A Systematic Review and Meta-Analysis of the Association between the FV H1299R Variant and the Risk of Recurrent Pregnancy Loss

Abstract

This study evaluated the association between the H1299R factor V (FV) variant (rs1800595) and recurrent pregnancy loss (RPL). Pubmed (MEDLINE) and Embase (OVID) bibliographic databases were searched from the inception to 31 May 2022 to identify suitable articles according to PRISMA and MOOSE guidelines. We included observational studies, case-control studies, cross-sectional studies, and cohort studies reporting a numerical and well-distinguished Het or Hom status of the H1299R variant obtained through PCR or other biochemical techniques and comparing RPL patients with a healthy control group. The review protocol was registered at PROSPERO (CRD42022330077). Two authors independently screened studies, extracted data, and carried out the risk of bias assessment using the Newcastle Ottawa scale (NOS). A meta-analysis was performed with RevMan software Version 5.4 using an odds ratio (OR) with an M-H, random effect, and 95% CI. We included 13 clinical studies for a total of 1669 RPL patients and 1466 healthy women as a control group. H1299R variant was slightly associated with RPL albeit without significance (OR 1.18, 95% CI: 0.78-1.80, p = 0.44). Subgroup analyses considering H1299R in heterozygosity (OR 1.13, 95% CI: 0.76-1.67, p = 0.56) and in homozygosity (OR: 2.11, 95% CI: 0.74-6.01, p = 0.16) revealed a similar trend. Lastly, we evaluated the association between H1299R and RPL based on the number of previous miscarriages (≥2 or ≥3). This comprehensive systematic review and meta-analysis sheds light on the specific influence of the H1299R variant in the F5 gene on RPL, constituting valid support for medical care during pregnancy and genetic counseling.

Keywords: H1299R; factor V (FV); miscarriages; recurrent pregnancy loss (RPL); thrombophilia; thrombophilic gene variants.

Figure 1

PRISMA Flow Diagram. The figure illustrates the PRISMA Flow Diagram for Search. The flow diagram was created according to PRISMA-P guidelines.

Figure 2

Preliminary analysis of the included studies. Charts on the geographical area distribution and number of previous miscarriages of the included studies. Charts describe: (A) the geographical area of included studies subdividing them into five macro areas; (B) the percentage of included studies reporting the minimum of previous miscarriages; (C) the percentage of subjects for every continent; (D) the percentage of RPL patients based on previous miscarriages.

Figure 3

Forest plot of the association between H1299R and RPL. Squares display the effect estimate (ORs) with the size of each blue square corresponding to the weight given to each study in the meta-analysis. Horizontal lines represent the 95% CIs corresponding to each effect estimate. The black diamond represents the overall effect of intervention with its width representing the overall 95% CI. The I² statistic represents a measure of heterogeneity. Overall effect OR: 1.18 [0.78, 1.80]; p = 0.44.

Figure 4

Forest plot of the association between H1299R heterozygous and RPL. The statistical value of every single study is expressed as OR. The horizontal black lines represent the confidence interval (95% CI). The blue squares indicate the weight of each study. The black diamond indicates the overall result of the statistical analysis. Heterogeneity is expressed as I². Overall effect OR: 1.13 [0.76, 1.67]; p = 0.56.

Figure 5

Forest plot of the association between H1299R homozygous and RPL. The forest plot illustrates the 95% CI for each study (black lines); the weight of each study (blue square) and the overall result (black diamond). Heterogeneity is expressed as I² measure. Overall effect OR: 2.11 [0.74, 6.01]; p = 0.16.

Figure 6

Subgroup analysis of the H1299R and RPL according to minimum previous pregnancy losses. The results of the meta-analysis are expressed as ORs. Black horizontal lines represent the 95% CIs of the single study. The weight given to each study is revealed by the size of the blue square. The black diamond represents the overall effect of the intervention. The statistical value I² indicates the heterogeneity. In the subgroup analysis the number of events indicates the presence of H1299R variant without distinction between Het and Hom. 2 or more pregnancy losses (OR: 1.18 [0.55, 2.53]; p = 0.67); 3 or more pregnancy losses (OR: 1.22 [0.87, 1.70]; p = 0.25). Overall effect OR: 1.18 [0.78, 1.80]; p = 0.44. Test for subgroup differences (p = 0.94).

Figure 7

Sensitivity analysis of the H1299R and RPL by excluding NOS low score studies. The forest plot illustrates the horizontal black lines representing the 95% CIs and the weight of each study as a blue square. The black diamond represents the estimate of the overall effect. I² is an index of heterogeneity. In the sensitivity analysis, the number of events indicates the presence of the H1299R variant without distinction between Het and Hom. Overall effect OR: 1.20 [0.75, 1.91]; p = 0.45.