Criteria for obstetric APS
1. 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
2. One or more premature birth of a morphologically normal neonate before the 34th week of gestation because of eclampsia or severe preeclampsia or recognized features of placental insufficiency
3. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomic causes excluded
An additonal aspect that has to be considered is the clinical setting of patients with obstetric APS. The presence of aPL in a patient with a well-defined systemic autoimmune disease (mainly systemic lupus erythematosus) and obstetrical morbidity seems to be a different condition from that occurring in a patient with aPL and REPL or fetal death in the absence of other medical problems. It seems that these two conditions are hardly comparable and that the recurrence rate is probably higher in the first one [6]. Another well-established risk factor for recurrences is a previous history of thromboembolism that requires, beside a specific management during pregnancy, a careful prophylaxis not only to protect fetal well-being but also to avoid possible thrombotic events in the mother [7].
Antiphospholipid antibody profile has been also investigated as possible risk factor for pregnancy loss recurrence. A recent collaborative Italian study demonstrated that triple positivity of aPL antibodies (LA, aCL, and anti-β2GPI) is an independent risk factor for pregnancy poor outcome despite conventional treatment [6]. Conversely a multicenter American study enlightened the role of LA as primary predictor of adverse pregnancy outcome after 12 weeks of gestation in the pregnancies of aPL-positive mothers; in this study positivity for aCL and anti-β2GPI, if LA is not also present, did not predict adverse pregnancy outcome [6].
The aPL titer (aCL and anti-β2GPI) is also considered in the frame of aPL profile. According to international recommendation [8] IgG isotype at medium high titer is considered a higher risk factor for APS clinical manifestations compared to low titer and IgM isotype. In fact low titer is not recognized as formal classification criteria.
Nevertheless in obstetric APS also low titers were suggested to be of significance [9, 10] being associated with poor obstetric outcome. This particular aspect is still debated; a study from Israel showed a good pregnancy outcome in 77 % of patients with low aPL titers, compared to 35 % of good outcomes reported in patients with high aPL titers [9]. Instead a French study described poor pregnancy outcomes in untreated mothers with low aPL titers that were not significantly different from those observed in patients with medium-high titers [10]. Furthermore an English study showed that over 50 % of women with pure obstetric APS had low titer aCL and/or anti-β2GPI in the absence of LA. Approximately 27 % of these patients had clinical features of high-risk obstetric APS [11]. Indeed the impression is that in obstetric APS also low titer aPL may play a notable role. Accordingly, low titer aCL were already described to be of clinical significance for women with purely obstetric APS in a large prospective cohort of European patients [12] as well as in women with stillbirth in a recent collaborative report [13].
In addition to classical aPL antibodies, increasing evidence demonstrates that several other autoantibodies, such as antibodies against phosphatidylethanolamine (aPE), anti-annexin 5, antiprothrombin (aPT), and/or anti-phosphatidylserine/prothrombin complex (aPT/PS), can be found associated with pregnancy loss. Starting in the 1990s Yetman et al. reported non-criteria aPL, including aPE, in 10.1 % of women with REPL [14]. Further studies confirmed an increased incidence of aPE in patients with REPL, in fetal death, and in infertile women with recurrent implantation failures [15, 16]. However, aPE was not shown to be an independent risk factor for further miscarriage in patients with REPL [17], but the combinations of IgG aPE with other aPL detected by tests included in the Classification Criteria can be useful predictors of severe pregnancy-induced hypertension, with a 30.8 % sensitivity and a 99.2 % specificity [17].
The association of antiprothrombin antibodies and pregnancy morbidity is still not clear also because of the known difference between antibody binding to prothrombin alone (aPT) and antibodies binding to phosphatidylserine/prothrombin complex (aPS/PT). Several groups found that women with REPL, either idiopathic or within APS, display higher frequency of aPT compared to normal subjects [18]. Recently the prevalence of aPT was investigated in a cohort of patients negative for classical aPL with previous uteroplacental insufficiency complications, including severe preeclampsia, HELLP syndrome, placental abruption, and fetal death. A significantly 10-fold higher prevalence of aPT IgG was reported in cases compared to controls (OR, 95 % CI: 10.92, 4.52–26.38); the strongest statistical association was reached with fetal death [19]. The association between the aPS/PT antibodies and pregnancy morbidity is also still matter of discussion, with studies that have found low rate of aPS/PT positivity in patients with REPL without APS [20], while a recent paper reported high rate of antibodies against aPS/PT in patient with APS (with or without SLE) [21]. The authors reported that aPS/aPT antibodies were the strongest independent risk factor for obstetric complications in their cohort.
High rate of anti-annexin 5 antibodies was found in several retrospective studies [22]. However, in a large prospective cohort study, the detection of anti-annexin 5 at the beginning of pregnancy was not related to the occurrence of pregnancy loss [23]. In women with obstetric APS characterized by REPL, a higher prevalence of anti-annexin 5 antibodies has been observed compared to aPL-negative women with the same obstetrical complications or to general obstetric population [24]. Therefore, it is actually suggested that anti-annexin 5 antibodies do not represent an independent risk factor for REPL, while they could represent an additional risk factor possibly contributing to the disruption of the annexin 5 crystal shield [25].
To achieve a successful outcome in APS pregnancy, an optimal management strategy is required. This includes a proper treatment (as enlighten in the Chap. 16), but the experience has thought us that pharmacological treatment by itself is not sufficient. Success, defined as fetal survival, is the result of careful obstetric monitoring, proper delivery timing, and skilful neonatal care [26]. The careful surveillance conducted by a multidisciplinary team (obstetricians, rheumatologists, and neonatologists) and the progress in neonatal intensive care are as important as drugs to achieve a good obstetric outcome and to reduce the possible adverse consequences of premature delivery.
7.2 Nomenclature
A major problem in comparing the published data of obstetric APS has been and still is the lack of uniform definitions for pregnancy loss and pregnancy complications. Therefore, in the interest of the readers, we think important to share common definitions.
The nomenclature used for the definition of pregnancy loss can be quite outdated, and in this case it does not reflect the modern understanding of reproductive biology. Traditionally pregnancy loss occurring at less than 20 weeks of gestation have been grouped together as spontaneous abortions, while those occurring after 20 weeks gestation have been defined stillbirths. More recently nomenclature that accurately reflects our current knowledge of the developmental process and that is more aligned with pathophysiology or causes of pregnancy loss has been proposed [27]; these definitions are outlined in Table 7.2.
Table 7.2
Proposed nomenclature
Proposed nomenclature | Definition | Previous nomenclature | Developmental stage |
|---|---|---|---|
Early pregnancy loss (04+0–09+6 weeks of gestation) | Either: | Early spontaneous abortion | Embryo |
Death of a conceptus measuring up to 29 mm in crown-rump length | |||
Sonographic documentation of a dead conceptus consistent with a gestational age up to 9 weeks and 6 days gestation (crown-rump length up to 29 mm) | |||
The embryo must be identified by ultrasound to rule out anembryonic pregnancy | |||
Fetal death (10+0–19+6 weeks of gestation) | Either: | Spontaneous abortion | Fetus |
Passage of a conceptus measuring at least 30 mm in crown-rump length or | |||
(a) Early fetal death (10+0–15+6 weeks gestation) | Sonographic documentation of a dead conceptus with crown-rump length consistent with a gestational age at least 10 weeks gestation | ||
(b) Late fetal death (16+0–19+6 weeks of gestation) | Loss of the conceptus after documented fetal cardiac activity at or beyond 10 weeks gestational age The fetus is dead at the time of delivery with Apgar scores of zero at one and 5 min. | ||
Neonatal death | Death of a formed fetus alive at birth in the first 28 days of life | Neonatal death | Neonate |
Stillbirth (at least 20 weeks of gestation) | Fetus at least 20 weeks of gestation that is dead at the time of delivery with Apgar scores of zero at one and 5 min. | Stillbirth | Fetus |
Preeclampsia | Increased blood pressure associated with proteinuria in pregnancy Diagnostic blood pressures include either a systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90 mmHg on at least two occasions (at least 4 h apart) Proteinuria is defined as the excretion of 300 mg of protein or greater in a 24-h specimen | Preeclampsia | |
Early (<33 weeks) | |||
Late (≥34 weeks of gestation) | |||
Eclampsia | An acute and life-threatening complication of pregnancy characterized by the appearance of tonic–clonic seizures (convulsions) | Eclampsia | |
HELLP syndrome | Hemolysis, elevated liver enzymes, and low platelet | HELLP syndrome |
In the following pages we try to apply the new terminology; however, some of the reported data were published before its definition; therefore, we had to deal with various descriptions of pregnancy complications and adverse outcomes and some imprecision has to be taken into account.
7.3 Recurrent Early Pregnancy Loss
In a general obstetric population, 10–15 % of pregnancies end in spontaneous abortion, mainly occurring during the pre-embryonic (up to 5+6 weeks of gestation) or embryonic period (up to 9+6 weeks of gestation), while the rate of fetal death, after 10 weeks of gestation, is very low. In addition, the recurrence of early miscarriages in the general population is not unusual, being recorded in about 1 % of them. A recent critical review, including only four prospective studies performed on general population with REPL, reported aPL positivity in about 2 % of the women [28]. The selection of the included papers was limited to the studies including details allowing to verify the reliability of the findings and therefore might be near to the real picture.
The attribution of early recurrent miscarriages to aPL-mediated damage implies the exclusion of several other possible causes:
1.
Chromosomal abnormalities, which often impair embryo formation, account for more than half of sporadic pre-embryonic or embryonic losses
2.
Genetic abnormalities of the conceptus are less common in women with three or more consecutive miscarriages
3.
Obstetric anomalies such as uterine anomalies, luteal phase insufficiency, and cervical infections
4.
Endocrinological disorders such as thyroid hormone dysfunctions and undiagnosed celiac disease
The need for at least three REPL in the first 10 weeks of gestation to fulfill the classification criteria of APS is probably based on these observations and allows to exclude most of the losses due to genetic abnormalities that can confuse the clinical picture.
Nevertheless, REPL, often misdiagnosed because of their frequency in the general obstetric population, can be considered to be the most frequently occurring pregnancy losses associated with aPL. In fact according to a recent report of the 10-year follow-up of 1,000 APS patients [5], 188 pregnancies in 127 women were observed and despite prophylactic treatment, REPL occurred in 16.5 % of pregnancies, while fetal death in 5 %.
Many published studies reports a positive association between aPL and REPL, but they are highly heterogeneous concerning clinical events (number of previous pregnancy losses, gestational age of pregnancy losses, inclusion of early miscarriage, and late fetal death in the same analysis) and laboratory criteria (different cutoffs, inclusion of patients with low titers, and lack of confirmatory testing). A recent meta-analysis [29] tried to evaluate the previous papers that have analyzed this association in patients without systemic autoimmune disease. The authors underlined that the comparison between studies was difficult due to many methodological causes: poor standardization of assays testing for aPL, heterogeneity of studies regarding the definitions of cases (minimum number of consecutive losses required), and controls (not matched for parity, few studies with appropriate controls). No studies were found examining the association between lupus anticoagulant (LA) and anticardiolipin (aCL) IgM with pregnancy loss before 13 weeks of gestation, and the association between anti-β2 glycoprotein-I (aβ2GPI) and recurrent abortion before 13 weeks was not statistically significant. Instead they reported a positive association between low and moderate-high titers aCL IgG and REPL occurring at less than 13 weeks of gestation; however, only two studies, including 907 patients, could be evaluated in this analysis.
The recent report of the antiphospholipid antibodies taskforce [30] included only studies recording losses occurring within 10 weeks of gestation. Forty-six original studies investigating the frequency of positive aPL tests in patients with REPL were identified and included in the analysis. High percentage (nearly 80 %, 27 out of 34) of the case-control studies found a significant association of aPL and REPL. Results of LA and aCL antibodies were available in most of the studies, with only a small number of papers analyzing anti-β2GPI. Fourteen out of 27 studies reporting a positive association between aPL and REPL included a significant number of patients (>100). Conversely, a number of studies found no association between aPL and REPL. Notably, some of them published in the 1990s did not include the evaluation of patients by all the three tests. Panton et al. described a higher prevalence of aCL IgG among 177 women with REPL compared to 254 healthy blood donors [31], but the finding was not statistically significant. Two large studies [15, 32] published in the 2000s found no association between aPL and REPL. In the first LA and aCL IgG were studied in 273 patients [15], while the other considered aβ2GPI IgG and IgM in 172 patients [32]; data from both the works showed no significant difference in the frequency of aPL in patients compared to healthy controls. Finally a very recent reported no significant association between aCL or LA and REPL in 52 Pakistani women [33].
The heterogeneous results of the studies mentioned above can be partially explained by different inclusion criteria and definitions of positive laboratory tests. Many papers (26/46) investigating aPL in patients with REPL were published before the first international consensus on aPL [2] and most of them did not use the criteria currently accepted to classify patients with APS. More than three pregnancy loss was the criteria used only in two third of the studies (30/46), and the majority of the published studies did not mention if patients had consecutive pregnancy loss; only four papers [34–37] strictly followed the pregnancy morbidity criteria for REPL described in Sapporo/Sidney consensus (“Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation”). The gestational age of the pregnancy loss used as inclusion criteria was also various among the publications with several studies including patients with both first and second trimester loss. Also the use of different cutoff in the diagnostic tests appears to have contributed to the discrepant findings, and the confirmation of aPL positivity was performed in only 8 out of 46 studies, increasing the risk of misclassification due to momentary aPL.
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