Several studies have discussed survivors of sIUFD, including all the causes of sIUFD, such as genetic or congenital abnormalities. However, this review focused on the outcomes of survivors after sIUFD, which were due to TTTS.
Over 19.3% of surviving co-twins developed anemia after birth in this literature review. In fact, the incidence of anemia might be underdiagnosed because intrauterine blood transfusion had been performed, and fetal anemia had been corrected in 19 patients, as reported by Quarello et al. [10]. Profound anemia can cause ischemia of the vital organs, such as the brain, liver, and kidney. In our patients, we found that a shorter interval between sIUFD diagnosis and delivery of the surviving co-twin resulted in lower hemoglobin levels. The only patient with a normal hemoglobin level was born at GA of 292/7 weeks, but with a long interval of 58 days between sIUFD diagnosis and delivery. We hypothesized that the length of the interval between sIUFD diagnosis and delivery might considerably affect the anemia severity, which has not been mentioned in previous studies. Fuisi et al. hypothesized that anemia was due to acute exsanguination of the surviving twin into the low-pressure hemodynamic circulation of the demised co-twin [5], which caused acute blood loss. Senat et al. also noted that cardiac contractility increased after sIUFD. We inferred that anemia might be acute and transient, which could be improved later after a long interval between sIUFD and delivery of the surviving co-twin.
Among the cases of the literature review and our cases, 17 (13.7%) patients of surviving co-twins without fetal laser photocoagulation therapy had developed neurological damage. The incidence of neurological impairment was similar to that reported by Akkermans et al. They showed that the incidence ranged from 8% to 18% after laser therapy [9]. Whether fetal laser photocoagulation could alleviate the neurological damage of the surviving co-twin remains uncertain. Two of our patients developed hemorrhagic infarctions soon after birth. One of them developed encephalomalacia within 24 h after birth, suggesting an antenatal white matter injury. Kiely et al. reported that cerebral abnormalities were usually detectable by prenatal ultrasound or MRI within 3–6 weeks of the death of the co-twin [10]. Furthermore, Eglowstein et al. found that one patient presented with periventricular leukomalacia 24 h after the demise of the co-twins [11], suggesting that the timing of neurological damage could be early before intrauterine death of the co-twins. Consequently, not only sIUFD could induce neurological damage, but patients with TTTS might be at risk of developing neurological injury.
Considering the progressive fetal brain development, distinct timing of sIUFD might result in various presentations of brain damage. The TTTS phenomenon usually becomes prominent during the second trimester. If sIUFD occurred early in the second trimester, it could cause disturbances in neuronal migration and leads to polymicrogyria [12]. During the third trimester, the brain size linearly increases by four-fold, while cortical folding and wiring begin developing. The brain is thus more vulnerable to cerebral ischemic damage during this period. Two of our patients with poor neurodevelopmental outcomes succumbed to sIUFD at GA 254/7 and 30 weeks, respectively. The other three survivors who did not develop poor neurodevelopmental outcomes had sIUFD at gestational age less than 20 weeks in one patient and over 32 weeks in the other two patients. Because the brain is undergoing rapid growth and maturation during the late second trimester and early third trimester, we suggest that sIUFD occurring between these periods should raise more concerns about poor neurodevelopmental outcomes.
Four patients had acute kidney injury, including three of our cases. One pathological study revealed that donor twins displayed renal tubular dysgenesis. [14] They hypothesized that TTTS-related hypoperfusion along with hypofiltration deferred proximal tubular development, leading to renal tubular dysgenesis [14]. Although two of our patients recovered from acute kidney damage, one patient progressed to chronic kidney disease. According to a recent study, the incidence of chronic kidney disease among twins with TTTS was high, with approximately 31%–50% of such patients requiring long-term renal replacement therapy [15]. However, this study excluded surviving twins after sIUFD. Therefore, further study recruiting surviving twins after sIUFD is warranted.
Only a few articles reported GI dysmotility in TTTS survivors after sIUFD. However, in our study, this was an important issue. The probability of preterm delivery was high among TTTS survivors. Nutrition was the key point for early discharge and prevention of several complications of prematurity. All of our patients demonstrated GI dysmotility. They exhibited GI dysmotility during the first week of life and were capable of full enteral feeding at a median of 46 days, which was longer than the usual clinical course. Robel–Tillig et al. reported that the pathological blood flow parameters in the superior mesenteric artery could predict problems in intestinal motility and tolerance to enteral feeding [16]. Neonates with decreased peak systolic flow velocity and increased superior mesenteric artery pulsatility indexes were at risk for poor enteral feeding after birth. According to the diving reflex theory, antenatal hypoxia may cause blood flow redistribution to the vital organs rather than the intestinal circulation, leading to persistent intestinal vascular bed vasoconstriction [16]. The increased GI blood flow after feeding helps satisfy the oxidative demand for intestinal absorption, which is called postprandial hyperemia [17]. During the neonatal period, pressure–flow autoregulation is insufficient. The high resistance within the intestinal vasculature compromises blood flow throughout the GI tract [12]. We suggest that the failure of vasodilation and upregulation of the intestinal blood flow in TTTS survivors after sIUFD may lead to feeding intolerance and GI dysmotility [17].
Our study documented that the mortality rate of the surviving twins of TTTS after sIUFD was up to 30%, which was much higher than that of the non-TTTS twins with sIUFD. [18.19] The mortality and morbidity rates might be affected by the interval between sIUFD and delivery time. Johsnosn et al. reported that the survival of the remaining fetuses was inversely related to the time of the first fetal demise. [20]. However, this study included all the causes of sIUFD and collected all monochorionic and dichorionic placentation. [20] One study showed that postnatal mortality will increase when sIUFD occurs during the second trimester, a vulnerable period, associated with a high incidence of growth retardation, premature labor, and perinatal mortality [21]. Moreover, both of our two mortality cases suffered from thrombocytopenia soon after birth. One of them had developed DIC within 24 h after birth, which implicated a possible thromboembolic effect. We suggest that the mechanism of this unfavorable insult among survivors after sIUFD might not only be due to hypovolemic-ischemic damage, but also due to thromboembolism from demised twins. Furthermore, Wang et al. found that the long-term presence of D-dimer in the maternal serum may indicate a severe underlying thromboembolic complication in the surviving twin after an intrauterine death of a monochorionic twin [22].
The limitations of our study were the small number of patients. However, we did not only focus on neurological complications, but also on kidney injury and GI tract dysmotility.
Further studies for the optimal management strategies among survivors after sIUFD to improve the mortality and morbidity rates are recommended. This review study that explored detailed neonatal outcomes of survivors after sIUFD caused by TTTS may provide some information to evaluate the morbidity and mortality rates among surviving co-twins after sIUFD.