Clinical criteria (one or more)
Vascular thrombosis: One or more objectively confirmed episodes of arterial, venous or small vessel thrombosis occurring in any tissue or organ
Pregnancy morbidity:
One or more unexplained deaths of a morphologically normal fetus <10th week of gestation; or
One or more premature births of a morphologically normal neonate <34th week of gestation because of eclampsia, severe pre-eclampsia or placental insufficiency; or
Three or more unexplained consecutive miscarriages <10th week of gestation
Laboratory criteria (one or more, present on two or more occasions at least 12 weeks apart using recommended procedures)
2. Anticardiolipin antibodies (aCL) of IgG and/or IgM isotype, moderate or high positive (>40 GPL or MPL, or >99th centile), measured by a standardized ELISA
3. Anti-β22-glycoprotein-1 antibodies (aβ2GPI) of IgG and/or IgM isotype, present at a level >99th centile, measured by a standardized ELISA
.
8.2 Hemostatic Changes in Normal Pregnancy
For a detailed description, the reader should refer to Chap. 1. There is a marked increase in blood procoagulant activity, characterized by an elevation of a number of coagulation factors [4], especially at term in normal pregnancy. This is associated with an increase in prothrombin fragment F1.2 and thrombin-antithrombin complexes [5, 6], both markers of coagulation activation. There is a decrease in physiological anticoagulants manifested by a significant reduction in protein S activity and [7] by acquired activated protein C resistance (APCR) [8]. The overall fibrinolytic activity is impaired during pregnancy but rapidly returns to normal following delivery [9]. This is largely due to placenta-derived plasminogen activator inhibitor type 2 (PAI-2), which is present in substantial quantities during pregnancy [10]. D-dimer, a specific marker of fibrinolysis resulting from breakdown of cross-linked fibrin polymer by plasmin, increases as pregnancy progresses [11]. Overall, there is a five- to ten-fold increased risk of VTE throughout gestation and the postpartum period.
8.3 Antiphospholipid Syndrome (APS) and Late Placenta-Mediated Pregnancy Complications
8.3.1 Diagnosis of Obstetric Antiphospholipid Syndrome
The antiphospholipid syndrome (APS) is the most common acquired form of thrombophilia. The International consensus (revised Sapporo) criteria for diagnosis of obstetric APS is based on clinical criteria for a diagnosis of APS and persistent positive aPL: lupus anticoagulant (LA) and/or moderate or high positive aPL (IgG and/or IgM anticardiolipin (aCL) and/or anti β2 glycoprotein I (aβ2GPI) antibodies) that are present on two or more consecutive occasions at least 12 weeks apart [3]. Women with aPL may present with (a) recurrent miscarriage (RM), i.e. three or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded; fetal demise beyond 10 weeks of gestation; (b) one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus; or (c) one or more premature births of a morphologically normal neonate before the 34th week of gestation (because of: (i) eclampsia or severe pre-eclampsia defined according to standard definitions; (ii) recognised features of placental insufficiency) (Table 8.1). These obstetric complications may occur alone (obstetric APS) or in combination with thrombotic manifestations. In a study of 60 pregnancies in women with APS, the most specific clinical features were reported to be thrombosis (both venous and arterial), RM, fetal loss in the second and third trimesters, and autoimmune thrombocytopenia [12].
8.3.2 Non-criteria Obstetric Antiphospholipid Syndrome
Several obstetric manifestations additional to those in the International consensus criteria have been proposed as ‘obstetric morbidity associated with APS (OMAPS)’. Non-criteria laboratory manifestations include low positive aCL and aβ2GPI (i.e. >95 centile and <99th centile). Clinical non-criteria manifestations include two unexplained miscarriages, three non-consecutive miscarriages, late pre-eclampsia, placental abruption, late premature birth, or two or more unexplained in vitro fertilization failures [13–17].
8.3.3 Pathogenesis of Pregnancy Complications in Antiphospholipid Syndrome
Pregnancy morbidity in the form of fetal loss or premature birth is a relatively common finding in women with APS [18]. APS is associated with placental vascular thrombosis, decidual vasculopathy, intervillous fibrin deposition, and placental infarction [19–21]. These pathological changes in the placenta may result in RM, early severe pre-eclampsia, IUGR, or stillbirth. A key mechanism of fetal loss is believed to be due to binding of aPL to trophoblast cells, resulting in defective placentation [22]. Thrombotic complications within the uteroplacental circulation have also been proposed as a contributing mechanism. aPL have been shown to reduce the levels of annexin V and accelerate the coagulation of plasma on cultured trophoblasts and endothelial cells, and therefore, the reduction of annexin V levels on vascular cells may be an important mechanism of thrombosis and pregnancy loss in APS [23]. Complement activation by aPL appears to play a major role in the pathogenesis of recurrent pregnancy loss, and may also have a role in the pathogenesis of thrombosis in APS [24]. Animal experiments indicate that aPL cause decidual tissue damage by altering the classical pathway of complement activation, followed by amplification through the alternative pathway [25].
In a mouse model of APS induced by passive transfer of human aPL antibodies, it has been shown that complement activation plays a causative role in pregnancy loss and fetal growth restriction, and that blocking activation of the complement cascade can prevent pregnancy loss.
8.3.4 Antiphospholipid Antibodies and Pre-eclampsia
An association between aPL and pre-eclampsia has been suggested in two systematic reviews and meta-analyses [26, 27]. Both these systematic analyses sought to include case–control, or controlled, cross-sectional studies until 2009. The analysis by do Prado et al. [26] included 12 of 64 studies. The key finding was an association between aPL and severe, but not mild, pre-eclampsia in pregnant women without autoimmune disease. The analysis by Abou-Nasser et al. [27] included 28 studies. LA and aCL were associated with pre-eclampsia in case-control but not cohort studies. aβ2GPI were associated with pre-eclampsia in cohort but not in case–control studies. The authors of both these analyses noted significant flaws in the available data. A prospective, observational, cohort study in 142 women suggested a significant association between aCL or IgG aβ2GPI and pre-eclampsia in women who had suffered a single previous embryonic loss (adjusted OR 3.09, 1.13–8.48 and 4.61, 1.53–13.88, respectively) [28].
8.4 Heritable Thrombophilia and Placenta-Mediated Obstetric Complications
Table 8.2 lists the thrombophilic factors that may be associated with placenta-mediated obstetric complications. For details on heritable thrombophilias, the reader should refer to Chap. 3. The prevalence of factor V Leiden (FVL), the most common cause of VTE in pregnancy [29], is very low in Asian and African populations, and higher at around 4 % in Caucasians. However, APCR may be present without FVL; the reported prevalence is 3.3 % [30, 31]. The prevalence of heterozygosity for the G20210A prothrombin gene mutation is approximately 2 % in Caucasians, and increases geographically from Northern to Southern Europe [32, 33]. Protein C and S deficiencies are quite rare, and carriers have a significantly increased risk of thrombosis when the inhibitory effect on coagulation is lost. Antithrombin (AT) deficiency may be the result of many different mutations and has a prevalence of 0.07 %. It is the most thrombogenic of the inherited thrombophilias, with a reported 70–90 % lifetime risk of thromboembolism in individuals with type 1 AT deficiency. Homozygosity for the C677T methylene tetrahydrofolate reductase (MTHFR) polymorphism has an observed prevalence varying from 15.2 % in Hispanic populations to 10.2 % in Caucasians, 8.8 % in Asians, and 2.4 % in African Americans. Several alleles (C and T) have been described. Homozygosity for the T variant results in elevated homocysteine levels, which can cause vascular injury [32–35].
Table 8.2
Classification and prevalence of thrombophilia
Thrombophilia | % of general population | |
|---|---|---|
Inherited | Antithrombin deficiency | 0.07 |
Protein C deficiency | 0.3 | |
Protein S deficiency | 0.2 | |
Factor V Leiden (heterozygous) | 4 | |
Factor V Leiden (homozygous) | 0.06 | |
G20210A prothrombin gene mutation | 2 | |
C677T methylenetetrahydrofolate reductase (homozygous) | 10 | |
Acquired | Antiphospholipid antibodies (Lupus anticoagulant Anticardiolipin antibodies Anti-β2-glyoprotein I antibodies) | 2 |
Acquired APC resistance | 3.3 | |
In the absence of factor V Leiden |
Associations between various thrombophilias and placenta-mediated complications are discussed below. The reader should refer to Chap. 3. Table 3.2 summarising results of a systematic review of thrombophilic defects in women with pregnancy complications [36]. A subsequent systematic review and a meta-analysis of prospective cohort studies, to estimate the association of maternal FVL or G20210A carrier status and placenta-mediated pregnancy complications, showed that women with FVL appear to be at a small absolute increased risk of late pregnancy loss; and that women with FVL and G20210A appear not to be at increased risk of pre-eclampsia or birth of small-for-gestational age (SGA) infants [37]. Of note, more recently, a prospective cohort of unselected, pregnant women (total 7343) were assessed for a composite of pregnancy loss, SGA < 10th percentile, pre-eclampsia or placental abruption. The conclusions were that carriers of FVL or G20210A are not at significantly increased risk of these pregnancy complications [38].
8.5 Placental Findings Associated with Heritable Thrombophilias and Pregnancy Complications
Many et al. [39] described placental findings in women who had severe obstetric complications during pregnancy and were carriers of heritable thrombophilia, and compared them to placental findings in women without thrombophilia who experienced severe obstetric complications during pregnancy. The study population comprised 68 women with singleton pregnancies who had severe pre-eclampsia, IUGR, abruptio placentae, or stillbirth. They were evaluated after delivery for the presence of mutations of FVL, C677T MTHFR homozygosity, prothrombin G20210A, and deficiencies of protein C, protein S, and AT. All were negative for aPL. Thirty-two women carried a thrombophilia and 36 women did not. All placentas were evaluated by a single pathologist who was blinded to the results of the thrombophilia assessment. There was no difference in the maternal age, parity, type of pregnancy complication, and fetoplacental weight ratio between the groups. The proportion of women with villous infarcts was significantly higher in women with thrombophilias (72 % vs. 39 %, p < 0.01), as was the proportion of women with multiple infarcts or fibrinoid necrosis of decidual vessels.
Conversely, in a study with a very similar design that also examined the relationship between placental histology and thrombophilia in women with severe obstetric complications, no specific histological pattern could be identified when thrombophilia-positive and thrombophilia-negative groups were compared [37]. Nevertheless, a high rate of placental infarcts (50 %) and thrombosis was confirmed in women both with and without thrombophilias. Likewise, placental pathology in early-onset pre-eclampsia and IUGR was similar in women with and without thrombophilia although a high rate of placental abnormalities was found [37, 38].
Arias et al. (1998) evaluated 13 women with thrombotic lesions of the placenta [39]. All women had obstetric complications such as pre-eclampsia, preterm labor, IUGR, or stillbirth. In 10 of the 13 (77 %), an inherited thrombophilia was found; 7 were heterozygous for the FV Leiden mutation and 3 had protein S deficiency. The most prominent placental lesions were fetal stem vessel thrombosis, infarcts, hypoplasia, spiral artery thrombosis, and perivillous fibrin deposition [39].
8.6 Heritable Thrombophilia and Intrauterine Growth Restriction (IUGR)
IUGR is an important cause of perinatal morbidity and mortality. Growth-restricted infants are at increased risk of developing neuropsychological defects and suffering educational disadvantages later in childhood [40, 41]. Moreover, there is epidemiological evidence that children whose intrauterine growth was restricted have a higher risk of cardiovascular and endocrine diseases in adulthood [42]. Numerous studies have reported on associations between obstetric complications and heritable causes of thrombophilia [43–96]. Kupferminc et al. [65] reported an association between inherited thrombophilia (FVL, prothrombin G20210A, and homozygosity for C677T MTHFR) and IUGR (defined as a birth weight below the 5th percentile for gestational age).
Martinelli et al. compared 61 women with a history of IUGR, defined as birth weight below the 10th percentile, and 93 parous women with uneventful pregnancies. Among women with IUGR, 13 % had FVL compared with 2.2 % of controls (OR, 6.9; 95 % CI 1.4–33.5), and 12 % had the G20210A prothrombin mutation compared with 1.6 % of controls (OR, 5.9; 95 % CI 1.2–29.4). In a regression-analysis model, these thrombophilias were independently associated with IUGR [68]. A subsequent report from the same group [43] tested for these mutations in neonates weighing less than 2.5 kg. Neonates delivered by mothers with FVL or prothrombin G20210A mutations accounted for 30 % of newborns weighing less than 1 kg, 18.7 % of those ranging from 1.001 to 2.499 kg, and only 9.5 % of those weighing 2.5 kg or more. Overall, 27.6 % of neonates of mothers with the mutations weighed less than 2.5 kg compared with 13.9 % of neonates of mothers without mutations (OR, 2.4; 95 % CI 1.5–3.7).
However, other studies failed to confirm an association between IUGR and thrombophilic mutations. In one such study [69], the prevalence of thrombophilia in mothers of 493 newborns with IUGR (<10th percentile) and 472 controls did not differ significantly. However, one-third of the study population was not Caucasian and the degree of IUGR was mild, with mean birth weight 2.393 ± 0.606 kg and 83 % of newborns delivered at 36–40 weeks’ gestation. In contrast, in the study by Kupferminc et al. (1999), the mean birth weight was 1.387 ± 0.616 kg and mean gestational week at delivery was 33 ± 4.0 [67]. Similarly, Martinelli et al. reported a mean gestational week at delivery of 35 ± 3 and a mean birth weight of 1.584 ± 0.586 kg [68]. It is therefore suggested that these studies have addressed noncomparable fetal and neonatal populations with differing clinical relevance.
8.7 Heritable Thrombophilia and Pre-eclampsia
The association of pre-eclampsia with thrombophilia is similarly controversial; a number of case-controlled studies demonstrate an association, while others fail to do so. FVL may be associated with severe pre-eclampsia and affected women may have a higher risk of serious maternal complications and adverse perinatal outcomes than those without thrombophilia [53, 74–77]. Kupferminc et al (1999) demonstrated an increased prevalence of thrombophilia (53 %) in women with severe pre-eclampsia compared with controls (18 %) [67]. The same study also highlighted that women with obstetric complications had a significantly higher incidence of combined thrombophilias. In a sample of 140 Italian women with a history of gestational hypertension, with or without significant proteinuria, a significantly higher prevalence of thrombophilias was documented regardless of the presence of proteinuria [78]. Logistic regression showed that FVL and prothrombin G20210A mutations were independently associated with occurrence of gestational hypertension. In contrast, several studies, including a large population-based study and systematic review suggest lack of an association between thrombophilia and pre-eclampsia [62].
The meta-analysis by Robertson et al (2006) suggested that heterozygosity for FVL or the prothrombin gene mutation is associated with a twofold-increased risk of severe early-onset pre-eclampsia [36]. Rodger et al. (2010) in a systematic review and meta-analysis of ten prospective cohort studies examining associations between FVL and prothrombin G20210A and placenta-mediated pregnancy complications found no association between FVL or prothrombin G20210A and pre-eclampsia [36].
Studies of the prevalence of thrombophilia in pre-eclampsia seem to differ in selection of controls and in ethnic backgrounds. The size of these studies of pre-eclampsia is generally small, especially if the aim was to detect any possible association between the less frequent thrombophilias, such as protein C, protein S, and AT deficiencies, and obstetric complications. Studies reporting a significant association are generally smaller than those reporting a lack of association. In many of the studies, groups of different thrombophilias or obstetric complications are pooled together, which sometimes results in significant associations that do not remain significant when the relevant sub-groups are analyzed separately. The pooling of study subjects can lead to inaccuracy in determining the exact impact of a specific mutation on each of the complications.
Excessive generation of plasminogen activator inhibitor-type 1 (PAI-1) is implicated in the pathogenesis of pre-eclampsia and related conditions. The PAI-1 (−675 4G/5G) promoter polymorphism affects transcriptional activity and is a putative genetic risk factor for pre-eclampsia. A systematic review and random effects meta-analysis of genetic association studies suggested that the fibrinolytic pathway regulated by the PAI-1 gene may contribute to the pathogenesis of pre-eclampsia and related conditions. The authors concluded that the association, if confirmed in larger genetic association studies, may inform research efforts to develop novel interventions or help to prioritise therapeutic targets that merit evaluation in randomised clinical trials [56].
Overall these data suggest that, while prothrombotic genotypes might not be causative factors for pre-eclampsia, they could be linked to the severity of disease expression once the condition arises.
8.8 Thrombophilia and Placental Abruption
van der Molen et al. investigated coagulation inhibitors and abnormalities of homocysteine metabolism as risk factors for placental vasculopathy [85]. They compared non-pregnant women with a history of placental vasculopathy with non-pregnant controls. Protein C activity was noted to be significantly lower in women that had adverse pregnancy outcome. Homozygotes for the C677T MTHFR polymorphism and carriers of the FVL mutation were significantly more common in the study group. The median levels of homocysteine, APCR ratio, protein S, and AT were not different between the groups. However, homocysteine levels above 14.4 mmol/L (the 80th percentile of control values) were associated with a significant increase in the odds ratio (OR). Also, a combination of risk factors such as homocysteine levels above 14.4 mmoL and protein S deficiency resulted in a significantly increased OR for placental vasculopathy. The risk factors for placental vasculopathy that emerged in this study were APCR and decreased levels of protein C, elevated homocysteine, and the C677T MTHFR polymorphism, or a combination of these.
Wiener-Megnagi et al. studied 27 women who had placental abruption and 29 controls and found that 63 % of cases had an APCR ratio >2.5 compared with 17 % of controls (OR 8.16, p = 0.001) [49]. Eight of 15 patients (53 %) tested were found to have the FVL mutation (5 heterozygous and 3 homozygous) compared with 1 heterozygote among the control subjects (3.4 %). Similarly, Kupferminc et al. [67] found a 70 % incidence of thrombophilias in women with placental abruption, of which 60 % had thrombophilic mutations and 10 % had AT deficiency or aPL. Of the 20 women who had an abruption, 3 also had mild pre-eclampsia, 7 had antepartum or postpartum hypertension, and 11 of the neonates were below the 10th percentile for gestational age. In this early study on the association between prothrombin G20210A in women with pregnancy complications, the OR for abruption with this mutation was 8.9 (95 % CI 1.8–43.6), whereas the ORs for the FVL mutation and MTHFR polymorphism were 4.9 (95 % CI 1.0–17.4) and 2 (95 % CI 0.5–8.1), respectively. In another study, the incidence of prothrombin G20210A in 27 women with placental abruption was 18.5 % compared to 3.2 % of controls (OR, 5.8; 95 % CI 1.8–18.6, p = 0.01) [60]. In the study by de Vries et al. (1997), 26 % of women with placental abruption had hyperhomocysteinemia and 29 %, protein S deficiency [48].
Prochazka et al. reported that FVL carrier status was not significantly different in women with placental abruption but was associated with a positive family history of venous thrombosis [86]. However, the same group reported that 20 of 142 (14.1 %) women with placental abruption were heterozygous for FVL, compared to 10 of 196 (5.1 %) of controls (OR 3.0, 95 % CI 1.4–6.7) [87–91].
Analysis of The New Jersey-Placental Abruption Study (2002–2007) suggested that women with lower protein C levels (<5th centile) had an increased risk of abruption, with an OR of 3.2 (95 % CI 1.2–9.9) [91]. Reduction in both protein S and APCR ratio was not associated with abruption.
In the systematic review and meta-analysis of prospective cohort studies by Rodger et al. [37], five of the ten studies analysed reported on the association between FVL mutation and placental abruption. 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). The pooled OR estimate for placental abruption in women with PGM mutation (homozygous or heterozygous) was 2.02 (95 % CI 0.81–5.02). There was moderate statistical heterogeneity across studies, suggested to be possibly attributable to the inconsistent and unclear definition of placental abruption across studies.
8.9 Heritable Thrombophilia and Late Fetal Loss
Preston et al. reported increased fetal loss in women with heritable thrombophilic defects [92]. The authors studied 1,384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). Of 843 women with thrombophilia, 571 had 1,524 pregnancies; of 541 control women, 395 had 1,019 pregnancies. The authors analyzed the frequency of fetal loss (<28 weeks of gestation) and stillbirth (>28 weeks of gestation) jointly and separately. The risk of fetal loss was increased in women with thrombophilia (OR, 1.35, 95 % CI 1.01–1.82). The OR was higher for stillbirth than for miscarriage (3.6; 95 % CI 1.4–9.4 vs. 1.27; 95 % CI 0.94–1.71). The highest OR for stillbirth was in women with combined defects (OR, 14.3; 95 % CI 2.4–86.0) compared with 5.2 (1.5–18.1) in AT deficiency, 2.3 (0.6–8.3) in protein C deficiency, 3.3 (1.0–11.3) in protein S deficiency, and 2.0 (0.5–7.7) with FVL. The authors concluded that women with familial thrombophilia, especially those with combined defects or AT deficiency, have an increased risk of fetal loss, particularly stillbirth.
Gris et al. performed a case–control study in 232 women with a history of one or more second- or third-trimester losses and no history of thrombosis who were matched with 464 controls and tested for thrombophilias and APS [63]. They found at least one thrombophilia in 21.1 % of the patients and in 3.9 % of the controls (p < 0.0001), with an OR of 5.5 (95 % CI 3.4–9.0) for stillbirth in women positive for any thrombophilia. After logistic regression analysis, four adjusted risk factors for stillbirth remained: protein S deficiency, IgG aCL, IgG aβ2GPI, and the FVL mutation.
Studies suggest that FVL heterozygotes have a higher relative risk of late pregnancy loss than early first-trimester loss. One possible explanation is that late pregnancy losses reflect thrombosis of the placental vessels, in contrast to first-trimester losses, which are more commonly attributable to other causes, in particular fetal chromosome abnormality. This hypothesis is supported by observations in the Gris et al study that the majority of placentas from women with late fetal loss were reported to show ‘maternal vascular disease of the placenta’ [63].
In a study of 18 pregnancies with AT deficiency [45, 46], 10 suffered an adverse outcome (55.6 %), including stillbirth (11.1 %), IUGR (33.3 %), abruption (6.7 %), and pre-eclampsia (6.7 %). A lower incidence of pregnancy complications was observed among women with antithrombotic treatment [45]. Of note, Rey et al. [94] and Robertson et al. [36] did not observe an association between AT deficiency and pregnancy loss.
Kupferminc et al. (1999) found a 50 % prevalence of thrombophilias in women with intrauterine fetal death (IUFD) occurring after 23 weeks’ gestation [67]. Martinelli et al (2000) reported on 67 women with fetal loss after 20 weeks of pregnancy and 232 controls, for FVL, prothrombin gene mutation, and MTHFR polymorphism. Sixteen percent of the 67 women with fetal loss and 6 % of the controls had either the FVL or the prothrombin gene mutation. The relative risks of late fetal loss in carriers of the FVL and prothrombin gene mutations were 3.2 (95 % CI 1.0–10.9) and 3.3 (95 % CI 1.1–10.3), respectively. Placental investigation showed histological evidence of thrombosis in 76 % of placentas examined [95]. A study that investigated women with IUFD at 27 weeks’ gestation or more found that, in 40 women with unexplained IUFD, the prevalence of inherited thrombophilias was 42.5 % compared with 15 % in controls (OR, 2.8; 95 % CI 1.5–5.3, p = 0.001) [66].
8.10 Management of Adverse Pregnancy Outcome Associated with Thrombophilia
The management of the obstetric patient with thrombophilia is complex [96–98]. Many women with an underlying thrombophilia are healthy with no history of thrombotic or pregnancy complications, while many others without identifiable thrombophilia experience medical and obstetric complications. The risk of thromboembolism and adverse pregnancy outcomes seems to arise from an interplay of medical, obstetric, and family history, along with genetic and environmental factors. Furthermore, current treatment with low molecular weight heparin (LMWH) anticoagulation, at prophylactic or therapeutic dose, is not without risks, albeit small, such as the potential for bleeding and allergic reactions, and is inconvenient. Table 8.3 summarizes observational studies on prevention of poor gestational outcome in carriers of thrombophilia [12, 99–104].
Table 8.3
Observational studies on prevention of poor gestational outcome in carriers of thrombophilia
Patients, n | Thrombophilia | Obstetric history | Treatment | Live birth with normal outcome | Reference no. |
|---|---|---|---|---|---|
60 | APS | RFL | LMWH | 70 % | Lima et al. [12] |
LDA | |||||
50 | Inherited and acquired | RFL | Enoxaparin (LDA for APS) | 46/61 (75 %) | Brenner et al. [99] |
25 | Factor V Leiden or factor II 20210GA | RFL pre-eclampsia IUGR | UFH or LMWH or LDA | 29/31 (93 %) | Grandone et al. [100] |
33 | Not specified | Pregnancy complications | 40 mg enoxaparin LDA | 30/33 (91 %) | Kupferminc et al. [101] |
276 | Inherited and acquired | pre-eclampsia and/or IUGR | 40 mg enoxaparin and LDA | Higher birth weight with LMWH | Riyazi et al. [102] |
160 | Inherited and acquired | Pregnancy complications | 40 mg enoxaparin and LDA | Higher birth weight with LMWH | Gris et al. [103] |
160 | Inherited | Placental abruption | 40 mg enoxaparin | Lower incidence of pregnancy complications | Gris et al. [104] |
8.10.1 Obstetric Antiphospholipid Syndrome
Screening for APS is recommended in women who suffer recurrent first-trimester miscarriage or who have had late fetal losses [1]. In these patients, the evidence supports a significant increase in live births following treatment with LDA plus heparin compared with LDA alone [105, 106].
In a meta-analysis of data from five trials involving 334 patients with recurrent miscarriage [107] the overall live birth rates were 74.3 and 55.9 % in women who received a combination of unfractionated/LMWH plus low dose aspirin (LDA) versus that in those treated with LDA alone. Patients who received combination treatment had significantly higher live birth rates (RR 1.301; 95 % CI 1.040, 1.629) than with aspirin alone. No significant differences in pre-eclampsia, preterm labour and birth weight were found between two groups. Accordingly, the British Committee for Standards in Haematology (BCSH) and American College of Chest Physicians (ACCP) recommend that women with obstetric APS with a history of pregnancy loss who meet international consensus criteria, should be treated with prophylactic or intermediate dose UFH or prophylactic LMWH combined with LDA (75–100 mg/daily), in the antepartum period after pregnancy is confirmed. The BCSH and ACCP also recommend that women with aPL should be considered for post-partum thromboprophylaxis [1, 108].
The situation is less clear as regards the management of women who exhibit the remaining International consensus criteria for obstetric APS, i.e. those who suffer one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, one or more premature births of a morphologically normal neonate before 34th week of gestation because of eclampsia, pre-eclampsia, or placental insufficiency [13]. The BCSH and ACCP guidance is that for women with APS and a history of pre-eclampsia, LDA is recommended. However, many high-risk antenatal services extrapolate the use of LMWH and LDA during pregnancy to these cases. Support for this approach comes from observations that defects in placentation are implicated not only in recurrent miscarriage, but also in late placenta-mediated obstetric complications.
The Obstetric Task Force at of the 14th International Congress on Antiphospholipid Antibodies in Rio (2013) stated that recommended treatments for all pregnancy morbidity associated with APS lack well-designed studies to confirm their efficacy [109].
8.10.2 Heritable Thrombophilia
A Cochrane review [110] revealed a paucity of studies on the efficacy and safety of aspirin and heparin in women with a history of RM without apparent causes other than those studies that address heritable thrombophilia. Therefore, the use of anticoagulants in unexplained RM is not recommended. Our knowledge of the optimal treatment during pregnancy in patients with heritable thrombophilia (except for the role of LDA in the prevention of pre-eclampsia: see below) is also limited. Previous data suggested that certain risk groups should be screened for thrombophilia, as the evidence suggested a high recurrence rate of complications in future pregnancies. These at-risk groups included women with a personal or family history of thromboembolism, recurrent first- and second-trimester loss, severe pre-eclampsia, IUGR, stillbirth, or abruptio placentae. Ideally, testing should take place between pregnancies since protein S levels fall and APCR increases during normal pregnancy [111].
Related posts:
Systemic Thromboembolism in Pregnancy: Heritable and Acquired Thrombophilias
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Acquired Bleeding Disorders in Pregnancy: Obstetric Hemorrhage
Peri-delivery Analgesia and Anesthesia in Women with Hemostatic or Thrombotic Disorders
Inherited Bleeding Disorders in Pregnancy: von Willebrand Disease, Factor XI Deficiency, and Hemophilia A and B Carriers
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