Intrauterine Fetal Demise in Multiple pregnancy

Single Intrauterine demise (sIUD) in a multifetal pregnancy is a complex clinical scenario with significant implications for both maternal and fetal outcomes^1,2. Chorionicity has implications for differences in pathophysiology, risk to the surviving twin, and recommended management strategies.

IUD is more common in twin gestations than singletons, with monochorionic twin pregnancies exhibiting significantly higher risk due to the presence of inter-twin vascular anastomoses within the shared placenta^3,4. These vascular connections can result in acute hemodynamic shifts at the time of fetal demise, predisposing the surviving twin to hypoxic–ischemic injury, multiorgan compromise, or even death. By contrast, in dichorionic twins, the absence of inter-twin placental vascular connections typically isolates the surviving twin from direct physiological insult, though preterm birth may still occur.

ICD-10 classification: 031.2

The incidence of sIUD in twin pregnancies ranges from 0.5% to 6.8%^3,4, and is more commonly observed in monochorionic twin pregnancies, with an estimated incidence of 7.5%, compared to approximately 3% in dichorionic twins⁵. The risk of morbidity for the surviving co-twin is significantly greater in monochorionic gestations⁶. Following sIUD, monochorionic and dichorionic twin pregnancies are associated respectively with co-twin death (15% vs. 3%), preterm birth before 34 weeks (68% vs. 54%), abnormal postnatal cranial imaging (34% vs. 16%), neurodevelopmental impairment in the surviving twin (26% vs. 2%) and abnormal cranial imaging (34% vs. 16%)^7,8.

A retrospective cohort study by McPherson et al. evaluated 2,161 twin pregnancies to determine the impact of chorionicity on IUD and reported that monochorionic twins were at significantly increased risk for both single (aOR 1.69) and double IUD (aOR 2.11) compared to dichorionic twins⁹.

In dichorionic twin pregnancies, the demise of one fetus is often an isolated event, typically related to fetal structural anomalies, aneuploidy, or placental insufficiency. In such cases, the co-twin is usually unaffected physiologically, although risks of preterm birth still exist. Risk factors include advanced maternal age, smoking, assisted reproductive technologies, and chronic maternal diseases such as hypertension or diabetes.

In contrast, monochorionic twins face increased vulnerability due to the presence of placental vascular anastomoses, which facilitate acute inter-twin hemodynamic shifts. As a result, the demise of one twin may lead to hypotension, ischemia, or multiorgan injury in the surviving co-twin. The UKOSS prospective study demonstrated that the most frequently associated cause of sIUD in monochorionic twin pregnancies was twin–twin transfusion syndrome (TTTS) (47%), with the majority of these cases having undergone prenatal therapeutic intervention prior to the demise¹⁰. The second most common etiology was spontaneous sIUD (27%) with no identifiable underlying pathology such as TTTS, selective fetal growth restriction (sFGR), or congenital anomaly. Structural or congenital abnormalities accounted for a smaller proportion of cases, while sFGR was the least frequently identified cause¹⁰.

Despite intensive antenatal ultrasound surveillance, monochorionic twins may suffer from high risk of an unexpected fetal demise¹¹.

The timing of sIUD in twin pregnancies is clinically significant and often categorized to guide prognosis and management. A commonly used distinction places "early fetal demise" before 14 weeks’ gestation, typically representing a vanishing twin phenomenon, which generally carries minimal risk to the co-twin¹². In contrast, "late" or "second-trimester demise" refers to events after 14 weeks, when risks, particularly in monochorionic twins, escalate due to the potential for acute hemodynamic shifts through placental vascular anastomoses. It is speculated that in first trimester, the shared placental vascular anastomoses may not be functional or large enough to result in circulatory changes which cause hypoxic insults¹³. Although this 14-week cutoff is not biologically absolute, it is important for practical considerations in prenatal care, such as implications for serum screening and non-invasive prenatal testing (NIPT) using cell free fetal DNA¹⁴.

The pathophysiology of sIUD in multiple pregnancies differs significantly between monochorionic and dichorionic twin pregnancies due to the presence or absence of inter-twin placental vascular connections. In dichorionic pregnancies, where each fetus has a separate placenta, the demise of one twin rarely results in direct physiological harm to the surviving co-twin. The main clinical concerns in this setting involve obstetric risks including preterm birth.

In monochorionic twin pregnancies, however, the demise of one fetus creates a high-risk situation for the surviving twin due to placental vascular anastomoses. The previous school of thought blamed thromboembolic events causing toxins that could travel to the surviving co-twin and cause cerebral damage. However, more recently, most experts opine that sudden loss of circulation, resulting in low pressure system, in the deceased twin causes an acute hemodynamic shift through these shared placental vascular anastomoses, leading to hypovolemia, ischemia, and multi-organ hypoxic injury in the survivor. In their retrospective cohort of 49 monochorionic twin pregnancies with sIUD, Van Klink et al reported the incidence of cerebral injury as 26%¹³. This was slightly lower than that reported (34%) by Hillman et al in their meta-analysis⁷; this is likely attributable to differences in methodology regarding assessment of cerebral injury. The most common patterns of brain injury due to hypoxic insult secondary to sIUD is reported to be cystic periventricular leukomalacia, middle cerebral artery infarction and injury to basal ganglia/thalamus and cerebral cortex¹³. Nevertheless, central nervous system (CNS) injury is often under-recognised.  As reported by Morris et al (10),  antenatal imaging was performed in only 61% of cases of single intrauterine demise in monochorionic twins, yet 21% of those imaged had radiological evidence of neurological damage, Additional postnatal imaging revealed further CNS abnormalities, especially in those born before 36 weeks. However, evidence of cerebral injury on imaging may not always result in long term neurodevelopmental sequelae, hence the importance for long term neurodevelopmental follow up for these children so that appropriate therapy can be initiated where needed¹⁵.

In addition to neurological sequelae, cutaneous manifestations have also been described in surviving co-twins following intrauterine demise, most notably aplasia cutis congenita. Aplasia cutis congenita (ACC), particularly Type V ACC, is a recognized but uncommon complication in surviving co-twins following single intrauterine demise in multiple pregnancies, most frequently described in monochorionic gestations. It is characterized by well-demarcated areas of absent skin, typically affecting the trunk or scalp, and is thought to result from acute hemodynamic disturbances at the time of co-twin demise. The underlying mechanism is believed to involve transient hypoperfusion and ischemia of the skin secondary to sudden circulatory shifts through placental vascular anastomoses. Lesions are often symmetrical and may follow a vascular distribution pattern. Although ACC itself is primarily a cutaneous finding and may heal with conservative management, its presence may serve as a marker of more widespread ischemic injury. Therefore, identification of ACC in the surviving twin should prompt careful evaluation for associated neurological or systemic sequelae.

The clinical management of sIUD in twin pregnancies must be individualized, with chorionicity being the most critical determinant. Management goals include minimizing the risk of complications to the surviving fetus, balancing the risks of prematurity, and providing maternal support. When sIUD occurs in a twin pregnancy, the woman should be referred to a tertiary‐level center with relevant expertise⁸.

In a retrospective cohort study by Cimpoca et al. involving 6,225 twin pregnancies (4,896 dichorionic and 1,329 monochorionic) with two live fetuses at 11–13 weeks’ gestation, the study found that among pregnancies complicated by single fetal demise with a surviving co-twin, the rate of early preterm birth was substantially elevated in both monochorionic and dichorionic groups when compared to those with ongoing twin gestations¹⁶. Moreover, there was a significant inverse relationship between the gestational age at the time of demise and the latency to delivery: the average interval to delivery was approximately 19 weeks when demise occurred at 15 weeks, decreasing to just 2.5 weeks following a demise at 30 weeks’ gestation¹⁶.

In dichorionic twins, where each fetus has an independent placenta, the surviving twin is generally not at risk of direct hemodynamic injury. As such, the management is largely expectant, with regular ultrasound surveillance to monitor fetal growth, amniotic fluid volume, and wellbeing. Delivery may be deferred until term if no maternal or fetal complications arise. However, obstetric risks such as preterm birth may necessitate closer monitoring. Serial ultrasound scans are used to track any secondary complications, and MRI is not routinely indicated unless signs of neurological impairment are suspected.

In monochorionic twin pregnancies the demise of one twin represents a medical emergency for the co-twin, who is at risk of neurological damage (26%), multiorgan injury, or subsequent death (15%) due to the placental vascular anastomoses.

In monochorionic twin pregnancies complicated by sIUD, evaluation should include assessment of the middle cerebral artery peak systolic velocity (MCA-PSV), to assess fetal anemia in the surviving twin⁸. Conservative management is typically favored, especially in preterm gestations, as immediate delivery does not mitigate the risk of neurological injury, which often occurs at or near the time of the co-twin’s demise. If the pregnancy is close to term, timely delivery is appropriate; however, prior to this, prolonging gestation is generally recommended to optimize neonatal maturity.

Parental counseling must be thorough and non-directive, emphasizing the possibility of long-term morbidity, including neurological impairment, which may have already occurred. Short-term surveillance should include fetal heart rate monitoring and serial Doppler studies. If expectant management is pursued, fetal growth and Doppler evaluation (including umbilical artery and MCA) should be conducted every 2–4 weeks, with delivery considered between 34 and 36 weeks following maternal corticosteroid administration. MCA-PSV values >1.5 multiples of the median (MoM) may suggest anemia¹⁷, but their predictive value for cerebral injury is limited (sensitivity ~70%, false-positive rate ~40%). Neuroimaging, ideally fetal MRI or neurosonography, should be performed 4–6 weeks post-demise to evaluate for cerebral injury^8,18. A retrospective cohort study by Shinar et al assessed early imaging predictors of cerebral injury in monochorionic twin pregnancies complicated by spontaneous sIUD¹⁹. Among 47 fetuses undergoing brain MRI within a median of 5 days after sIUD, 34% demonstrated cerebral injury. Early MRI within two weeks of sIUD, particularly using diffusion-weighted imaging (DWI), proved valuable in identifying early ischemic changes. In 56.3% of cases with injury, DWI abnormalities were accompanied by changes on susceptibility-weighted and T2-weighted imaging. Notably, when initial DWI was normal and follow-up MRI was performed later, no ischemic injury was detected on T2-weighted imaging¹⁹. On the other hand, Segev et al. conducted a retrospective MRI-based cohort study and reported a low prevalence of structural brain lesions in surviving monochorionic twins following sIUD, with only one lesion detected that was missed on ultrasound²⁰. Based on these findings, the authors argued against routine use of fetal brain MRI; however, given that access to expertise in dedicated neurosonography may not always be available, MRI remains a valuable complementary tool for evaluating cerebral injury in such cases²¹.

In cases where significant neurological damage is confirmed or highly suspected, and where legally permissible, late termination of pregnancy may be discussed. Additionally, long-term neurodevelopmental follow-up, particularly at 2 years of age, is advised. While intrauterine transfusion (IUT) has been reported in cases of fetal anemia, its role in preventing long-term neurological sequelae remains unproven²². A recent systematic review by D’Antonio et al. including six studies of 78 monochorionic twin pregnancies complicated by sIUD and signs of fetal anemia found very low-quality evidence regarding the effectiveness of IUT²³. Due to the absence of matched comparative data and significant heterogeneity, the meta-analysis could not establish whether IUT improves survival or neurodevelopmental outcomes.

In triplet or higher-order gestations, management is further complicated by the number of fetuses and chorionicity configurations. Expert fetal medicine input is essential, and individualized  care plans should include detailed imaging protocols and referral to a tertiary center.

Though rare, maternal complications following sIUD such as intrauterine infection, were reported. In a UKOSS prospective observational study by Morris et al, maternal morbidity was notable, with 6% requiring intensive care due to infection related complications¹⁰.

In dichorionic twin pregnancies, outcomes for the surviving fetus are generally favorable, particularly when delivery is not prematurely indicated. In monochorionic twin pregnancies, the prognosis is guarded and highly dependent on the gestational age at demise, whether complicated by anemia in the surviving co-twin, timing of delivery, and neuroimaging findings. The absence of injury on ultrasound and MRI provides reassurance, but long-term follow-up is often needed to evaluate subtle developmental delays. A cohort study by Duyos et al. examining 68 monochorionic twin pregnancies with sIUD found cerebral injury in 20.6% of the surviving co-twins²⁴. The risk was higher following spontaneous sIUD (37.5%) compared to post-therapy cases (15.4%) (p=0.07). In their cohort, the key predictors of cerebral damage included later gestational age at demise (OR 1.21), presence of fetal anemia in the survivor (OR 9.27), and a trend toward increased risk in cases complicated by selective intrauterine growth restriction (OR 2.85; 95% CI 0.68–11.85; p=0.15). Most postnatal cerebral lesions were found to be associated with extreme prematurity.

Clear communication of the implications of chorionicity, gestational age, and imaging findings is essential. Parents should be informed about the role of serial neurosonography and fetal MRI in assessing the risk of cerebral injury, and the potential for delayed manifestations of neurological sequelae. Where brain injury is identified, neonatal neurology referral and long-term developmental follow-up are recommended.

In dichorionic pregnancies, reassurance regarding the typically isolated nature of the event may be appropriate, although counseling should still include discussion of preterm birth and maternal risks. The psychological toll of such events is considerable. Referral to bereavement counseling, perinatal mental health services, or support groups should be offered proactively.

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