Mid-trimester severe intrauterine growth restriction is associated with a high prevalence of thrombophilia
*Correspondence: Dr M. J. Kupferminc, Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel.
Objective To investigate the association between severe mid-trimester IUGR, whose causes are unknown in most cases, and maternal thrombophilias.
Design Case–control study.
Setting Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, The Sackler Faculty of Medicine, Tel Aviv University.
Population Twenty-six women with severe mid-trimester (22–26 weeks of gestation) IUGR (birthweight <3rd centile) and 52 matched multiparous women with normal pregnancies (controls).
Methods After excluding pregnancies with vascular maternal disease, chromosomal and structural aberrations and cytomegalovirus infection, 26 women out of 35 with severe mid-trimester IUGR remained and composed the study group. Each was matched for age, ethnicity and smoking status with two healthy women who had normal pregnancies. All the women were tested for genetic and acquired thrombophilias at least eight weeks after delivery.
Main outcome measures Prevalence of maternal thrombophilias.
Results The frequency of thrombophilias was 69% in the study group compared with 14% in the control group [odds ratio (OR) 4.5; 95% confidence interval (CI) 2.3–9, P< 0.001]. The frequencies of factor V Leiden mutation, prothrombin gene mutation and protein S deficiency were significantly increased in the study group compared with the control group. The frequency of multiple thrombophilias was 33% in the study group versus none among the controls. Of the 26 pregnancies with severe mid-trimester IUGR, 13 ended in intrauterine fetal death before 25 weeks of gestation: 10 of these women had thrombophilia.
Conclusion Women with mid-trimester severe IUGR have an increased prevalence of inherited and acquired thrombophilias.
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IUGR contributes significantly to fetal morbidity and mortality, but its aetiology is unknown in most cases. It has been suggested to be associated with abnormal placental vasculature and disturbances of haemostasis leading to inadequate maternal–fetal circulation1. Other causal considerations include intrinsic fetal genetic aberrations, multifactorial malformations, intrauterine infections, maternal vascular disease, maternal substance abuse and malnutrition2. Several mutations in thrombophilic proteins are known to be associated with an increased risk for venous and arterial thrombosis3. Our group4,5 and others6 have shown a strong association between inherited and acquired maternal thrombophilia and pregnancy complications, such as severe pre-eclampsia, preterm labour, placental abruption and intrauterine fetal death, and that IUGR <5th centile may be associated with a 62% prevalence of thrombophilia4.
The earlier an IUGR is diagnosed during pregnancy, the graver is the prognosis for the fetus or infant2. The combination of extreme prematurity and small for gestational age birthweight carries a high risk of long term serious sequelae7,8. The focus of the current study is to address the association between mid-trimester severe IUGR and the presence of maternal thrombophilia.
From 1999 to 2001, we studied 35 consecutive women whose pregnancy was complicated by severe mid-trimester (22–26 weeks of gestation) IUGR, defined as birthweight ≤3rd centile associated with an amniotic fluid index ≤3rd centile for gestational week. There were 17,300 deliveries during these 24 months, of which these 35 pregnancies constituted 0.2%.
The third centile for birthweight for gestational age was defined according to the criteria of Hadlock et al.9, which were confirmed by new data presenting birthweight centiles according to the sex of the fetus10. All 35 index pregnancies were investigated for congenital malformations, chromosomal abnormalities and cytomegalovirus infection.
Only singleton pregnancies were included. Exclusion criteria were a history of chronic maternal disease such as systemic lupus erythematosus or chronic hypertension (n= 4), congenital malformations or chromosomal abnormalities (n= 3), recent maternal cytomegalovirus infection (n= 2) and drug or alcohol abuse during pregnancy (n= 0). The remaining 26 women composed the study cohort. Each study participant was matched for age, ethnicity and smoking status with two healthy women who had at least one normal pregnancy and who delivered within the study period (control group, n= 52). All women with mid-trimester IUGR had Doppler studies as part of their routine evaluation.
The study was approved by the Ethics Committee of the Tel Aviv Sourasky Medical Center and informed consent was obtained from each woman.
All 78 study participants were assessed for the presence of thrombophilia at least eight weeks postpartum. The thrombophilia work up included factor V Leiden mutation, prothrombin gene 20210 mutation, homozygosity for a cytosine–thymine mutation at nucleotide 677 in the methylenetetrahydrofolate reductase (MTHFR) gene, protein C deficiency, protein S deficiency, antithrombin III deficiency, anticardiolipin antibodies and lupus anticoagulant. Thrombophilia assays were performed as previously described elsewhere4.
The results of the two groups were compared by two-tailed Student's t tests, Fisher's exact tests, Pearson's χ2 tests and calculations of odds ratios and 95% confidence intervals. Statistical analyses were performed with the SPSS programme for Windows version 6 (SPSS, Chicago). Values were considered as significant at P < 0.05.
The characteristics of the study and control women are shown in Table 1. As dictated by the recruitment criteria, the gestational age at delivery and birthweight were significantly lower in the study group. The number of primiparous women was significantly higher (P= 0.04) in the study group.
Table 1. Clinical characteristics of the study and control women.
|Age (years)||27 (5)a||28 (4)||NS|
|Gestational week at delivery||25.1 (1.3)||39.4 (1.3)||<0.001|
|Birthweight (g)||468 (154)||3440 (350)||<0.001|
Three of the four multiparous women in the study group had had obstetric complications in a previous pregnancy: two had IUGR and one had severe pre-eclampsia.
The frequency of inherited thrombophilias was 69% in the study group compared with 14% in the control group [odds ratio (OR) 4.5; 95% confidence interval (CI) 2.3–9, P < 0.001] (Table 2). The frequency of factor V Leiden, prothrombin mutation and protein S deficiency was significantly increased in the study group compared with the control group (Table 2). Six of the 18 study patients had multiple thrombophilias compared with none in the control group (OR 3.0; 95% CI 1.9–4.9, P < 0.01) (Table 2). Each of the women with multiple thrombophilias was considered only once for the statistical analysis, while the sum of all individual thrombophilias was taken for individual thrombophilias. Doppler studies showed an absence of end-diastolic flow in the umbilical artery in 16 of the 26 (62%) fetuses with IUGR: 7 of these 16 also had reverse end-diastolic flow. Fourteen of 18 (78%) of the women with IUGR and thrombophilia showed an absence of end-diastolic flow in the umbilical artery compared with two out of eight (25%) of the women without thrombophilia (P= 0.025).
Table 2. Prevalence of thrombophilias in the study and control groups. Values are given as n (%).
|All thrombophiliasa||18 (69.2)||7 (13.5)||<0.001||14.5 (4.5–45.8)|
|FV Leidenb||9 (35)||2 (3.8)||<0.001||13.2 (2.6–67.4)|
|Prothrombin mutationc||4 (15.4)||2 (2.0)||<0.05||9.2 (1.0–87.8)|
|MTHFR homozygote||5 (19.2)||5 (9.6)||NS||2.2 (0.6–8.6)|
|Protein S deficiency||5 (19.2)||0||<0.01||3.5 (2.4–5.0)|
|Protein C deficiency||1 (3.8)||0||NS||NA|
|Multiple thrombophiliasd||6 (23)||0||<0.01||15.3 (1.7–135.2)|
Of the 26 pregnancies with IUGR, 13 ended in intrauterine fetal death before 25 weeks of gestation, of which 10 were associated with the presence of thrombophilia. The other 13 women were delivered between 25 and 26 weeks of gestation: five ended in early neonatal death (38%) and eight neonates (62%) survived.
The objective of this study was to examine the relationship between early mid-trimester IUGR and the presence of maternal thrombophilia. The results indicate that in nearly 70% of such affected pregnancies the women carried at least one thrombophilia.
IUGR is a complex problem that is associated with increased morbidity and mortality, both antepartum and postpartum11. When accompanied by extreme prematurity, it is considered an especially ominous situation by being associated with an even higher risk for both short term12 and long term adverse outcome7,8.
The aetiologies of IUGR can be divided into two broad categories: intrinsic fetal malformations (such as aneuploidy, congenital infections and multifactorial malformations) and cases in which a structurally normal fetus is subjected to chronic oxygen and substrate deprivation. Maternal vascular disease, nutritional abnormalities and substance abuse have long been recognised as causes for IUGR in non-anomalous fetuses. Recent research has demonstrated the important role played by maternal thrombophilic disorders in pregnancy complications such as severe pre-eclampsia, placental abruption, intrauterine fetal death and IUGR4.
Placental thrombosis and vascular occlusion are considered by some authors as comprising the hallmark of placental pathology in pregnancy complications13. Indeed, we reported14 an increased number of single and multiple placental infarcts in women with both pregnancy complications and thrombophilias. Peeters15 recently showed that placental vascular occlusion can have direct negative effects on uteroplacental blood flow even in the absence of pre-eclampsia.
The association between thrombophilia and IUGR was investigated in several studies which have shown an increased incidence of thrombophilia in pregnancies complicated by IUGR. Our group also found an association between specific thrombophilias and the occurrence of IUGR4,5. A study by Martinelli et al.16 showed that both factor V Leiden and the prothrombin gene mutation were independently associated with IUGR.
Intrinsic fetal growth aberrations are commonly considered to be associated with early growth restriction (i.e. starting before 26 weeks of gestations)17. On the other hand, growth restriction due to impairment of uteroplacental perfusion classically manifests itself later in gestation (i.e. starting at 28–32 weeks) at the period of accelerated growth rate when the discrepancy between fetal demand and placental supply of nutrients becomes more profound15. In one study that specifically addressed the link between thrombophilia and IUGR16, the mean gestational age at delivery was 34 weeks (SD = 3.4). Our study is the first to demonstrate a very high incidence of thrombophilia in early severe IUGR: 69% of our study group, which was comprised of women with mid-trimester severe IUGR unexplained by fetal anomaly or infection, had at least one thrombophilic condition, compared with a 14% occurrence in the apparently normal control group (OR 4.5, 95% CI 2.3–9, P < 0.001). Two mutations were detected in one-third of the cases with both IUGR and thrombophilia, while no woman in the control group had multiple thrombophilias. The strongest association that emerged was between IUGR and factor V Leiden, the prothrombin gene mutation and protein S deficiency. The selectivity of our group may explain the high rate of the absence of end-diastolic flow in the umbilical artery, particularly in those women with thrombophilias. Specifically, our study inclusion criteria required the combination of severe IUGR and oligohydramnios which, when seen together in combination with an abnormal flow in the umbilical artery, may implicate the presence of thrombophilia. Notably, Sickler et al.18 showed that early IUGR associated with polyhydramnios was a very strong predictor for major anomalies and aneuploidy.
Our finding that nearly 70% of women with early severe mid-trimester IUGR had at least one thrombophilia is compelling evidence to justify a work up for thrombophilias in women with this complication of pregnancy.
The authors would like to thank Esther Eshkol for editorial assistance.