Thrombotic events were initially considered the major pathological cause of pregnancy complications in OAPS [3]. It is now accepted that thrombosis alone cannot explain the pregnancy morbidity observed in OAPS. Indeed, the currently accepted first-line treatment for OAPS is LDA plus prophylactic unfractionated or low-molecular weight- heparin [4]. However, in approximately 20%-30% of OAPS cases, a live birth cannot be achieved [5]. Currently, thrombotic and non-thrombotic underlying mechanisms may play a role in the pathogenesis of aPL-related injury. Inflammatory, complement-mediated pathway activation seems to play a major role [3].
Placental dysfunction, due to microthrombosis and inflammation in APS, significantly reduced placental blood flow and fetal blood volume. Furthermore, fetal hypovolemia leads to oligohydramnios accompanying fetal growth restriction. When the placenta is insufficiently perfused, fetal ischemia and hypoxia redistribute blood. Decreased blood flow in the lung and kidney resulted in a decline of urine and lung fluid production, which contributed to a further decrease in amniotic fluid. Amniotic fluid plays an important role in the growth and development of the fetus. Oligohydramnios is an extremely dangerous signal. There are two peaks in the incidence of oligohydramnios, between 13 and 21 weeks, and between 34 and 42 weeks. Since the production of amniotic fluid in the midtrimester increases progressively, extreme and persistent oligohydramnios prior to 22–24 weeks may impede the fetal lung development, resulting in a level of pulmonary hypoplasia that poses a risk of perinatal mortality as high as 80%, or possibly in a growth delay, compression-related skeletal deformities and pregnancy loss[6]. A poor perinatal outcome with an overall survival rate of only 10.2–14.4% may be observed in the second trimester, which is very low as compared with that of 57.7–85.3% in the third trimester [7]. Moreover, umbilical cord compression causes fetal heart rate anomalies, and oligohydramnios may also be accompanied by abruption of the placenta. The case we reported showed an increase S/D from 3.7 at 20 weeks to 4.14 at 21 weeks of pregnancy in umbilical cord blood flow. At 22 weeks of pregnancy, oligohydramnios (AFI 3.33) was occurred, which companied with intrauterine growth restriction latter. Moreover, literature has reported that oligohydramnios with increased uterus-placenta vascular resistance have poor efficacy after maternal intravenous hydration [8].
TNF-α and IL-10 are crucial to implantation, placentation and pregnancy evolution [9]. An increase in the TNF-a: IL-10 ratio seems to promote early and late pregnancy complications [3]. Induction of tissue factor (TF) expression by aPL, which is considered to be directly involved in the procoagulant state of APS, was mediated exclusively by TNF-α [10]. A capture of TNF-α by adalimumab prevented TF induction in monocytic cells and endothelial cells [10]. Berman et al. have shown that aPL induce TNF-α production and that TNF-α-deficient mice or treatment with soluble TNF-α receptor prevented aPL induced fetal resorption [11]. Therefore, TNF-α was a critical effector in aPL-related placental injury and further miscarriage. In a series of 18 patients accepted in vitro fertilization with previous triple therapy and refractory aPL-related obstetric outcomes, the combination of LDA plus LMWH with TNF-a blockers rendered good overall obstetric results in almost 70% of cases, 50% which were OAPS and 100% in the ONAPS [12]. Meta-analysis, included 3 literatures, reported a total of 10 intrauterine growth retardation (IUGR) cases in the 82 recurrent spontaneous abortion women with APS treated by low-dose aspirin-heparin therapy [13]. The incidence of low birth weight, below the 10th percentile, is 6.7% in LMWH/LAD group from The HepASA Trial [14]. This patient was treated with TNF-α blockers on the basis of LMWH and LAD. At 24 weeks' gestation, the patient's amniotic fluid index returned to normal. Although ultrasound at 29 weeks of pregnancy indicated that fetal long bones were equivalent to 26 weeks, the fetus was delivered at 37 weeks of age, weighing 2600g, and all indicators were within the normal range. The combination of LDA plus LMWH with TNF-a blockers might reduce the risk of recurrent placenta-mediated pregnancy complications including preterm birth, IUGR and low birth weight.
In conclusion, clinical practice in OAPS is highly variable, in part because it is a rare disorder, and the understanding of its diagnosis, clinical manifestations, and management are continuously being advanced. The case demonstrated that NOAPS, with the presence of intermittent aPLs and treated by LDA plus LMWH, still had severe midtrimester oligohydramnios and IUGR with high perinatal mortality, which was rescued by TNF-a blockers. This therapy appears to be a promising treatment for refractory obstetric complaints related to aPL.