Obstetric complications, together with thrombosis, are the most frequent clinical features of APS (Table 7.8).
Human reproduction is inefficient, with an estimated 50% of conception failing; the majority of these go unrecognized. Approximately 10-15% of pregnancies end in spontaneous abortions prior to 12-14 weeks' gestations (from last menses), most of which are pre-embryonic or embryonic in nature, and 5% of all pregnancies end in pregnancy loss from 14 weeks' gestation through term. Several mechanisms have been proposed in APS (Table 7.9 and 7.10).
There are substantial differences between pregnancy stages (Table 7.11)(Fig. 7.14), and in each stage, pregnancy loss will be determined by different causes (Table 7.12). History taking and obtaining the postmortem findings in previous pregnancy losses are very important (Fig. 7.15). In considering the etiology of first trimester losses, it is also important that obstetricians exclude other relevant causes. It thus seems imperative
Table 7.8. Obstetric manifestations associated with APS.
Miscarriages (before 10 weeks)
Fetal death (after 10 weeks)
Pre-eclampsia, eclampsia, and HELLP syndrome
Placental insufficiency (prematurity, fetal growth restriction)
Table 7.9. Pathogenic mechanisms for pregnancy morbidity in APS.
Placental thrombosis, necrosis and/or infarction Spiral arterial vasculopathy of decidual vessels Complement activation Decreased Annexin V Acquired protein C resistance
Table 7.10. aPL and pregnancy morbidity: proposed mechanisms.
Block placental prostaglandin & thromboxane
Compete with annexin V
Displace annexin V
Inhibit throphoblast proliferation
Block placental gonadotropin
Pre-embryonic (<4 week after fertilization): implantation and trilaminar pre-embryo with neural axis development. Embryonic (5-9th weeks of gestation): main organogenesis. Fetal (from the 10th week until delivery): growth, little organogenesis, and differentiation of formed structures.
Pre-embryonic period conception to week 4 trophoblast differentiate & implantation
Fig. 7.14. Pregnancy stages.
to assess carefully all cases before aPL can be attributed to be the cause of the pregnancy loss.
Recurrent pregnancy loss (loss of >2 consecutive pregnancies) occurs in an estimated 0.5-1% of women. One previous fetal death increases 5-20 fold the risk to suffer another one. Thorough evaluation of each case is therefore mandatory (Table 7.13).
The pathogenesis of the adverse pregnancy outcome in APS has not yet been fully elucidated although there is active research in this field.
Several studies have proved the strong association between aPL and pregnancy loss. Although in general population early miscarriages (<10 weeks) are the most frequent pregnancy losses, second and third trimester fetal losses are the
Embryonic period week 5 - 9 organogenesis
Embryonic period week 5 - 9 organogenesis
> week 10 fetal growth & differentiation
Table 7.12. Causes of pregnancy loss.
Sporadic miscarriage <10 weeks' gestation Chromosomal abnormalities of the conceptus/placenta Fetal loss
Parental structural chromosome abnormalities
Thrombophilia, especially factor V Leiden, resistance to activated prot-C, prothrombin 20210 mutation, prot-S deficiency Intrauterine infection (especially viral)
Alloimmunization to Rh D antigen and other blood group ag
Poorly controlled DM
Recurrent pre-embryonic or embryonic pregnancy loss Prenteral structural chromosome abnormalities Uterine anatomic abnormalities, including congenital malformations APS
Numeric chromosome abnormalities of the conceptus
Molecular genetic abnormalities of the conceptus or placenta
Hormonal and metabolic disorders
Luteal phase defects
Hypersecretion of luteinizing hormone
Table 7.13. Suggested routine evaluation for recurrent pregnancy loss.
Pattern and trimester of pregnancy losses and whether a live embryo or fetus was present
Exposure to environmental toxins or drugs
Known gynecologic or obstetric infections
Genetic relationship between reproductive partners (consanguinity) Family history of recurrent miscarriage or syndrome associated with embryonic or fetal loss Previous diagnostic tests and treatments
General physical examination Examination of vagina, cervix and uterus
Hysterosalpingogram or hysteroscopy
Parental karyotypes aPL (LA, aCL, anti-b2-glycoprotein1)
Thrombophilia evaluation (factor V Leiden, Prothrombin 20210 mutation)
Luteal phase endometrial biopsy; repeat in next cycle if abnormal Other lab tests suggested by history and physical examination most characteristic obstetric complication in APS (present in 50-75% of patients). In patients with SLE and secondary APS, some studies suggest this may be as high as 90%, although this is likely to be an overestimate.
In pregnancies that do not end in miscarriage or fetal loss, there is a high incidence of early onset pre-eclampsia, intrauterine growth restriction, placental abruption, and premature delivery. Because patients with APS form a heterogeneous group, the incidence of these complications varies between units.
It is impossible to predict which women will develop complications in pregnancy, and some women with persistently elevated aPL titers and a history of thromboses and/ or thrombocytopenia will have no obstetric complications at all. Previous poor pregnancy outcome remains the most important predictor of future risk.
The strongest relationship between aPL and fetal losses has been found after 14 weeks. Lupus anticoagulant (LA) has shown the strongest association with recurrent fetal losses before 24 weeks' gestation, although it has not been possible to analyze the association of LA with early miscarriages (<13weeks). aCLs are also related with recurrent losses before 24 weeks. IgG aCL is the only one that has been associated with early miscarriages.
Factor V Leiden, the Prothrombin 20210 mutation, and homozygous state for the Homocysteine MTHFR mutation C677T have also been strongly associated with late pregnancy complications and second/third trimester losses.
The physiological changes in the hemostatic system in pregnancy result in an acquired thrombophilic state. In fact, Virchow's triad (venous stasis, hypercoagulability, and vascular damage) occur in the course of uncomplicated pregnancy and delivery.
Pulmonary thromboembolism (PE) remains a major cause of direct maternal mortality, which normally arises from deep venous thrombosis (DVT). PE is more likely to occur postpartum than antepartum, and is strongly associated with cesarean section in epidemiological studies. On the other hand, heritable thrombophilic conditions are found in over 50% of gestational venous thromboembolism.
Women with aPL or obstetric-APS without a history of thrombosis appear to have a substantial high(er) risk of thrombosis during pregnancy and in the postpartum.
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