Beruflich Dokumente
Kultur Dokumente
Hereditary
Thrombophilia and
Recurrent Pregnancy
Loss
ASHLEY M. PRITCHARD, MD,* PAUL W. HENDRIX, DO,*
and MICHAEL J. PAIDAS, MD*w
*Department of Obstetrics, Gynecology and Reproductive Sciences,
Division of Maternal Fetal Medicine, Yale School of Medicine; and
w Yale Women and Childrens Center for Blood Disorders and
Preeclampsia Advancement, New Haven, Connecticut
Abstract: The challenging nature of recurrent preg- and frustrating task for the obstetrician.
nancy loss (RPL) is multifactorial, but largely begins The challenging nature of this clinical
withdetermining whomeets diagnosticcriteria forRPL
as definitions vary and frequently change. Many problem is multifactorial, but largely be-
patients seek obstetrical intervention after losses, even gins with determining who meets diagnos-
if they do not meet the criteria for RPL, and even those tic criteria for RPL as definitions vary and
strictlymeeting criteriaoften presentaconundrumasto frequently change. Commonly used defi-
the etiology of their condition. The contribution of nitions include the following:
hereditary thrombophilia to RPL, the impact of each
disorder on the clotting cascade, available evidence Two or more failed clinical pregnancies
regarding pregnancy outcomes, and current recom- as documented by ultrasonography or
mendations for evaluation and treatment is presented. histopathologic examination.1
Key words: recurrent pregnancy loss, hereditary throm- Three consecutive pregnancy losses,
bophilia, clotting cascade which are not required to be
intrauterine.2
A retrospective cohort study of 587
women who had 3 or more consecutive
Introduction pregnancy losses before 12 weeks gesta-
Management of patients with recurrent tion demonstrated that biochemical preg-
pregnancy loss (RPL) can be an emotional nancies and pregnancies of unknown
location have a similarly negative impact
Correspondence: Ashley M. Pritchard, MD, Depart- on future live birth as intrauterine preg-
ment of Obstetrics, Gynecology and Reproductive Sci- nancy losses.3 Many patients seek obstet-
ences, Division of Maternal Fetal Medicine, Yale School
of Medicine, FMB 339B, New Haven, CT. E-mail: rical intervention after losses, even if they
ashley.pritchard@yale.edu do notmeet the above criteria for RPL, and
The authors declare that they have nothing to disclose. even those strictly meeting criteria often
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488 Pritchard et al
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Hereditary Thrombophilia and Recurrent Pregnancy Loss 489
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490 Pritchard et al
Intrinsic Pathway
XI
Extrinsic (Tissue Factor)
Antithrombin Pathway
XII XIIa X
XIa TF
VI
IX IXa VIIIa VIIa
I
PLT APC
PS
Antithrombin
Fibrinogen
(I)
Xa
the mutation is between 2% and 4% among factor for thrombosis in pregnancy, data
European whites; it is less common among connecting this thrombophilia and preg-
women of African and Asian descent.9,13 nancy loss, recurrent or not, are contra-
Althoughthe connection between PGM dictory and definitive conclusions cannot
and VTE in pregnancy is clear, data be made based on available information.
regarding the impact of the PGM on early
and RPL is uncertain. On the basis of Reys
meta-analysis of 31 case-control, cohort, Protein C Deficiency
and cross-sectional studies, as outlined Although FVL and the prothrombin gene
above, the mutation was linked to recur- mutation G20210A often result in similar
rent first trimester loss (OR = 2.32; 95% or predictable phenotypes, protein C defi-
CI, 1.12-4.79) and recurrent fetal loss ciency has been linked to >160 distinct
before 25 weeks (OR = 2.56, 95% CI, mutations resulting in variable pheno-
1.04-6.29). There also was a significant types. The prevalence of protein C muta-
association with nonrecurrent fetal loss tion is estimated at 0.2% to 0.3% when
when studies across all gestational were determined by a functional assay with
included (OR = 2.05; 95% CI, 1.18- cutoff between 50% and 60%.8,13 The
3.54).10 In contrast, a systemic review that mutation may be more common among
included 4 prospective studies addressing those of Asian or African descent.9 Protein
PGM and fetal loss at all gestational ages C deficiency is inherited in an autosomal
failed to find an association (OR = 1.13; dominant pattern, with deficiency de-
95% CI, 0.64-2.01).12 Reviews of these scribed by 2 distinct subtypes, Type I and
data highlight the limitations and inherent Type II.TypeI is morecommonandresults
bias of the studies included. Overall, in both a decreased amount and activity of
although PGM is a common heritable risk protein C with extensive heterogeneity in
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Hereditary Thrombophilia and Recurrent Pregnancy Loss 491
Protein S Deficiency
Protein S is a vitamin K-dependent protein Antithrombin Deficiency
intimately involved in the protein C anti- Antithrombin deficiency was the first he-
coagulation mechanism. Deficiency in reditary thrombophilia identified; it is also
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492 Pritchard et al
the most thrombogenic. There are >250 definitive causative relationship is not yet
associated mutations serving to decrease established.
gene transcription, leading to decreased
antithrombin antigen levels and activity or
normal antigen levels but decreased activ-
ity.8 Inheritance patterns are autosomal Methylenetatrahydrofolate
dominant with variable penetrance. Prev- Reductase (MTHFR)
alence of the mutation is estimated at 1 per MTHFR is an enzyme involved in folate
2500 patients, or a 0.02% to 1.15% among metabolism. MTHFRs role is to reduce
European whites. The prevalence may be 5,10 methylenetatrahydrofolate to 5-
higher in Asians with estimated prevalence methyltetrahydrofolate. The resulting en-
of 2%to 5%.9 Antithrombin is synthesized zyme acts to reduce homocysteine to
intheliverandendothelialcells;itsprimary methionine. Homozygosity for a MTHFR
mechanism of action is through an inhib- mutation is the most common cause of
itory effect on thrombin, working to pre- hyperhomocysteinemia. Homozygosity of
vent activated thrombins conversion of the MTHFR C677T and A1298C poly-
fibrinogen to fibrin. Antithrombin also morphisms is present in 10% to 16% and
acts as an inhibitor of clotting factors IX, 4% to 6% of all Europeans, respectively.
X, XI, XII and tissue-factor bound VIIa.5 The C677T allele has a carrier frequency
Similar to the thrombophilias outlined from 7% in sub-Saharan Africans to 44%
above, antithrombin deficiency is defined in Italians.17 The activity of the resulting
by subgroups. Type I is a quantitative enzyme is thermolabile, and is therefore
dysfunction and Type II is a qualitative less active at temperatures >371C. Homo-
dysfunction. Type II is again further div- zygotes for the C677T mutation demon-
ided into subcategories; Type IIa is char- strate elevated plasma homocysteine when
acterized by a defect in the reactive site of folate deficient, but normal levels when
the protein, and the resulting phenotype is folate replete. The second mutation,
often more thrombogenic. Type IIb has a A1298C, results in a more modest decrease
defect in the heparin-binding site, but the in enzyme function. Despite the potential
resulting phenotype is less thrombogenic. for decreased folate in individuals homo-
Type IIc includes both of the aforemen- zygous for these mutations, hyperhomo-
tioned defects. cysteinemia is quite rare given common
Given the rarity of antithrombin defi- folate food fortification and diets rich in
ciency, it is challenging to draw conclu- folate.
sions as to the thrombophilias effect on When homocysteinemia is present, it
pregnancy loss and related sequelae. The acts as a procoagulant. However, elevated
EPCOTstudyfounda modest increaserisk homocysteine levels remain a weak risk
in early fetal loss, as defined by gestational factor for VTE.8 Similarly, there does not
age <28 weeks (OR = 1.7, 95% CI, 1.0- seem to be connection between MTHFR
2.8). They also found a significant associ- and homocysteinemia with adverse preg-
ation with nonrecurrent losses at all gesta- nancy outcomes. At best, available data
tional ages (OR = 2.1; 95% CI, 1.2-3.6) are inconsistent with 1 meta-analysis find-
andafter28weeks(OR = 5.2;95%CI,1.5- ing a small link to recurrent fetal losses
18.1).14 Meta-analyses found no associa- <16 weeks (OR = 2.7; 95% CI, 1.4-5.2).18
tion with fetal loss, recurrent or not, but A 2000 study evaluating the pregnancies of
studies were limited by small numbers and 5883womenand14,492pregnanciesfound
retrospective design.10 In summary, data some correlation between elevated homo-
suggest an association between antithrom- cysteine and stillbirth, but the correlation
bin deficiency and pregnancy loss, but a did not meet statistical significance.19
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Hereditary Thrombophilia and Recurrent Pregnancy Loss 493
More recent work has not indicated a link demonstrated success in prolonging preg-
between MTHFR homozygosity or ele- nancies in early-onset severe preeclampsia
vated homocysteine with adverse preg- with antithrombin treatment. Currently,
nancy outcomes. there is a large multicenter double-blinded
randomized controlled trial underway
studying recombinant antithrombin ther-
apy for severe preeclampsia between 23 and
Other Adverse Pregnancy 30 weeks. Nonetheless, there has been no
Outcomes clear connection or causative relationship
Although the focus of this chapter remains demonstrated between any of the inherited
the impact of inherited thrombophilias on thrombophilias and preeclampsia.21
RPL, data suggest these conditions may
impact ongoing pregnancies, both in terms FETAL GROWTH RESTRICTION
of fetal and maternal health. The condi- Fetal growth restriction has links to nu-
tions outlined below are important causes merous maternal, fetal, and placental con-
of perinatal morbidity and they share ditions. Thus, a link between fetal growth
pathophysiology with some cases of preg- restriction and inherited thrombophilia
nancy loss. has been extensively studied. A meta-
analysis that evaluated the relationship
PREECLAMPSIA between fetal growth restriction, homozy-
Preeclampsia remains an increasingly com- gous and heterozygous FVL, homozygous
mon, but poorly understood disease of and heterozygous PGM, and MTHFR
pregnancy. Given the high degree of ma- homozygosity found no relationship or a
ternal morbidity and mortality, copious weak relationship between these entities
ongoing studies strive to understand risk and fetal growth restriction.22
factors for disease development as well as
treatment. Although case-control studies PLACENTAL ABRUPTION
suggest an association between FVL and A consistent association between any in-
preeclampsia, meta-analysis of prospective herited thrombophilia and placental
studiesfailtoshowasignificantrelationship abruption has not been demonstrated.
(OR = 1.23; 95% CI, 0.89-1.70).12 Similar This may be in part due to the relatively
studies have been conducted among those rare occurrence of placental abruption in
withthePGM.Anestedcase-controlcohort combination with the rarity of diagnosed
evaluation through the Danish National inherited thrombophilias, making it chal-
Birth Cohort found no association between lenging to conduct well-designed studies in
PGMandpreeclampsiawithseverefeatures this area.
(OR = 0.81; 95% CI, 0.29-2.30).20 One
meta-analyses suggest a connection be-
tween protein C and protein S deficiency Who Should be Tested and
andpreeclampsia.However,studiesremain
few and small in participant numbers.16 Should Treatment be
Although antithrombin deficiency has Considered?
not been found to be a risk factor for When a patient experiences RPL, there is
preeclampsia, antithrombin is currently temptation to consider broad diagnostic
being evaluated as a therapy for pre- testing in an effort to offer some explan-
eclampsia. Antithrombin has both antico- ation for this emotional outcome. How-
agulant and anti-inflammatory properties, ever, given the clinical evidence to
making it a plausible candidate for thera- date, routine inherited thrombophilia
peutic intervention. Several smaller studies screening is not recommended for those
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494 Pritchard et al
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Hereditary Thrombophilia and Recurrent Pregnancy Loss 495
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496 Pritchard et al
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Hereditary Thrombophilia and Recurrent Pregnancy Loss 497
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tation factor (PIF) detection in maternal circulation regulatory and neuroprotective properties of pre-
in early pregnancy correlates with live birth (bovine implantation factor: From newborn to adult.
model). Reprod Biol Endocrinol. 2013;11:105114. Pharmacol Ther. 2015;156:1025.
31. Barnea ER, Kirk D, Ramu S, et al. PreImplanta- 34. Ornaghi S, Mueller M, Barnea ER, et al. Throm-
tion Factor (PIF) orchestrates systemic antiin- bosis during pregnancy: Risks, prevention, and
flammatory response by immune cells: effect on treatment for mother and fetusharvesting the
peripheral blood mononuclear cells. Am J Obstet power of omic technology, biomarkers and in vitro
Gynecol. 2012;207:e1e11. or in vivo models to facilitate the treatment of
32. Barnea ER, Kirk D, Paidas MJ. Preimplantation thrombosis. Birth Defects Res C Embryo Today.
factor (PIF) promoting role in embryo 2015;105:209225.
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