 3.0]). Quality of life was significantly higher for the peer group for both parent (HCP 54.5 [51.1, 58.0]; peer 80.6 [78.3, 82.9]) and child (HCP 67.6 [62.7, 72.6]; peer 80.6 [78.1, 83.1]) scales. CONCLUSIONS: Children with HCP experience reduced quality of life and self-concept compared with typically developing peers.

Mannose-binding lectin haplotypes may be associated with cerebral palsy only after perinatal viral exposure.

OBJECTIVE: The objective of the study was to investigate the associations between infection, polymorphisms in the mannose-binding lectin gene (MBL), and cerebral palsy (CP). STUDY DESIGN: This was a case-control study using deoxyribonucleic acid from newborn screening cards of 443 Caucasian CP cases and 883 Caucasian controls to screen for 6 polymorphisms within the MBL gene. These polymorphisms combine to create haplotypes with high (HYPA), intermediate (LYQA, LYPA), low (LXPA), and defective (HYPD, LYQC, LYPB) circulating MBL levels. RESULTS: chi(2) Analyses demonstrated significant differences between CP cases and controls (less than 37 weeks chi(2) 14.99, P = .02; less than 32 weeks chi(2) 13.62, P = .02). The MBL haplotype LYPA was associated with CP at all gestations (odds ratio [OR] 1.57, 95% confidence interval [CI], 1.00 to 2.46), less than 37 weeks (OR 2.43, 95% CI, 1.41 to 4.18), and less than 32 weeks (OR 2.54, 95% CI, 1.34 to 4.76). LYPA was also associated with hemiplegic CP for babies born at less than 37 weeks (OR 2.77, 95% CI, 1.02 to 7.26) and less than 32 weeks (OR 4.48, 95% CI, 1.55 to 12.65). HYPD was associated with quadriplegic CP at all gestations (OR 3.47, 95% CI, 1.41 to 8.31) as well as for babies born at less than 32 weeks (OR 7.86, 95% CI, 1.67 to 29.48). Subanalysis on samples previously testing positive for exposure to viral infection demonstrated similar patterns of significance as those presented above, whereas analysis on samples negative for exposure to viral infection showed no positive associations between any of the MBL haplotypes and CP. Potential type I error from multiple analyses is a caveat. CONCLUSION: MBL haplotypes LYPA or HYPD may be associated with an increased risk of CP in the presence of exposure to viral infection and may act as susceptibility factors for CP.

Trends in state/population-based Down syndrome screening and invasive prenatal testing with the introduction of first-trimester combined Down syndrome screening, South Australia, 1995-2005.

OBJECTIVE: The purpose of this study was to review trends in the us of maternal serum Down syndrome screening and invasive prenatal testing before and after the introduction of a state-based first-trimester combined Down syndrome screening program. STUDY DESIGN: A retrospective population-based study was performed on first- and second-trimester Down syndrome screening, invasive prenatal testing, and prenatal detection of Down syndrome from 1995 to 2005 in South Australia with data from state-based registers. Chi-square tests were used to evaluate trends. RESULTS: There was a significant decrease in the use of second-trimester Down syndrome maternal serum screening (from 75% in 1995 to 25% in 2005; P < .001) and a corresponding significant increase in first-trimester combined screening (from 0.8% in 2000 to 49% in 2005; P < .001). The proportion of all confinements that involved invasive prenatal testing fell (from 9.3% in 1995 to 7.6% in 2005; P < .001). There was a significant decrease in the number of invasive prenatal tests that were needed to detect 1 Down syndrome fetus (from 86 tests in 1995 to 40 tests in 2005; P < .001), with no significant change in the proportion of Down syndrome cases that were detected prenatally. CONCLUSION: The introduction and increased use of first-trimester combined Down syndrome screening has been associated with more efficient use of invasive prenatal testing in South Australia and has maintained a high level of overall prenatal detection.

The association between inherited cytokine polymorphisms and cerebral palsy.

OBJECTIVE: The purpose of this study was to investigate associations between inherited cytokine polymorphisms and cerebral palsy. STUDY DESIGN: This was a case-control study that used DNA from the newborn infant screening cards of 443 white infants with cerebral palsy and 883 white control infants to test for the following cytokine polymorphisms: tumor necrosis factor-alpha-308, mannose-binding lectin-221, and 3 polymorphisms in exon-1 of the mannose-binding lectin gene at codon-52, -54, and -57. RESULTS: At all gestational ages mannose-binding lectin codon-54 increased the risk of the development of diplegia (homozygous or heterozygous odds ratio, 1.55; 95% CI, 1.03-2.32). For babies who were born at term, the risk of the development of quadriplegia was associated with heterozygous tumor necrosis factor-alpha (odds ratio, 1.82; 95% CI, 1.04-3.15), and mannose-binding lectin codon-54 was associated with diplegia (homozygous or heterozygous odds ratio, 2.12; 95% CI, 1.10-4.05). The presence of any polymorphism in mannose-binding lectin exon-1 at term approximately doubled the risk of the development of diplegia (odds ratio, 1.94; 95% CI, 1.05-3.62). Homozygous or heterozygous tumor necrosis factor-alpha was associated with hemiplegia for babies who were born at <32 weeks of gestation (odds ratio, 2.38; 95% CI, 1.02-5.58). Overall, the presence of any cytokine polymorphism was associated with cerebral palsy (odds ratio, 1.37; 95% CI, 1.02-1.84). CONCLUSION: Carriage of polymorphisms in the tumor necrosis factor-alpha and mannose-binding lectin genes are associated with an increased risk of cerebral palsy.

Associations between fetal inherited thrombophilia and adverse pregnancy outcomes.

OBJECTIVE: The purpose of this study was to investigate associations between fetal inherited thrombophilia and adverse pregnancy outcomes, including pregnancy-induced hypertensive disorders (PIHD), antepartum hemorrhage (APH), small-for-gestational age <10th percentile (SGA), and preterm birth (PTB). STUDY DESIGN: Seven hundred and seventeen cases and 609 controls were genotyped for Factor V Leiden (FVL, G1691A), Prothrombin gene mutation (PGM, G20210A), and Methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C using DNA from newborn screening cards. RESULTS: For babies born <28 weeks' gestation, PGM was associated with an increased risk of SGA (OR 6.40, 95%CI 1.66-24.71) and APH with SGA (OR 6.35, 95%CI 1.63-24.75). Homozygous MTHFR A1298C was associated with an increased risk of SGA for babies born 28-31 weeks gestation (OR 4.00, 95%CI 1.04-15.37), and with APH and SGA for babies born <32 weeks' gestation (OR 3.57, 95%CI 1.09-11.66). Homozygous MTHFR C677T was associated with a reduced risk of PTB and SGA (OR 0.52, 95%CI 0.28-0.96) for babies born 32 to 36 weeks' gestation. Homozygous FVL decreased the risk of PTB <32 weeks' gestation (OR 0.55, 95%CI 0.31-0.98). CONCLUSION: Fetal thrombophilic polymorphisms may be related to adverse pregnancy outcomes, in particular SGA.

Associations between inherited thrombophilias, gestational age, and cerebral palsy.

OBJECTIVE: This study was undertaken to investigate associations between inherited thrombophilic polymorphisms and cerebral palsy (CP) in a large case-control study. STUDY DESIGN: This is a population-based case-control study. Genomic DNA from newborn screening cards of 443 white CP cases and 883 white controls was tested for factor V Leiden (FVL, G1691A), prothrombin gene mutation (PGM, G20210A), and methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C. RESULTS: MTHFR C677T was associated with an increased risk of developing any CP (32-36 weeks' gestation, homozygous odds ratio [OR] 2.55, 95% CI 1.12-5.74; heterozygous OR 1.91, 95% CI 1.01-3.66). MTHFR C677T was also associated with diplegia at both less than 32 weeks' gestation (homozygous OR 2.76, 95% CI 1.21-6.12) and all gestations (heterozygous OR 1.58 95%, CI 1.02-2.45). For children less than 32 weeks, FVL homozygosity may be associated with an increase in the risk of developing quadriplegia (OR 9.12, 95% CI 0.86-53.71). MTHFR A1298C (heterozygous) was associated with a reduced risk of diplegia developing at 32 to 36 weeks' gestation (OR 0.16, 95% CI 0.02-0.70). There were no associations between any type of CP and thrombophilia for children born 37 weeks or greater. Heterozygous PGM and homozygous MTHFR C677T combined were associated with quadriplegia at all gestational ages (OR 5.33, 95% CI 1.06-23.25). CONCLUSION: MTHFR C677T approximately doubles the risk of CP in preterm infants. A combination of homozygous MTHFR C677T and heterozygous PGM increases the risk of quadriplegia 5-fold at all gestational ages.

The prevalence of inherited thrombophilias in a Caucasian Australian population.

AIMS: To describe the prevalence of four inherited thrombophilias and their combinations for the first time in a large Caucasian Australian population. METHODS: Newborn screening cards of 883 Caucasian babies born in South Australia in 1986-1999 were de-identified and tested for the following inherited thrombophilic polymorphisms: factor V Leiden (G1691A), prothrombin gene mutation (G20210A), methylenetetrahydrofolate reductase gene (MTHFR) C677T and A1298C, as well as compound heterozygosity for the MTHFR polymorphisms. RESULTS: The birth prevalences of heterozygosity and homozygosity for the four thrombophilic polymorphisms were: factor V Leiden 9.5% and 0.7%, prothrombin gene 4.1% and 0.2%, MTHFR C677T 37.3% and 12.4%, and MTHFR A1298C 38.3% and 11.8%, respectively. Compound heterozygosity for MTHFR C677T and A1298C was seen in 16.6% of the population. Overall, 64.2% and 24.5% of the population studied were homozygous and heterozygous, respectively, for at least one of the four polymorphisms studied. CONCLUSION: Inherited thrombophilic polymorphisms are common in the Caucasian Australian population. Knowledge of the background prevalence of these polymorphisms will allow further study of their associations in future disease research.

Fetal and maternal candidate single nucleotide polymorphism associations with cerebral palsy: a case-control study.

OBJECTIVE: Previous studies have suggested associations between certain genetic variants and susceptibility to cerebral palsy (CP). This study was designed to assess established and novel maternal and child genetic and epidemiologic risk factors for CP along with their interactions. METHODS: DNA from 587 case and 1154 control mother-child pairs was analyzed. A panel of 35 candidate single nucleotide polymorphisms (SNPs) were examined and included SNPs in genes associated with (1) thrombophilia, (2) inflammation, and (3) risk factors for CP (eg, preterm birth). Comparisons were specified a priori and made by using a χ(2) test. RESULTS: There were 40 fetal and 28 maternal associations with CP when analyzed by CP subtype, gestational age, genotypes of apolipoprotein E, and haplotypes of mannose-binding-lectin. After Bonferroni correction for multiple testing, no fetal or maternal candidate SNP was associated with CP or its subtypes. Only fetal carriage of prothrombin gene mutation remained marginally associated with hemiplegia in term infants born to mothers with a reported infection during pregnancy. Odds ratio directions of fetal SNP associations were compared with previously reported studies and confirmed no trend toward association. CONCLUSIONS: Except for the prothrombin gene mutation, individual maternal and fetal SNPs in our candidate panel were not found to be associated with CP outcome. Past reported SNP associations with CP were not confirmed, possibly reflecting type I error from small numbers and multiple testing in the original reports.

Fetal MBL2 haplotypes combined with viral exposure are associated with adverse pregnancy outcomes.

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  < 10th 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  < 32 weeks OR 5.37, 95% CI 1.50-17.27), antepartum hemorrhage (LYPA  < 37 weeks OR 2.29, 95% CI 1.25-4.18), and PIHD (LYQC < 32 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.