Associations between fetal inherited thrombophilia and adverse pregnancy outcomes

Article Outline

• Abstract
• Material and methods
  • Patient selection
  • Statistical analysis
• Results
  • Small for gestational age <10th percentile
    • Small-for-gestational age <5th percentile
  • Hypertension
  • Pregnancy-induced hypertensive disorders
  • Pregnancy-induced hypertensive disorders and SGA <10th percentile
  • Antepartum hemorrhage
  • Antepartum hemorrhage and SGA <10th percentile
  • Preterm birth <37 weeks
  • Preterm birth and SGA <10th percentile
• Comment
  • Prothrombin gene mutation
  • Factor V Leiden
  • Methylenetetrahydrofolate Reductase gene
• Acknowledgments
• Appendix
• References
• Copyright

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.

Key words: Fetal thrombophilia, Polymorphisms, Adverse pregnancy outcomes

Obstetric complications leading to adverse pregnancy outcomes, such as severe preeclampsia, birth resulting in a baby small-for-gestational age <10th percentile and early preterm delivery (<32 weeks gestation) occur in up to 5% of pregnant women.¹ Maternal inherited thrombophilic disorders have been shown to be associated with such adverse outcomes.¹ Common inherited thrombophilias, which predispose to thrombosis by promoting excessive coagulation or impairing anticoagulation,² include: heterozygosity or homozygosity for Factor V Leiden (FVL) causing activated protein C resistance (APCR); heterozygosity or homozygosity for the Prothrombin gene mutation G20210A (PGM); and heterozygosity or homozygosity for the 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C, associated with an increased tendency to hyperhomocysteinaemia; and compound heterozygosity for both MTHFR polymorphisms.

So far, researchers have focused on the role of maternal inherited thrombophilia, with only limited research investigating the role of fetal inherited thrombophilia in the development of adverse pregnancy outcomes.³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰ These few studies have given conflicting results. Studies by Infante-Rivard, Glanville, and McCowan⁶, ⁷, ⁸ showed no effect of fetal thrombophilia on pregnancy outcome, whereas studies by Dizon-Townson, von Kries, Anteby, and Dekker³, ⁵, ⁹, ¹⁰ showed positive associations. All these studies differed widely in selected pregnancy outcomes, sample sizes, and selected inherited thrombophilia, which may explain the discordant results.

The aim of this study was to investigate the role of fetal thrombophilia in a wide range of adverse pregnancy outcomes, including birth resulting in a baby small-for-gestational age <10th percentile (SGA), pregnancy-induced hypertensive disorders (PIHD), antepartum hemorrhage (APH), and preterm birth (PTB).

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Material and methods 

Factor V Leiden, PGM, and MTHFR polymorphisms C677T and A1298C were sought in DNA extracted from newborn screening cards using previously detailed methods.¹¹

Patient selection 

The cases and controls in this cohort were selected as part of a study investigating the role of inherited thrombophilic polymorphisms in the subsequent development of cerebral palsy. The selection process for these cases and controls has been detailed elsewhere.¹¹

Briefly, the study population comprised all children with cerebral palsy born in 1986-1999 in South Australia to white mothers (n = 443), ascertained by South Australia's cerebral palsy register. The controls were 883 babies born to white mothers from 1986-1999. Newborn screening cards were identified for each case and control. Four potential controls were selected from screening cards filed (by date of receipt) before (n = 2) and after (n = 2) the cards of cases. The dates of birth of the controls were within a few days of the case, the hospital from which the screening cards were taken was of the same category (metropolitan teaching, metropolitan private, or country), and samples were taken on approximately the same day of life as for the cases. The control population included a higher proportion of preterm infants than the general population, as many of the cases of cerebral palsy were born preterm and had been referred to metropolitan teaching hospitals. Linkage of cases and controls to the South Australian Pregnancy Outcome Unit Database was successful for all cases and 1691 controls. We excluded 268/1691 (15.8%) controls because they had non-white mothers (n = 102), had a birth defect notified to the state's birth defects register (n = 161), or died in the first year of life (n = 37). Some controls were excluded for more than 1 reason. Random numbers were then used to select controls from the remaining controls. All testing was undertaken with blinding to case/control status. This research was approved by the Research Ethics Committee of the Women's and Children's Hospital.

For this analysis, we disregarded cerebral palsy as an outcome, and combined our cohort of 443 CP cases and 883 controls (total 1326) before separating them on the basis of adverse pregnancy outcomes.

A total of 717 of the 1326 babies (54.1%) met the following selection criteria for cases. Some cases had more than 1 condition: (1) preterm birth <37 weeks' gestation (451/717, 62.9%); (2) pregnancy resulting in the birth of a small-for-gestational age (SGA) baby less than the 10th percentile, calculated from Roberts¹² (241/717, 33.6%); (3) antepartum hemorrhage (any recorded bleeding at or after 20 weeks' gestation, including placenta previa, abruption, other, and unknown causes), (340/717, 47.4%). The classification of APH within the South Australian Perinatal Data Collection of births includes diagnosis of placenta previa and placental abruption, as well as other and unknown causes of APH. (4) Pregnancy-induced hypertensive disorders (PIHD) (blood pressure ≥140/90 or higher on 2 occasions at least 4 hours apart, or ≥170/110 or higher on 1 occasion, first noted after 20 weeks' gestation. The South Australian Pregnancy Outcome Unit Database does not contain data on proteinuria; therefore, in this study cases with PIHD include both gestational hypertension and preeclampsia (23/717, 3.2%). The remaining 609 babies (45.9%) had none of the above selection criteria, and were designated healthy term controls. A priori subanalysis was also performed, using the following selection criteria: pregnancy resulting in the birth of a small-for-gestational age (SGA) baby less than the 5th percentile (136/717, 19%); all pregnancy-induced hypertension plus SGA (9/717); all antepartum hemorrhage plus SGA (108/717); all preterm birth <37 weeks' gestation plus SGA (82/717).

Statistical analysis 

These inherited thrombophilic polymorphisms were genotyped from newborn screening samples that had been stored for up to 18 years. As controls were not matched for important covariates such as gestational age, analysis was undertaken using all controls without taking account of matching. Data analysis (GraphPad Instat version 3.06, San Diego, CA) then considered cases by gestational age range (<28 weeks, 28-31 weeks, <32 weeks, 32-36 weeks, <37 weeks, ≥37 weeks, and all gestational ages). Results are expressed as odds ratios (OR) with 95% CIs. Homozygosity and heterozygosity were compared for each polymorphism separately with homozygosity for the wild-type allele. Data for homozygosity and heterozygosity combined compared with the wild-type allele are also presented. Tables detailing all calculated odds ratios and CIs are available as supplementary material online; only the significant results are presented in the main text. Some combinations of thrombophilic polymorphisms and adverse pregnancy outcomes types were not seen in some subgroups: these odds ratios are not reported. P values less than .05 are highlighted in the tables. No adjustments were made for multiple testing in this largely exploratory study.

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Results 

Small for gestational age <10th percentile 

Two hundred and forty-one babies (33.6%) had SGA (inclusion criterion 2). Heterozygosity for PGM was associated with an increased risk of SGA for babies born <28 weeks' gestation (OR 6.40, 95%CI 1.66-24.71). Homozygosity or heterozygosity for PGM was also associated with an increased risk of SGA for babies born <28 weeks' gestation (OR 5.71, 95%CI 1.49-21.93) (Table I). Babies homozygous for MTHFR A1298C at gestational ages 28-31 weeks were 4 times more likely to have SGA (OR 4.00, 95%CI 1.04-15.37) (Table II).

Table I. Significant odds ratios (95% CI) for adverse pregnancy outcomes for prothrombin gene mutation

SGA, Small-for-gestational age; APH, antepartum hemorrhage; PTB, preterm birth.

Table II. Significant odds ratios (95% CI) for adverse pregnancy outcomes for Methylenetetrahydrofolate reductase gene mutations

SGA, Small-for-gestational age; APH, antepartum hemorrhage; PTB, preterm birth.

We also investigated whether more severe restriction of growth <5th percentile was associated with inherited thrombophilic polymorphisms, in addition to the less severe SGA <10th percentile. One hundred thirty-six babies (19.0% of total, 56.4% of SGA <10th percentile) had SGA <5th percentile. Heterozygosity for PGM was associated with an increased risk of SGA for babies born <28 weeks' gestation (OR 5.33, 95%CI 1.08-26.43) (Table I). There were no other associations between the thrombophilic polymorphisms and SGA <5th percentile.

Hypertension 

The mothers of 42 babies in this cohort (5.9%) suffered from hypertension, either pregnancy-induced (23) or preexisting (20). One mother suffered from both.

Pregnancy-induced hypertensive disorders 

Of the 42 mothers displaying signs of hypertension in this cohort, 23 (54.8%) developed pregnancy-induced hypertensive disorders (PIHD) (inclusion criterion 4). The low overall frequency of PIHD in this study (3.2%) is most likely explained by the high incidence of preterm birth (62.9% of the overall study population). No significant associations were observed for any of the inherited thrombophilia at any gestational age.

Pregnancy-induced hypertensive disorders and SGA <10th percentile 

Of the 23 mothers who developed PIHD, 9 (39.1%) also gave birth to a baby with SGA. No significant associations were observed for any of the inherited thrombophilia at any gestational age.

Antepartum hemorrhage 

The mothers of 340 of 717 babies in this case cohort (47.4%) suffered from antepartum hemorrhage (APH) (inclusion criterion 3). There were no associations between the thrombophilic polymorphisms and APH at any gestational age.

Antepartum hemorrhage and SGA <10th percentile 

Of the 340 mothers diagnosed with APH, 108 (31.8%) gave birth to an SGA baby. For babies born <28 weeks' gestation, PGM was associated with APH and growth-restriction (heterozygous OR 7.11, 95%CI 1.81-27.89; homozygous or heterozygous OR 6.35, 95%CI 1.63-24.75) (Table I). Homozygosity for MTHFR A1298C was associated with APH and growth-restriction at both 28-31 weeks' gestation (OR 5.00, 95%CI 1.21-20.60) and <32 weeks' gestation (OR 3.57, 95%CI 1.09-11.66) (Table II).

Preterm birth <37 weeks 

Four hundred fifty-one (62.9%) of the cases were born prematurely (inclusion criterion 1). FVL was associated with a decreased risk of preterm birth <32 weeks (heterozygous OR 0.48, 95%CI 0.26-0.89; homozygous or heterozygous OR 0.55, 95%CI 0.31-0.98) (Table III). There were no increased risks of preterm birth for any of the thrombophilic polymorphisms genotyped.

Table III. Significant odds ratios (95% CI) for adverse pregnancy outcomes for Factor V Leiden

PTB, Preterm birth; WT, wild-type.

Preterm birth and SGA <10th percentile 

Of the 451 preterm babies, 82 (18.2%) were also SGA. PGM was associated with prematurity and SGA (heterozygous OR 6.40, 95%CI 1.66-24.71; homozygous or heterozygous OR 5.71, 95%CI 1.49-21.93) (Table I). MTHFR C677T was associated with a decreased risk of preterm birth at 32-36 weeks' gestation and SGA (homozygous or heterozygous OR 0.52, 95%CI 0.28-0.96) (Table II).

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Comment 

This study assessed the association between fetal inherited thrombophilia for a wide range of adverse pregnancy outcomes, including intrauterine growth restriction resulting in the birth of an SGA infant, PIHD, APH, and PTB.

Prothrombin gene mutation 

PGM is a dominantly inherited thrombophilia which results in increased plasma prothrombin concentrations and a 2.8-fold increase in the risk of thrombosis.¹³, ¹⁴ The majority of analyses demonstrated no associations between adverse pregnancy outcomes and PGM. Positive associations were mainly seen in the extremely preterm infants born <28 weeks' gestation. The positive associations were seen for SGA babies. A number of associations were seen with hypertension and SGA for the PGM mutation; these associations demonstrated confidence intervals that did not cross unity, but showed a P value > .05 (please refer to supplementary material). This is probably due to the small numbers involved in some of the analysis. These results are consistent with those of Anteby,⁹ but differ from those of Infante-Rivard and McCowan,⁶, ⁸ who both demonstrated a lack of association between PGM and an increased risk of an SGA baby. Both of these studies had mixed ethnic groups, whereas this cohort was entirely White. The present study only demonstrated associations with SGA for babies born <28 weeks' gestation, and babies whose mothers were hypertensive were not excluded, which may explain the variation in results between the studies.

Factor V Leiden 

Factor V Leiden is a dominantly inherited thrombophilia, with individuals homozygous for FVL having an 80- to 100-fold increased risk of developing thromboembolism.¹⁵ Results demonstrated that for the majority of analyses, FVL was not associated with any of the adverse pregnancy outcomes studied, consistent with previous research demonstrating a lack of association between FVL and an increased risk of SGA babies.⁶, ⁸ These results also suggested that a fetus carrying FVL is at a lower risk of preterm birth 32 weeks' gestation. Since preterm birth <32 weeks used to be almost uniformly lethal, this finding might represent another selective advantage of FVL. This finding does, however, contrast with findings from Göpel et al,¹⁶ who found that the prevalences of FVL and PGM were increased in a population of very-low birth weight babies (<1500 g). We did not analyze by birth weight, but by gestational age and also SGA, which takes into account both the birth weight and gestational age of the baby.

Methylenetetrahydrofolate Reductase gene 

Two common polymorphisms have been described in the MTHFR gene: C677T and A1298C. Homozygosity for the 677 C→T base pair substitution occurs in 6% to 12% of White populations.¹⁷ This polymorphism can result in hyperhomocysteinemia, particularly in conditions of folate or vitamin B12 deficiency. Hyperhomocysteinemia may exert thrombophilic effects by altering the normal antithrombotic phenotype of the endothelium, enhancing the activities of factors XII and V, as well as depressing the activation of protein C, and also via recruiting leukocytes and augmenting leukocyte-induced endothelial cell activation.¹⁸, ¹⁹ A second common polymorphism has been described at position 1298 in the MTHFR gene, where there is an A→C base pair substitution.²⁰ This polymorphism also results in decreased enzyme activity, but not necessarily in hyperhomocysteinaemia.²⁰

For the majority of results, the present study is consistent with the few papers published in this area.⁶ MTHFR C677T was found to decrease the risk of PTB and SGA, consistent with a previous report showing that this polymorphism was associated with a reduced risk of SGA.⁶ It has been proposed that this reduced risk might be caused by increased availability of 5,10 methylenetetrahydrofolate, leading to increased thymidine synthesis and increased methylation of uracil⁶; however, further investigations are required to confirm or refute this theory. Homozygosity for MTHFR A1298C was associated with APH and premature delivery of babies who were SGA. Maternal thrombophilia is strongly associated with APH and placental abruption,²¹ perhaps as a result of via spiral artery thrombosis followed by retroplacental haematoma. Given that homozygosity for MTHFR A1298C is not usually associated with hyperhomocysteinemia, a putative cause of such thrombosis, the mechanism by which fetal MTHFR A1298C is associated with APH remains unclear, and needs further investigation.

It is important to note that this is a pathology-enriched cohort of babies, with much higher incidences of these adverse pregnancy outcomes than would normally be expected in the general population. This study was designed to investigate possible pathogenetic associations, and does not attempt to measure effect size. Further prospective large trials on fetal and maternal genotypes will be required to assess the magnitude of effect of inherited thrombophilia on the development of adverse pregnancy outcomes.

This was an exploratory study and 642 separate analyses were performed on the individual polymorphisms, with 16 yielding significant associations. Such multiple analyses increase the likelihood of such associations being caused by chance. Also, absence of associations cannot be confidently excluded in some of the subanalyses because of small numbers. Any findings must therefore be interpreted with caution. Further large-scale studies are necessary to determine definitively if there are associations between fetal inherited thrombophilia and adverse pregnancy outcomes.

One important limitation of this study is that the maternal genotype, and its effect on pregnancy outcome, was not assessed. The mothers of babies homozygous for a thrombophilic polymorphism must be at least heterozygous for that polymorphism, and the combination of polymorphisms in both mother and fetus may be required for the development of adverse pregnancy outcomes. Both the fetal and maternal circulations should be considered when investigating the role of inherited thrombophilia in the development of adverse pregnancy outcomes, and future studies should investigate further the interactions between maternal and fetal thrombophilia.

Another important limitation of this study is that we were unable to analyze our data according to other study criteria because of our sample selection. This would have made comparisons between our study and others much easier, and a clearer understanding of the possible role of fetal inherited thrombophilias may have been identified.

There was a much lower than expected incidence of PIHD in this cohort (5.9% compared with 9.2% in all South Australian pregnancies).²² The most likely explanation for the low incidence of PIHD is the large percentage of preterm babies in this case cohort (62.9%). Most cases of PIHD occur at or near term, and a high rate of prematurity would therefore appear to “protect” against later-onset PIHD. Also, the SA Pregnancy Outcome Unit Database does not contain data on proteinuria or the severity of gestational hypertension, and we were therefore unable to assess for severity of PIHD in our cohort.

SGA is a feature of all the significant associations identified in this study. This is consistent with the hypothesis that fetoplacental thrombosis resulting in intrauterine growth restriction (IUGR) may be the common factor involved in the pathogenesis of the adverse pregnancy outcomes studied. Larger studies are required to elucidate further such associations.

This study has demonstrated that fetal thrombophilic polymorphisms are associated with, and may be involved in the pathogenesis of, adverse pregnancy outcomes. Hypercoagulability in the fetus may therefore contribute to the development of such adverse outcomes, most likely in combination with other factors, such as maternal thrombophilia (both inherited and acquired), viral infection, or cytokine imbalance. Our research group is currently working to address these questions.

In summary, the evidence presented here suggests that fetal thrombophilia is related to adverse pregnancy outcomes, in particular to IUGR resulting in SGA infants. Future studies should investigate the contribution of the combination of maternal and fetal inherited thrombophilia to the development of such outcomes.

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Acknowledgments 

We thank the staff of the Molecular Pathology Department (Institute of Medical and Veterinary Sciences) and the Neonatal Screening Laboratory (Women's and Children's Hospital) for their technical assistance.

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Appendix 

Other authors and members of the South Australian Cerebral Palsy Research Group include: Annabelle Chan, Epidemiology Branch, Department of Health, Adelaide, SA; Zbigniew Rudzki, Division of Molecular Pathology, Institute for Medical and Veterinary Sciences, Adelaide, SA; Phillipa Sharpe, Department of Genetic Medicine, Women's and Children's Hospital, Adelaide, SA; T. Yee Khong, Department of Histopathology, Women's and Children's Hospital, Adelaide, SA; Mark R. Morton, Department of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, SA; Enzo Ranieri, Department of Genetic Medicine, Women's and Children's Hospital, Adelaide, SA; Heather Scott, Department of Genetic Medicine, Women's and Children's Hospital, Adelaide, SA; Heather Tapp, Department of Oncology, Women's and Children's Hospital, Adelaide, SA; and Graeme Casey, Division of Molecular Pathology, Institute for Medical and Veterinary Sciences, Adelaide, SA.

Table IV. Odds Ratios (95% CI) for all SGA <10th percentile for specified thrombophilic polymorphisms

Bolding indicates that the 95% confidence intervals do not cross unity.

Table V. Odds Ratios (95% CI) for all SGA <5th percentile for specified thrombophilic polymorphisms

Bolding indicates that the 95% confidence intervals do not cross unity.

Table VI. Odds Ratios (95% CI) for all pregnancy-induced hypertensive disorders for specified thrombophilic polymorphisms

All P values are non-significance.

Table VII. Odds Ratios (95% CI) for pregnancy-induced hypertensive disorders and SGA for specified thrombophilic polymorphisms

All P values are non-significance.

Table VIII. Odds Ratios (95% CI) for all antepartum hemorrhage for specified thrombophilic polymorphisms

All P values are non-significance.

Table IX. Odds Ratios (95% CI) for all APH and SGA for specified thrombophilic polymorphisms

Bolding indicates that the 95% confidence intervals do not cross unity.

Table X. Odds Ratios (95% CI) for preterm births (<37 weeks GA) for specified thrombophilic polymorphisms

Bolding indicates that the 95% confidence intervals do not cross unity.

Table XI. I Odds Ratios (95% CI) for preterm births (<37 weeks GA) and SGA for specified thrombophilic polymorphisms

Bolding indicates that the 95% confidence intervals do not cross unity.

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