#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies


Background:
Factor V Leiden (FVL) and prothrombin gene mutation (PGM) are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications.

Methods and Findings:
A comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1) prospective cohort design; (2) clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3) maternal FVL or PGM carrier status; (4) sufficient data for calculation of odds ratios (ORs). We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2%) was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06–2.19) as compared with women without FVL (absolute risk 3.2%). There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89–1.70) or between FVL and SGA (OR = 1.0, 95% CI 0.80–1.25). PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79–1.99) or SGA (OR 1.25, 95% CI 0.92–1.70).

Conclusions:
Women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants.

: Please see later in the article for the Editors' Summary


Published in the journal: . PLoS Med 7(6): e32767. doi:10.1371/journal.pmed.1000292
Category: Research Article
doi: https://doi.org/10.1371/journal.pmed.1000292

Summary

Background:
Factor V Leiden (FVL) and prothrombin gene mutation (PGM) are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications.

Methods and Findings:
A comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1) prospective cohort design; (2) clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3) maternal FVL or PGM carrier status; (4) sufficient data for calculation of odds ratios (ORs). We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2%) was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06–2.19) as compared with women without FVL (absolute risk 3.2%). There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89–1.70) or between FVL and SGA (OR = 1.0, 95% CI 0.80–1.25). PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79–1.99) or SGA (OR 1.25, 95% CI 0.92–1.70).

Conclusions:
Women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants.

: Please see later in the article for the Editors' Summary

Introduction

Pregnancy loss, pre-eclampsia, small for gestational age (SGA) pregnancies, and placental abruption are distressing and often devastating pregnancy outcomes for women, their families, and society [1][3]. Frequently occurring as a result of placental insufficiency, they affect more than one in 20 pregnancies [3],[4]. Thrombophilia describes an increased tendency to develop thrombosis, either venous or arterial. Thrombophilias may either be inherited or acquired and include protein C deficiency, protein S deficiency, antithrombin deficiency, and the less potent factor V Leiden (FVL) and prothrombin gene mutation (PGM). The combined prevalence of these thrombophilias in the general population exceeds one in ten [5][11]. A successful pregnancy requires the development of adequate placental circulation. It is hypothesised that thrombophilias may increase the risk of placental insufficiency because of placental micro- and/or macro-vascular thrombosis, as well as effects on trophoblast growth and differentiation [12].

Individual case control studies variably demonstrate an association between the placenta-mediated pregnancy complications and thrombophilia but when meta-analysed suggest a weak positive association [13][15]. Case control studies are limited by (1) retrospective data collection leading to potential bias in outcome classification and incomplete and/or poor confounder data acquisition and (2) possible differential participation bias where more severe cases are recruited. Prospective cohort studies limit these potential biases but have limited power to detect weak associations [16]. Prospective cohort studies also provide absolute risk estimates that can be used to counsel patients. Our objective was to undertake a systematic review and a meta-analysis of prospective cohort studies to estimate the risk of these common and important placenta-mediated pregnancy complications in the women with and without FVL or PGM.

Methods

Search Strategy

Following our systematic review protocol, a systematic literature search strategy was conducted to identify potential studies in MEDLINE (1950 to November 2007) and EMBASE (1980 to November 2007) using the OVID interface. The search was updated in February 2010.We identified the following relevant MeSH and free terms for the exposures and outcomes by literature review and by recommendations from experts in the field (MAR, MC): Thrombophilia, activated protein C resistance (APCR), FVL, and PGM (PGM, PGV, G202110A, G1691A) for the exposure. For the outcome we used the subject headings pregnancy complications, abruption placentae, abortion spontaneous, stillbirth, pre-eclampsia, HELLP syndrome, hypertension-pregnancy induced, fetal growth retardation, low birth weight, and the free term miscarriage. Different subject headings were used for EMBASE or MEDLINE when appropriate. These searches were limited to observational studies by applying validated filters for MEDLINE and EMBASE available in the Scottish Intercollegiate Guidelines Network [17]. The search was also restricted to humans. There were no restrictions on language, publication year, or type of publication. Our full systematic search strategy is documented in Table S1. In addition to the electronic search, we examined reference lists of retrieved articles and identified additional articles and abstracts from recommendations of experts in the field. Duplicate reports of the same cohort reporting the same outcomes with the same exposures were excluded. Records of selected articles were examined by two independent reviewers (MTB and MAR) to identify all relevant citations.

Selection Criteria

Using a structured question format to aid our literature search strategy, we reviewed all potentially relevant articles that satisfied all of the following criteria: (1) unselected pregnant women enrolled prospectively in the first or second trimester of pregnancy; (2) women investigated for FVL (diagnosed by DNA-based PCR assay for FVL mutation) or PGM (by DNA-based PCR assay) carrier status (homozygotes, heterozygotes, or both); and (3) reported any of the following placenta-mediated pregnancy complication outcomes: pregnancy loss, pre-eclampsia, placenta abruption, or SGA.

Outcome Measures

The primary outcome measure was the incidence of placenta-mediated complications during pregnancy (pregnancy loss, pre-eclampsia, SGA, and placental abruption). Pre-eclampsia was defined as systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher occurring after 20 wk of gestation in a woman whose blood pressure has previously been normal; plus proteinuria, with excretion of 0.3 g or more of protein in a 24-h urine specimen or proteinuria ≥2 by dipstick [18],[19]. Pregnancy loss included (1) spontaneous miscarriage (involuntary termination of pregnancy before 20 wk of gestation, dated from the last menstrual period) or below a fetal weight of 500 g [20],[21] and (2) stillbirth (complete expulsion or extraction of a dead fetus at or after 20 wk of pregnancy, or when the fetal weight was at least 500 g in cases where the gestational age is not known) [22]. Placental abruption was defined as ante partum retroplacental, marginal, or preplacental hemorrhage confirmed by imaging studies or visual inspection of the placenta [23]. SGA was defined as a birth weight less than 10th percentile of population-specific birth weight adjusted for gender and gestational age. Severe SGA was defined as a birth weight less than 5th percentile of population-specific gender and gestational age-adjusted birth weight [24],[25].

Data Extraction and Quality Assessment

Two reviewers (MTB and MAR) independently applied the inclusion criteria to the identified articles from the initial search strategy. Articles for potential full review were discussed between the two reviewers. A data-extraction form was designed, piloted, and revised. Reviewers independently extracted baseline characteristics of the included studies and obtained a 2×2 table with the number of placenta-mediated complications in exposed and unexposed patients (i.e., FVL or PGM status). The corresponding authors of studies with missing data were contacted. Discrepancies were noted and discussed between reviewers. Adjudication by a third party to resolve conflicts was not necessary.

The methodological quality of the studies was evaluated using the validated Newcastle–Ottawa scale (NOS) for prospective cohort studies as recommended by the Cochrane Non-Randomized Studies Methods Working Group [26]. The quality of a study was judged on the selection of the study groups, the comparability of the groups, and the ascertainment of the outcome of interest. For all eligible studies, two reviewers (MTB and MAR) independently assessed study quality and extracted the data using a standardized data abstraction form. Likewise, any discrepancies were documented and discussed between the reviewers.

Data Synthesis and Analysis

We chose to use the pooled estimate of the odds ratio (OR) as our measure of effect, to analyze the results based on 95% confidence intervals (CIs), and to report two-sided p-values. Statistical heterogeneity between and within groups was measured using I2 statistic [27]. I2<25% was considered low heterogeneity, 25%–50% was moderate heterogeneity, and >50% was considered high heterogeneity [28]. We used Mantel-Haenszel analysis with 0.5 zero cell replacement method for this meta-analysis given event rates over 1% for the placenta-mediated pregnancy complications, imbalance in exposed/nonexposed groups, and imbalance in cases and controls [29]. In sensitivity analyses Peto ORs were also determined. Fixed-effect method was used to pool results for all models. We used sensitivity analysis to explore the causes of heterogeneity and to determine the impact that differences in outcome definition or measurement had on our results [30]. We also planned to examine funnel plots to assess publication bias if sufficient number of studies were included to permit assessment of publication bias.

The analysis was conducted using SAS 9.1 and RevMan 5.0 software from the Cochrane reviews.

Results

A total of 322 articles and one abstract (see Figure 1 for study selection flowchart) were identified. Of these, 95 were deemed relevant on the basis of their title. After abstract review, 30 articles and one abstract were selected for full article review or direct data retrieval from the authors. Of the 30 studies, 12 studies did not meet the inclusion criteria, and eight studies did not have sufficient data for inclusion after full article review. After contacting authors, we obtained data on the number of events and study design features for one of the eight published articles with insufficient data for this review [31]. We also obtained complete data for the abstract [32]. After reviewing the full text of the papers and contacting the authors we included ten articles in the review [31][40]. We did not exclude any study on the basis of the definition of outcome used by the authors.

Fig. 1. Study selection.
Study selection.

Included Studies Characteristics

The association between thrombophilias (FVL or PGM) and placenta-mediated pregnancy complications was summarized from ten prospective cohort studies. Of the included studies, there were cohorts from Dublin, Ireland [38]; Tel Aviv, Israel [31]; multiple centers in the United States, which gave rise to two publications, one reporting on FVL thrombophilia [34] and one reporting on PGM thrombophilia [40]; Glasgow, UK [33]; Avon, UK [35]; Melbourne, Australia [39]; Patras, Greece [36]; Malmo, Sweden [37] and Ottawa, Canada [32].

The characteristics of the selected studies are summarized in Table 1 and Table S2. The cohorts were homogeneous and consistent in terms of participants, exposures, and outcomes except for the outcomes of pregnancy loss and placental abruption. The latter definitions were either unclear and/or inconsistent across studies. Participants were women with spontaneous singleton pregnancy in either their first or second trimester except for one study where all patients were enrolled before 8 wk of gestation [36] and one study where a small number of multiple pregnancies were included [39]. Gestational age at enrollment ranged from 6 to 22 wk and most women were under 35 y of age. We were not able to find information on gestational age at enrollment for one study [35]. FVL prevalence (either homozygous or heterozygote) varied across selected studies from 2.7% [38] to 10.9% [37].

Tab. 1. Characteristics of included studies.
Characteristics of included studies.
Abbreviations: +/−, heterozygous carrier; ++, homozygous carrier; NOS, Newcastle Ottawa Scale for cohort studies (maximum n of starts: selection, 4; compatibility, 2; outcome, 3); PA, placental abruption; PET, pre-eclampsia; PL, pregnancy loss.

The quality of the included studies as assessed using the Newcastle–Ottawa quality assessment scales scored high in selection and comparability of the study groups as well as in ascertainment of the outcome of interest (see Table 1).

The limited number of studies included in our meta-analysis did not permit assessment of publication bias.

Maternal FVL/PGM and Pregnancy Loss

We identified seven studies reporting information on pregnancy loss [32][34],[36][39]. Most studies included patients with spontaneous miscarriage or stillbirth as pregnancy losses but there were important inconsistencies in the definition of this outcome. The pooled OR estimate from these seven studies is 1.52 (95% CI 1.06–2.19) in 16,959 total women with an observed FVL prevalence of 4.7% (see Figure 2). The absolute risk of pregnancy loss in women with FVL was 4.2% as compared with 3.2% for FVL negative women.

Fig. 2. Odds of placenta-mediated pregnancy complications in FVL (homozygous or heterozygous)-positive women.
Odds of placenta-mediated pregnancy complications in FVL (homozygous or heterozygous)-positive women.

A fixed effect model was used for assessment of pregnancy loss despite substantial statistical heterogeneity across studies (I2 = 51%, p = 0.06). The pooled estimate remained statistically significant when a random effect model was used 1.96 (95% CI 1.13–3.38) or when we used a Peto OR fixed model 1.64 (1.07–2.51). We suspected that differences in the definition of pregnancy loss across studies was the most likely explanation for this heterogeneity (see Table S2). Heterogeneity was significantly reduced when the two studies that included either spontaneous abortion only [38] or stillbirth only [39] were removed from the pooled analysis (I2 = 15%, p = 0.32). After removing these two studies the pooled OR was no longer significant at 1.34 (95% CI 0.90–1.98). In addition, most studies enrolled both primiparous or multiparous women except the aforementioned two studies [38],[39], which included primiparous women only.

There were four studies reporting on the association of PGM and pregnancy loss with a pooled OR estimate of 1.13 and wide 95% CIs (0.64–2.01) (see Figure 3).

Fig. 3. Odds of placenta-mediated pregnancy complications in PGM (homozygous or heterozygous)-positive women.
Odds of placenta-mediated pregnancy complications in PGM (homozygous or heterozygous)-positive women.

Maternal FVL/PGM and Pre-eclampsia

All ten selected studies reported information on pre-eclampsia. The presence of FVL mutation did not significantly increase the risk of pre-eclampsia, with a pooled OR estimate of 1.23 (95% CI 0.89–1.70) in 21,833 total women with a FVL prevalence of 4.9% (see Figure 2). The absolute risk of pre-eclampsia in FVL positive women was 3.8% as compared with 3.2% for FVL-negative women. There was no statistical heterogeneity across studies and the definition of the outcome pre-eclampsia was fairly consistent across the studies (see Table S2).

The combination of six studies reporting on PGM status and pre-eclampsia did not show significant association between PGM (heterozygous or homozygous) and pre-eclampsia with a pooled OR = 1.25 (95% CI 0.79–1.99) in 14,254 total women with a PGM prevalence of 4.1%.(see Figure 3). The absolute risk of pre-eclampsia in women with PGM was 3.5% as compared with 3.0% for PGM negative women.

Maternal FVL/PGM and SGA Neonate (Birth Weight <10th Percentile)

There were seven studies reporting information on SGA and FVL [31],[32],[34],[35],[37][39]. All studies had a fairly homogeneous definition of SGA although some heterogeneity may have been introduced by three studies that used country-specific birth-weight standardized charts (see Table S2) [32],[35],[39]. The presence of FVL did not significantly increase the risk of SGA, with a pooled OR estimate of 1.0 (95% CI 0.80–1.25) in 20,654 total women with a FVL prevalence of 6.0% (see Figure 3). The absolute risk of SGA <10th percentile in women with FVL was 6.5% as compared with 7.4% for FVL-negative women. This lack of association did not vary after exclusion of the three studies that used country-specific birth-weight charts (OR = 0.91, 95% CI 0.64–1.28) [32],[35],[39].

Five studies reported PGM status and SGA <10th percentile [31],[32],[35],[39],[40] in 17,287 total women with a PGM prevalence of 5.1%. The absolute risk of SGA <10th percentile in women with PGM (heterozygous or homozygous) was 5.4% as compared with 5.7% for PGM negative women. We did not find a significant association between PGM (heterozygous or homozygous) and SGA <10th percentile (pooled OR = 1.25, 95% CI 0.92–1.70) (see Figure 3).

Maternal FVL/PGM and Severe SGA Neonate (Birth Weight <5th Percentile)

Five studies reported FVL status and birth weight under 5th percentile [33],[34],[36],[37],[39],[41],[42] with a total of 12,936 women, FVL prevalence 4.9%. The absolute risk of SGA <5th percentile in women FVL positive was 3.8% as compared with 4.3% for women FVL negative. The combined OR for this population showed no significant association between FVL status and SGA <5th percentile (pooled OR = 0.92, 95% CI 0.61–1.40). The pooled OR estimate of three studies reporting on SGA <5th percentile and PGM was 1.46 (0.81–2.62) in 6,285 total women with a prevalence of 3.3% for PGM. The prevalence of SGA <5th percentile in women with PGM was 5.7% as compared with 4.3% for PGM negative women.

Maternal FVL/PGM and Placental Abruption

There were five studies reporting the association between FVL mutation and placenta abruption [32],[34],[36],[37],[39]. These studies included 12,308 women with a pooled FVL prevalence of 5.1%. The absolute risk of placenta abruption in FVL positive women was 1.3% as compared with 0.9% for FVL negative women. The pooled OR estimate for placental abruption in women with FVL mutation (homozygous or heterozygous) was 1.85 (95% CI 0.92–3.70) (see Figure 2). The moderate statistical heterogeneity with I2 = 33% may be attributable to the inconsistent and unclear definition of placental abruption across studies (see Table 1).

The pooled OR estimate for placental abruption in women with PGM mutation (homozygous or heterozygous) was 2.02 (95% CI 0.81–5.02) with moderate heterogeneity across studies (I2 = 49%) (see Figure 3).

The results for all four individual outcomes were not substantially different in sensitivity analysis using Peto ORs.

Maternal FVL/PGM and the Composite of Any Placenta-Mediated Pregnancy Complications

There was no association between FVL and the composite outcome of any of the placenta-mediated pregnancy complications (pregnancy loss, placental abruption, pre-eclampsia, and SGA [>10th percentile]) with a pooled OR = 1.08 (95% CI 0.87–1.52) from four studies reporting on the four outcomes (see Figure 4). There was no association between PGM and the composite outcome of any placenta-mediated pregnancy complications (pregnancy loss, placental abruption, pre-eclampsia, and SGA [>10th percentile]) with a pooled OR = 1.27 (95% CI 0.94–1.71) from four studies reporting on the four outcomes (see Figure 5).

Fig. 4. FVL and composite placenta-mediated pregnancy complications.
FVL and composite placenta-mediated pregnancy complications.

Fig. 5. PGM and composite placenta-mediated pregnancy complications.
PGM and composite placenta-mediated pregnancy complications.

Discussion

The principal findings of our meta-analysis of prospective cohort studies examining a potential association between FVL or PGM are (1) we have shown that FVL is likely weakly associated with pregnancy loss and (2) we have shown that neither FVL nor PGM are associated with pre-eclampsia or birth of an SGA infant. Further research is required to determine if FVL or PGM are associated with placental abruption and whether PGM is associated with important increases in pregnancy loss.

Pregnancy loss, especially recurrent or late pregnancy loss, is a painful event for pregnant women and their families [3]. Despite demonstrating that the odds of pregnancy loss in women with FVL appears to be 52% higher as compared with women without FVL, women with FVL should be reassured that the absolute event rate for pregnancy loss is low (4.2%) and only appears slightly higher than the rate of pregnancy loss in women without FVL (3.2%). As discussed below, this finding must be interpreted with caution given the statistical and clinical heterogeneity in this analysis. If a theoretical intervention was demonstrated to completely eliminate this increased risk of pregnancy loss in women with FVL (i.e., 100% relative risk reduction) it would result in a number needed to treat (NNT) of 100. That is 100 women would require treatment to prevent one pregnancy loss. Our findings are also in sharp contrast to the initial case control study reports of a strong association between FVL and pregnancy loss (e.g., ORs 4.9 with FVL and stillbirth) [41] but consistent with later meta-analyses [14].

We unfortunately had insufficient sample size to detect important increases in the risk of pregnancy loss in women with PGM. With a PGM prevalence of 2.9% in a sample size of 9,225, we only have 80% power to detect an absolute increase of >4% from the observed control group event rate of 3.6%. As such we had limited power to detect important differences in absolute risk of pregnancy loss (e.g., 1% or 2%) in women with PGM.

We found substantial statistical heterogeneity across studies reporting pregnancy loss. It is well known that nonuniform definitions of pregnancy loss across studies may create heterogeneity [42]. The likely explanations of the heterogeneity we observed in our meta-analysis include the wide range of gestational ages at enrollment (6 to 22 wk) in the component studies, the inconsistent definition of pregnancy loss across studies, and perhaps differences in parity in inclusion criteria between studies. Pregnancy loss was defined as any loss (i.e., spontaneous miscarriage or stillbirth) for most of the studies, but as spontaneous miscarriage only for one study [38], and as stillbirth only for one study [39]. Heterogeneity was significantly reduced when two studies including only primiparous women [38],[39] were removed from meta-analysis.

Pre-eclampsia is the most important cause of premature delivery with the resultant impact on fetal and neonatal morbidity and mortality [2]. Our study failed to demonstrate an association between the genetic thrombophilias and pre-eclampsia yet had excellent power to detect these associations. We had over 90% power to detect an absolute increase of 2% (from control 3.2% to FVL 3.2%+2% = 5.2%) in the rate of pre-eclampsia in women with FVL and an increase of 3% (from control 3.4% to PGM 3.4%+3.0% = 6.4%) in the rate of pre-eclampsia in women with PGM, yet we did not detect any increased risk. This finding should allow clinicians to provide reassurance to women with these thrombophilias that they are not at significantly increased risk of pre-eclampsia.

SGA often results in long-term effects in the developing child, including developmental delay and poor school performance and, as adults, children with SGA are significantly less likely to attain higher academic and professional achievement [43]. A recently published meta-analysis of case control and cohort studies identified a significant association between FVL and SGA (<10th percentile) in case control studies but identified evidence of publication bias in these case control studies [44]. In their analysis of retrospective and prospective cohort studies, there was no evidence of association between FVL and SGA (<10th percentile) (n = 3 studies with 8,256 patients), and the authors failed to identify any cohort studies examining an association between PGM and SGA [44]. Our meta-analysis, which only included prospective cohort studies, included more publications and more patients (FVL, n = 7 with >20,000 patients; PGM, n = 5 with >17,000 patients) as we included abstracts and we contacted the authors to obtain missing information, hence we can provide more robust and precise estimates of association. Our study failed to demonstrate an association between the genetic thrombophilias and SGA yet had excellent power to detect an association. We had over 90% power to detect an absolute increase of 3% (from control 7.4% to FVL 7.4%+3% = 11.4%) in the rate of SGA (<10th percentile) in women with FVL and an increase of 3% (from control 5.4% to PGM 5.4%+3% = 8.4%) in the rate of SGA (<10th percentile) in women with PGM, yet we did not detect any increased risk. This finding should allow clinicians to provide reassurance to women with these thrombophilias that they are not significantly more likely to give birth to an SGA child.

We had inadequate power to detect a doubling of risk of placental abruption in women with FVL or women with PGM. Unfortunately small sample sizes and low event rates limit conclusions regarding an association between the inherited thrombophilias, FVL or PGM, and placenta abruption. Furthermore, our analyses were limited by considerable statistical heterogeneity likely resulting from variable definitions for placental abruption.

The strengths of our study include: (1) the large number of pregnancies collectively examined in prospective cohort studies, which allows us to detect/exclude relatively small effects as outlined above; (2) the inclusion of only prospective cohort studies, which allows for more accurate directed data collection that minimised outcome misclassification and likely improves completeness and accuracy of confounder data collection; (3) prospective design that allows participant recruitment prior to outcome determination thereby minimising selection bias; (4) we suspect that prospective cohort studies are less likely than case control studies to suffer from publication bias, as explained below; and (5) the combination of prospective data without heterogeneity from different parts of the western world increases the generalizability of the study.

The limitations of our meta-analysis include: (1) prospective cohort studies enrolling pregnant patients beyond the late first trimester do not permit examination of early pregnancy events, such as early pregnancy loss, prior to enrollment. Only one out of seven studies reporting information on pregnancy loss exclusively enrolled patients early in their first trimester of pregnancy [36]. Hence, we could not examine for an association with early pregnancy loss. Only “conception” or prepregnancy prospective cohorts would permit prospective examination of this issue; (2) we had insufficient data and hence power to detect important associations between PGM and pregnancy loss as well as FVL or PGM and placental abruption; (3) there are insufficient prospective cohort studies examining the less common and more potent thrombophilias such as antithrombin, protein C, and protein S deficiencies to elucidate associations between these thrombophilias and placenta-mediated pregnancy complications. Given the expense of biological assays for these thrombophilias, the need for repeat confirmatory testing and false positives with protein S in pregnancy it is unlikely that adequately powered prospective cohort studies will be conducted to address the question of an association between these thrombophilias and placental-mediated pregnancy complications.

Our findings are in sharp contrast to the initial case control study reports of a strong association between thrombophilia and pre-eclampsia and SGA [43], and in contrast to later meta-analyses of case control studies [13],[15],[16],[41]. Several explanations are possible for the discrepancy between case control and prospective cohort studies in this area: (1) Publication bias: given the tremendous expense and effort in completing prospective cohort studies, negative studies are probably more likely to be published than small inexpensive negative case control studies. If this is the case, then proportionately more positive case control studies may be published and lead to the discrepant findings, indeed meta-analyses of case control studies in this area have suggested publication bias [44],[45]. The small number of cohort studies included in our analysis of prospective cohort studies limits the ability to detect publication bias in these prospective cohort studies; (2) Interaction: it may be that thrombophilias do not cause pre-eclampsia and SGA but synergise additional risk factors for these complications (i.e., have an interactive effect). Given that selection bias in case control studies may lead to more severe cases being included than in cohort studies, interactive effects may be more easily detected in case control studies and associations with thrombophilia may be confounded by additional risk factors that are more likely in selected case control studies.

The negative findings described in this publication are important. The small step of previously describing an association in case control studies has led a number of clinicians and opinion leaders to take the large leap of accepting this relationship as being causal and potentially treatable with anticoagulant interventions. Many have adopted low molecular weight heparin as part of routine care for women with a history of placenta-mediated complications who have tested positive for a laboratory marker of thrombophilia [1],[46],[47], and some have even adopted this practice in women with prior placenta-mediated pregnancy complications without thrombophilia, on the presumption that they harbour yet to be discovered thrombophilia. However, recent randomised trials have shown that low molecular weight heparin in unselected women with prior recurrent early loss do not benefit from low molecular weight heparin [48],[49]. Further trials are needed to determine if low molecular weight heparin will be of benefit in thrombophilic women with prior placenta-mediated pregnancy complications and in unselected women with the other placenta-mediated pregnancy complications (late loss, SGA, pre-eclampsia, abruption). Our findings highlight that in the absence of “no intervention” controlled studies, adopting anticoagulant prophylaxis to prevent these complications is premature and should be considered experimental.

In summary, women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants. Further research is required to determine if PGM is associated with pregnancy loss and whether FVL or PGM are associated with placental abruption. Adopting anticoagulant prophylaxis to prevent these complications in thrombophilic women is premature and should be considered experimental.

Supporting Information

Attachment 1

Attachment 2

Attachment 3

Attachment 4


Zdroje

1. BrennerB

2003 Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications - Yes. J Thromb Haemost 1 2070

2. BrennerB

2006 Thrombophilia and adverse pregnancy outcome. Obstet Gynecol Clin North Am 33 443 456 ix

3. RodgerMA

PaidasM

McLintockC

MiddeldorpS

KahnS

2008 Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol 112 320

4. KujovichJL

2004 Thrombophilia and pregnancy complications. Am J Obstet Gynecol 191 412

5. BrownK

LuddingtonR

WilliamsonD

BakerP

BaglinT

1997 Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3′-untranslated region of the prothrombin gene. Br J Haematol 98 907

6. KosterT

BlannAD

BrietE

VandenbrouckeJP

RosendaalFR

1995 Role of clotting factor VIII in effect of von Willebrand factor on occurrence of DVT. Lancet 345 152

7. KraaijenhagenRA

AnkerPS

KoopmanMMW

ReitsmaPH

PrinsMH

2000 High plasma concentration of Factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 83 5

8. PoortSR

RosendaalFR

ReitsmaPH

BertinaRM

1996 A common genetic variation in the 3′ -untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 88 3698

9. RodeghieroF

TosettoA

1997 The epidemiology of inherited thrombophilia: the VITA Project. Vicenza Thrombophilia and Atherosclerosis Project. Thromb Haemost 78 636

10. SoutoJC

CollI

LlobetD

del RioE

OliverA

1998 The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost 80 366

11. van der MeerFJ

KosterT

VandenbrouckeJP

BrietE

RosendaalFR

1997 The Leiden Thrombophilia Study (LETS). Thromb Haemost 78 631

12. IsermannB

SoodR

PawlinskiR

ZoggM

KallowayS

2003 The thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med 9 331

13. HowleyHE

WalkerM

RodgerMA

2005 A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction. Am J Obstet Gynecol 192 694

14. ReyE

KahnSR

DavidM

ShrierI

2003 Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 361 901

15. WuO

RobertsonL

TwaddleS

LoweGD

ClarkP

2006 Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess 10 1

16. FunaiEF

2009 Inherited thrombophilia and preeclampsia: is the evidence beginning to congeal? [comment]. Am J Obstet Gynecol 200 121

17. SIGN. Scottish Intercollegiate Guidelines Network 2008 Search filters for study designs. Available: http://www.sign.ac.uk/methodology/filters.html. Accessed 12 April 2010

18. HelewaME

BurrowsRF

SmithJ

WilliamsK

BrainP

1997 Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy. CMAJ 157 715

19. SchroederBM

American College of Obstetricians and Gynecologists 2002 ACOG practice bulletin on diagnosing and managing preeclampsia and eclampsia. American College of Obstetricians and Gynecologists. American Family Physician 66 330 331

20. CoddingtomCC

JonesRO

2007 Pregnancy loss and spontaneous abortion. Manual of obstetrics.

EvansAT

Philadelphia Lippincott Williams & Wilkins

21. CunninghamFG

HaulthJC

LevenoKJ

BloomSL

WenstromKD

2005 Williams obstetrics New York McGraw-Hill

22. CorabianP

2005 Protocols for stillbirth investigation Calgary, Alberta Alberta Heritage Foundation for Medical Research 14

23. HelenK

2003 Placenta previa and abruption. Danforth's obstetrics & gynecology.

ScothhJR

GibbsRS

KarlanBY

HaneyAF

Philadelphia Lippicott Williams & Wilkins

24. AndersonMS

HayWW

2005 Intrauterine growth restriction and the small-for-gestational-age infant. Avery's neonatology.

MacDonaldMG

SeshiaMM

MulletMD

Philadelphia Lippicott Williams & Wilkins

25. GalanHL

HobbinsJC

2003 Intrauterine growth restriction. Danforth's obstetrics & gynecology.

ScothhJR

GibbsRS

KarlanBY

HaneyAF

Philadelphia Lippicott Williams & Wilkins

26. WellsGA

SheaB

O'ConnellD

PetersonJ

WelchV

2009 The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed 9 May 2010

27. HigginsJP

ThompsonSG

DeeksJJ

AltmanDG

2003 Measuring inconsistency in meta-analyses. BMJ 327 557

28. HigginsJP

ThompsonSG

2002 Quantifying heterogeneity in a meta-analysis. Stat Med 21 1539

29. BradburnMJ

DeeksJJ

BerlinJA

RussellLA

2007 Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 26 53

30. MullanRJ

FlynnDN

CarlbergB

TleyjehIM

KamathCC

2009 Systematic reviewers commonly contact study authors but do so with limited rigor. J Clin Epidemiol 62 138

31. SalomonO

SeligsohnU

SteinbergDM

ZalelY

LernerA

2004 The common prothrombotic factors in nulliparous women do not compromise blood flow in the feto-maternal circulation and are not associated with preeclampsia or intrauterine growth restriction. Am J Obstet Gynecol 191 2002

32. RodgerM

2007 Abstract: Factor V Leiden (FVL) and prothrombin gene variant (PGV) may be only weakly associated with placenta mediated pregnancy complications: a large prospective cohort study. J Thromb Haemost 5 0S 054

33. ClarkP

WalkerID

GovanL

WuO

GreerIA

2008 The GOAL study: a prospective examination of the impact of factor V Leiden and ABO(H) blood groups on haemorrhagic and thrombotic pregnancy outcomes. Br J Haematol 140 236

34. Dizon-TownsonD

MillerC

SibaiB

SpongCY

ThomE

2005 The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol 106 517

35. DuddingT

HeronJ

ThakkinstianA

NurkE

GoldingJ

2008 Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: a genetic association study and meta-analysis. J Thromb Haemost 6 1869

36. KarakantzaM

AndroutsopoulosG

MougiouA

SakellaropoulosG

KourounisG

2008 Inheritance and perinatal consequences of inherited thrombophilia in Greece. Int J Gynaecol Obstet 100 124

37. LindqvistPG

SvenssonP

DahlbackB

2006 Activated protein C resistance in the absence of factor V Leiden and pregnancy. J Thromb Haemost 42 361

38. MurphyRP

DonoghueC

NallenRJ

D'MelloM

ReganC

2000 Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 20 266

39. SaidJM

HigginsJR

MosesEK

WalkerSP

BorgAJ

2010 Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women. Obstet Gynecol 115 5

40. SilverRM

ZhaoY

SpongCY

SibaiB

WendelG

2010 Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol 115 14

41. KupfermincMJ

EldorA

SteinmanN

ManyA

Bar-AmA

1999 Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 340 9

42. GrisJ-C

2009 Thrombophilia and pregnancy loss: cause or association. Thromb Res 123 S105

43. StraussRS

2000 Adult functional outcome of those born small for gestational age: twenty-six-year follow-up of the 1970 British Birth Cohort. JAMA 283 625

44. FaccoF

YouW

GrobmanW

2009 Genetic thrombophilias and intrauterine growth restriction: a meta-analysis. Obstet Gynecol 113 1206

45. KistWJ

JanssenNJ

KalkJJ

HagueWM

DekkerGA

2008 Thrombophilias and adverse pregnancy outcome - A confounded problem! Thromb Haemost 99 77

46. BrennerB

2003 Inherited thrombophilia and pregnancy loss. Best Pract Res Clin Haematol 16 311

47. NorrieG

FarquharsonRG

GreavesM

2009 Screening and treatment for heritable thrombophilia in pregnancy failure: inconsistencies among UK early pregnancy units. Br J Haematol 144 241 244

48. ClarkP

WalkerID

LanghorneP

CrichtonL

ThomsonA

2010 SPIN: the Scottish Pregnancy Intervention Study: a multicentre randomised controlled trial of low molecular weight heparin and low dose aspirin in women with recurrent miscarriage. Blood In press

49. KaandorpSP

GoddijnM

van der PostJA

HuttenBA

VerhoeveHR

2010 Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 362 1586 1596

Štítky
Interní lékařství

Článek vyšel v časopise

PLOS Medicine


2010 Číslo 6
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#