Absence of Association of Thrombophilia Polymorphisms with Intrauterine Growth Restriction

Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada
New England Journal of Medicine (Impact Factor: 55.87). 08/2002; 347(1):19-25. DOI: 10.1056/NEJM200207043470105
Source: PubMed


Previous data have demonstrated associations between thrombophilia polymorphisms in pregnant women and an increased risk of intrauterine growth restriction in their offspring, but this finding remains uncertain.
We performed a hospital-based case-control study and a family-based study including 493 newborns with intrauterine growth restriction (defined by birth weight below the 10th percentile for gestational age and sex according to Canadian norms) and 472 controls (with birth weight at or above the 10th percentile). We determined the presence or absence in newborns and their parents of the following polymorphisms: methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, factor V Leiden G1691A, and prothrombin G20210A. Mothers were interviewed to obtain information on other risk factors for intrauterine growth restriction.
The risk of intrauterine growth restriction was not increased among mothers carrying a polymorphism associated with thrombophilia. In the case-control study, the odds ratios associated with two copies of the variant, after adjustment for newborn genotype and other risk factors, were 1.55 for MTHFR C677T (95 percent confidence interval, 0.83 to 2.90) and 0.49 for MTHFR A1298C (95 percent confidence interval, 0.25 to 0.93); heterozygotes for factor V Leiden had an odds ratio of 1.18 (95 percent confidence interval, 0.54 to 2.55), and heterozygotes for prothrombin G20210A had an odds ratio of 0.92 (95 percent confidence interval, 0.36 to 2.35). These polymorphisms in the newborn were not associated with an increased risk. Newborns who were homozygous for the MTHFR C677T variant had a decreased risk of intrauterine growth restriction (odds ratio after adjustment for mother's genotype and other confounders, 0.52 [95 percent confidence interval, 0.29 to 0.94]). The results of the family-based study supported those of the case-control study.
Our findings do not indicate that there are associations between maternal or newborn polymorphisms associated with thrombophilia and an increased risk of intrauterine growth restriction.


Available from: Emmanuelle Genin
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    • "Combination with certain serum markers gave additional information on the probability of APO [9–17]. Also the presence of thrombophilia is in discussion to be a contributing factor [2, 18–24]. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective To identify patients at very high risk for adverse pregnancy outcome (APO) at the 20- to 23-week scan and to assess the effectiveness of Aspirin (ASS) and low molecular weight heparin (LMWH) starting after this examination. Patients and methods By applying an algorithm based on multivariate logistic regression analysis using the parameters maternal age, parity, body mass index (BMI), mean pulsatility index of both uterine arteries (meanPI), presence of uni- or bilateral notch, and depth of notch (mean notch index (meanNI), we retrospectively calculated the individual risk for APO of 21,302 singleton pregnancies. We isolated a subgroup of 426 patients with the highest calculated probability for APO (cpAPO > 27.8 %). 147 had been treated with ASS; 73 with LMWH, 15 patients with a combination of ASS and LMWH, and 191 patients had not received anticoagulants. Results Administration of ASS starting after 20 gestational weeks in comparison to non-treated patients significantly reduced the frequency of intrauterine/neonatal death (IUD/NND), preeclampsia <33 weeks (PE < 33), and preterm delivery <33 weeks (PD < 33), while the frequency of IUGR showed a tendency to be elevated (P = 0.061). The subgroup of high-risk patients treated with LMWH was characterised by a higher a priori risk for APO and showed no significant reduction of any form of APO but an increased frequency of PE. Conclusion Individual assessment of risk for APO by applying a simple algorithm based on biometrical/biographical as well as sonographic parameters may serve as basis for drug intervention studies. The administration of ASS in high-risk patients starting after 20 gestational weeks reduced the frequency of most of the severe forms of adverse pregnancy outcome in high-risk patients. A complication-reducing effect of LMWH starting after 20 weeks of gestation in patients could not be proven. From an ethical point of view, it may not be justified any more to preclude high-risk patients from administration of ASS or to perform studies of ASS against placebo.
    Full-text · Article · Feb 2013 · Archives of Gynecology
    • "There is a strong association between preeclampsia and FGR due to deficient trophoblastic invasion [10] . Other diseases, such as insulin-dependent diabetes mellitus with vasculopathy, cyanotic cardiopathies, restrictive pneumopathies, severe renal conditions, autoimmune diseases (collagenoses, antiphospholipid antibody syndrome), hereditary or acquired thrombophilia, hyperhomocysteinemia, and severe anemia are also associated with FGR [11, 12]. 2. Nutritional disorders: chronic malnutrition prior to pregnancy is associated with a 40 % incidence of lowweight newborns, resulting both from prematurity and FGR, with mortality rates during the first year of life being four times higher [13]. 3. The use of drugs: smoking stands out and is a preventable cause of FGR. "
    [Show abstract] [Hide abstract] ABSTRACT: Fetal growth restriction (FGR) is a condition that affects 5-10 % of gestations, and it is the second primary cause of perinatal mortality. In this review the most recent knowledge about FGR is presented focusing on its concept, etiology, classification, diagnosis, management, and prognosis. Searches were conducted in Pubmed, Embase and Lilacs database using the term fetal growth restriction. FGR is classified as type I (symmetric), manifested early, in which there is a proportional reduction of all fetal parts, generally associated with chromosome abnormalities; type II (asymmetric), with late onset, in which there is a more accentuated reduction of the abdomen, generally related to placental insufficiency; and type III (mixed), with early manifestation, resulting from infections or exposure to toxic agents. Diagnosis may be clinical, although ultrasound associated with arterial and venous Doppler is essential for diagnosis and follow-up. Currently there is no treatment capable of controlling FGR, and the moment of interruption of pregnancy is of vital importance in order to protect maternal and fetal interests. Early diagnosis of FGR is very important, because it permits the etiological identification and adequate monitoring of fetal vitality, minimizing the risks related to prematurity and intrauterine hypoxia.
    No preview · Article · Apr 2012 · Archives of Gynecology
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    • "However, previous reports observed that the maternal 1298CC genotype was associated with a greater reduction in the risk of low birth weight as compared with the 1298AA genotype.21 The 1298CC homozygous genotype was also reported to be protective against IUGR in Canadians.53 Hyperhomocysteinemia might have increased the risk of placental vasculopathy via oxidative stress, endothelial cell dysfunction, and/or coagulopathies leading to feto-placental hypoperfusion.5 "
    [Show abstract] [Hide abstract] ABSTRACT: Background Intracellular folate hemostasis depends on the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Because 5,10-MTHFR 677TT homozygosity and tobacco smoking are associated with low folate status, we tested the hypothesis that smoking in mothers with 5,10-MTHFR C677T or A1298C polymorphisms would be independently associated with lower birth weight among their offspring. Methods We assessed 1784 native Japanese mother-child pairs drawn from the ongoing birth cohort of The Hokkaido Study on Environment and Children’s Health. Data (demographic information, hospital birth records, and biological specimens) were extracted from recruitments that took place during the period from February 2003 to March 2006. Maternal serum folate were assayed by chemiluminescent immunoassay, and genotyping of 5,10-MTHFR C677T/A1298C polymorphisms was done using a TaqMan allelic discrimination assay. Results The prevalence of folate deficiency (<6.8 nmol/L) was 0.3%. The 5,10-MTHFR 677CT genotype was independently associated with an increase of 36.40 g (95% CI: 2.60 to 70.30, P = 0.035) in mean infant birth weight and an increase of 90.70 g (95% CI: 6.00 to 175.50, P = 0.036) among male infants of nonsmokers. Female infants of 677TT homozygous passive smokers were 99.00 g (95% CI: −190.26 to −7.56, P = 0.034) lighter. The birth weight of the offspring of smokers with 5,10-MTHFR 1298AA homozygosity was lower by 107.00 g (95% CI: −180.00 to −33.90, P = 0.004). Conclusions The results suggest that, in this population, maternal 5,10-MTHFR C677T polymorphism, but not the 5,10-MTHFR A1298C variant, is independently associated with improvement in infant birth weight, especially among nonsmokers. However, 5,10-MTHFR 1298AA might be associated with folate impairment and could interact with tobacco smoke to further decrease birth weight.
    Full-text · Article · Mar 2012
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