The occurrence of surviving cotwins born at term without brain injury subsequent to sIUFD in the second trimester within an MCMA twin pregnancy is exceedingly rare. Following sIUFD, maternal D-dimer levels significantly increased throughout the entire gestational period. Upon birth, the surviving full-term newborn experienced a transient elevation in D-dimer levels within 8 days, concomitant with unexplained noninflammatory exudative lesions observed in the bilateral pulmonary region. However, the coagulation status of the mother, surviving fetus, and newborn following sIUFD remains uncertain in the literature. To comprehensively understand this uncommon complication, a thorough literature review was conducted encompassing cases of monochorionic pregnancies complicated by spontaneous sIUFD in the second or third trimester, excluding those attributed to TTTS or sFGR. This review aimed to elucidate the clinical characteristics of such cases, identify potential risk factors contributing to neonatal pulmonary lesions, and underscore the heightened importance of prenatal assessments encompassing maternal-neonatal D-dimer levels and potential end-organ damage in surviving cotwins, particularly concerning the respiratory system, in the context of pregnancies with MCMA pregnancies with elevated maternal D-dimer levels.
The cause of the single fetal death in this patient remains unknown. An examination at delivery revealed that the dead fetus was a fetal papyraceus with an atrophic umbilical cord and that the insertion points of the two umbilical cords were 1 cm apart without velamentous insertion. A large portion of fetal deaths observed in monoamniotic twin pregnancies are caused by fetal defects, while in structurally normal monoamniotic twin pregnancies, fetal deaths are often explained by tight cord entanglement [9]. All these factors may have contributed to the single fetal death in this patient.
In our review (Table 1), five surviving cotwins (7.6%, 5/66) experienced intrauterine death, 50 cotwins (82%, 50/61) were born prematurely, 14 neonates (23.0%, 14/61) died after birth, 26 neonates (44.1%, 26/59) suffered from intracranial lesions, and 7 preterm newborns developed other organ impairments, such as lung damage, kidney abnormalities, intestinal injury and cardiac failure, which may be mainly due to complications of prematurity. Additionally, brain MRI showed that the surviving fetus had normal cranial imaging in this patient, even as a term newborn. In fact, the surviving twin is at a high risk of abnormal postnatal brain imaging in cases of single fetal death, especially in monochorionic pregnancies, with an incidence of approximately 43% [10], which was similar to our reviewed case series.
There are two main theories to explain the increased risk of morbidity and mortality of the surviving cotwin in monochorionic pregnancies: “twin embolization syndrome” and “hemodynamic imbalance.” The latter theory, which states that placental intertwin anastomoses allow the transfer of blood from the surviving cotwin to the dead twin, resulting in periods of hypoperfusion and adverse outcomes such as neurological changes, is widely accepted. This theory was based on the finding that fetal anemia was clearly documented in fetal blood sampling of the surviving cotwin [11–13]. Sonographic measurement of the MCA PSV is a reliable and noninvasive way to detect fetal anemia. Bajoria et al. established that superficial intertwin arterio-arterial or veno-venous anastomoses increase the incidence of intrauterine death, fetal anemia, and neurological handicap [14]. As shown in Table 1, of the 17 surviving fetuses with placental intertwin arterio-arterial or veno-venous anastomoses, 11 (64.7%, 11/17) developed anemia, and 10 of the 11 anemic fetuses (90.9%, 10/11) developed brain damage. In contrast, of the nine surviving fetuses with placental intertwin arterio-venous or veno-arterial vascular shunts, two (22.2%, 2/9) developed anemia followed by neurological impairment. The risk to the surviving monochorionic cotwin may depend upon the type and size of the placental anastomoses. Cotwin anemia and even death can be explained by acute hemodynamic imbalances caused by large placental anastomoses, such as arterio-arterial and veno-venous anastomoses. Fortunately, the MCA PSV of the surviving cotwin in our patient was normal, indicating that our patient did not have large arterio-arterial or veno-venous anastomoses. Since delineation of superficial placental anastomoses by power Doppler ultrasound or MRI has now become possible in the field of research, we may use this indicator to predict the prognosis of the surviving fetus and guide clinical management.
Furthermore, the neonate in our case had transient D-dimer elevation with a maximum of 29.88 mg/L, which was extremely high. Nonetheless, it was reported that the results of coagulation screening tests on the surviving infant twin at delivery were almost always normal when the complications of prematurity were excluded [26]. Khalilov et al. reported that the mean D-dimer level measured in healthy term neonates at one week (2.44 ± 2.45 mg/L) was greater than that reported in the literature for adults (< 0.5 mg/L) and that D-dimer levels gradually decreased over time in the first month [27]. The high D-dimer levels in the neonatal period might be due to diminished renal clearance of D-dimer, birth stress, circulatory adaptation, short-term hypoxia, or intrauterine activation [27]. The transient elevation of D-dimer in the newborn patient in our case might be attributed to intrauterine activation derived from the mother. The gradient is such that thromboembolic material cannot flow from the dead fetus to the circulation of the survivor.
In our patient, after 3 days of intubation and mechanical ventilation and 10 days of anti-inflammatory treatment with ampicillin sulbactam sodium and ceftazidime, the neonatal exudative lesions in both lungs, as well as other clinical symptoms, improved significantly. It is well known that neonatal wet lung disease is usually self-limiting, with complete remission within 2–3 days. Respiratory distress syndrome is a progressive disease commonly encountered in premature infants and mothers with diabetes. The characteristics of respiratory distress syndrome include reduced transparency, a ground-glass opacities, and even white lungs on chest radiographs. Our case was not very similar to either of these two diseases. The fetus lacks pulmonary circulation during the intrauterine period. Once the fetus is born, thrombotic material may flow into the neonate’s pulmonary circulation, resulting in pulmonary damage. However, this kind of lung damage is usually mild, which is not consistent with our case. In this case, the two fetuses shared a single amniotic sac. When sIUFD occurs, the necrotic material from the deceased fetus is released into the shared amniotic cavity. The surviving fetus might have inhaled some amniotic fluid containing necrotic material via breath-like movements. The inhaled necrotic material might have blocked the fetal lung, resulting in obvious exudative changes in both lungs. However, it is important to note that this is a speculative interpretation, and further research is warranted to confirm this hypothesis. Szymonowicz W et al. reported three cases of pulmonary complications in monochorionic diamniotic twin pregnancies, of which two were pulmonary infarction and one was pulmonary artery embolism [16]. The gestational ages at delivery were 28, 31, and 32 weeks, respectively. Therefore, lung damage due to complications of prematurity cannot be excluded. Notably, the surviving term twin in this patient did not develop brain damage; however, special pulmonary lesions were present postnatally. The possible risk factors contributing to the special pulmonary lesions in our patient were elevated maternal D-dimer and MCMA.
When sIUFD occurs, maternal disseminated intravascular coagulation (DIC) is extremely rare in multiple pregnancies [28–29], although the reason remains unclear. Maternal coagulation function results were available for eight patients, of whom two had decreased fibrinogen and five had normal fibrinogen. Only our patient showed increased maternal D-dimer levels from 1.18 mg/L to 9.21 mg/L following single fetal demise at 17 weeks of gestation, which indicated the activation of maternal fibrinolysis following fibrin formation. Moreover, the D-dimer concentration tended to decrease to 4.05 mg/L at 20 weeks of gestation, possibly due to self-regulation of the maternal coagulation-fibrinolysis system and the effect of low-molecular-weight heparin (LMWH). D-dimer levels are useful markers for the early diagnosis of DIC and thromboembolism [30–31]. Nevertheless, there were no complaints or clinical manifestations of thromboembolic complications in this mother. Of course, the formation of small emboli in deep pelvic veins cannot be ruled out because imaging is less sensitive for diagnosing pelvic DVT during pregnancy. Even if there was a pelvic DVT, it was estimated to only consist of small emboli and had little impact. Similarly, Daniilidis and his colleagues [32] also reported elevated D-dimer levels, with a maximum of approximately 10 mg/L at 33 weeks of gestation following a single twin death, without the occurrence of DIC or thromboembolism in the mother. Hence, a baseline coagulation profile, including D-dimer levels, needs to be followed up with serial coagulation studies.
D-dimer, a fibrinolytic-specific degradation product, is a highly sensitive marker of fibrin formation. A high D-dimer concentration indicates activation of both the coagulation and fibrinolytic systems. During normal pregnancy, it increases gradually, reaches its peak in the third trimester and is maintained until 48 hours postpartum in response to the increased demand for fibrin formation and fibrinolysis to maintain proper blood flow to the placenta and fetus and reduce the risk of postpartum bleeding [33–37]. Previous research has demonstrated that elevated maternal D-dimer levels are independent risk factors for postpartum hemorrhage [34, 38]. Severe pelvic bleeding occurred two days postpartum in our patient. This may be attributed to the delivery process as well as an increase in fibrinolysis indicated by elevated D-dimer levels, i.e., the consumption of fibrinogen results in relatively low levels of fibrinogen, and a low antenatal fibrinogen level increases the risk of postpartum hemorrhage. The pathological mechanism of D-dimer elevation and the effects of continuous D-dimer elevation on maternal and fetal prognosis, especially its relationships with maternal pelvic hemorrhage and neonatal pulmonary lesions, require further clinical and laboratory studies for verification.
In this case, following a single fetal death and an increase in maternal D-dimer, LMWH was administered until 38 weeks and 2 days of gestation. During this time, the D-dimer levels fluctuated at relatively high levels. Fortunately, there was no cerebral impairment in the neonate. However, pelvic hemorrhage occurred two days postpartum, and the newborn was complicated with unexplained pulmonary lesions with transient elevated D-dimer. It was unclear whether these complications were related to the use of LMWH, although LMWH administration during the prenatal period is safe.
Since MCMA twins are always accompanied by multiple complications, the diagnosis of chorionicity and amnionicity in the first trimester is needed for further pregnancy follow-up [39]. After the first trimester, we typically perform ultrasounds every 2 weeks to check fetal viability and screen for growth restriction, TTTS, and twin anemia-polycythemia sequences. When an intrauterine single fetal death was detected, the MCA PSV of the surviving cotwin was detected immediately, maternal coagulation function, including D-dimer levels, was examined every week for the following month, and LMWH was administered when necessary. Cranial images of the cotwin were obtained 3 weeks later by MRI, and the patient was followed up throughout the pregnancy. It would be even better if the type and size of placental intertwin anastomoses could be examined by MRI or ultrasound.