Mediu intrauterin comun, evoluții diferite: enterocolita ulceronecrotică la gemeni

Introduction

Necrotizing enterocolitis (NEC) represents a gastrointestinal emergency of the neonatal period, and remains one of the leading causes of morbidity and mortality among preterm infants. The disease is characterized by acute intestinal inflammation, variable degrees of intestinal wall necrosis and, in advanced stages, perforation, peritonitis and sepsis^(1,2). Despite major advances in neonatal intensive care, NEC continues to have a significant impact on survival and long-term outcomes.

The global incidence is estimated at 1-3 cases per 1000 live births; however, it increases dramatically among preterm infants born before 32 weeks of gestation or with a birth weight below 1500 g, where it may reach 7-10%^(2,4). NEC accounts for approximately 5-10% of admissions to neonatal intensive care units among very low birth weight infants^(1,7). Approximately 20-40% of cases progress to severe forms requiring surgical intervention, and overall mortality ranges between 15% and 30%, exceeding 40% in complicated cases^(4,6).

In twin pregnancies, the risk of necrotizing enterocolitis is considered indirectly increased due to the higher incidence of prematurity, intrauterine growth restriction (IUGR) and placental complications. IUGR is associated with impaired mesenteric perfusion and deficient postnatal vascular adaptation, potentially predisposing to relative intestinal ischemia^(5,9). Small-for-gestational-age (SGA) neonates frequently exhibit fetal blood flow redistribution (the “brain-sparing effect”), which may chronically compromise intrauterine intestinal perfusion.

However, the literature describes a notable phenomenon: discordant occurrence of NEC in twins, where only one neonate develops the disease despite similar maternal and perinatal exposures^(8,11). This finding indicates the involvement of individual pathogenic mechanisms that extend beyond the effects of a shared intrauterine environment.

Twin gestations are associated with a significantly higher rate of prematurity compared to singleton pregnancies. More than 50% of twins are born before 37 weeks of gestation, and a substantial proportion have low birth weight. These factors indirectly heighten the susceptibility to NEC^(5,9).

Pathophysiology

Necrotizing enterocolitis is considered a complex multifactorial disease resulting from the interaction between intestinal immaturity, abnormal microbial colonization, exaggerated activation of the innate immune system and local hemodynamic factors^(2,7,12).

The premature intestine exhibits incomplete structural and functional development. The epithelial barrier is fragile, intercellular tight junctions are insufficiently matured, and mucus and secretory IgA production are reduced. Impaired intestinal motility promotes enteral stasis and bacterial overgrowth. These characteristics raise the susceptibility to bacterial translocation and excessive inflammatory activation^(7,12).

A central role in NEC pathogenesis is played by Toll-like receptors, particularly TLR4, which are overexpressed in the premature intestine. The activation of TLR4 by bacterial lipopolysaccharides triggers an intense inflammatory cascade, leading to the release of proinflammatory cytokines such as TNF-a and IL-6, inducing enterocyte apoptosis and compromising mucosal integrity. Furthermore, TLR4 activation inhibits intestinal stem cell proliferation, impairing the epithelial restorative capacity^(2,7). Instead of aiding in immune maturation, excessive activation leads to progressive intestinal wall injury.

Oxidative stress further contributes to enterocyte damage by increasing reactive oxygen species accumulation. In the premature intestine, antioxidant mechanisms are insufficiently developed, thereby amplifying tissue injury.

More recently, dysregulated intestinal angiogenesis has been implicated. Vascular endothelial growth factor (VEGF) and other proangiogenic factors may exhibit altered expression in the premature intestine, causing ischemic vulnerability^(7,12).

In twin pregnancies, subtle genetic or epigenetic differences may modulate the expression of these molecular pathways, which could account for the selective susceptibility observed in one twin.

The intestinal microbiota represents another essential component. Recent studies show that, prior to the clinical onset of necrotizing enterocolitis, microbial diversity decreases and Enterobacteriaceae predominate, accompanied by a decrease in protective commensal bacteria^(1,12,16). Dysbiosis may promote a proinflammatory environment and increased intestinal permeability. The existing data suggest associations between caesarean section delivery and the occurrence of NEC in twin neonates with low gestational age or very low birth weight; however, this relationship may be considered indirect and possibly attributable to the previously discussed dysbiosis^(13,14).

In addition to inflammatory mechanisms, intestinal ischemia substantially contributes to pathogenesis. Hypoperfusion secondary to perinatal hypoxia, hemodynamic instability or blood flow redistribution may cause mucosal injury, facilitating bacterial invasion^(3,5). Although isolated ischemia does not fully explain the disease, it remains an important co-determinant factor.

Prolonged early neonatal antibiotic exposure has been correlated with alterations in microbiota composition and increased NEC risk^(12,16). Red blood cell transfusion and associated hemodynamic instability have also been discussed as potential precipitating factors in certain cohorts⁽¹⁸⁾.

Nutrition plays a major role. Human milk has a well-documented protective effect due to its immunomodulatory factors, prebiotic oligosaccharides, lactoferrin and immunoglobulins. Formula feeding has been associated with an increased NEC risk^(10,12), likely through modulation of microbiota composition and intestinal inflammatory responses.

Among twins, these mechanisms may operate differently, even under seemingly similar conditions. Genetic variability, minor differences in placental perfusion and variations in postnatal cardiovascular adaptation may establish distinct biological substrates for each neonate.

Surgical versus non-surgical NEC

Bell’s staging classification is the clinical standard for necrotizing enterocolitis stratification⁽³⁾. Non-surgical forms, corresponding to stages I and II, are characterized by abdominal distension, feeding intolerance, bilious vomiting and radiological evidence of pneumatosis intestinalis. The treatment is conservative, and includes bowel rest, broad-spectrum antibiotic therapy, parenteral nutrition and hemodynamic support^(6,9). The prognosis is favorable in the absence of major systemic complications.

In contrast, surgical necrotizing enterocolitis (Bell stage III) is identified by rapid clinical deterioration, refractory metabolic acidosis, hemodynamic instability and pneumoperitoneum, indicating intestinal perforation^(6,8). The surgical management involves exploratory laparotomy, segmental resection and often temporary enterostomy. These forms are associated with higher mortality and long-term complications, including short bowel syndrome, cholestasis and neurodevelopmental impairment^(4,6,17).

Identifying predictive biomarkers for severe NEC is an important research direction. Elevated levels of procalcitonin, IL-6 and C-reactive protein have been associated with more severe disease^(6,16). Other studies have evaluated intestinal fatty acid-binding protein (I-FABP) as a marker of early enterocyte injury⁽¹⁹⁾.

In cases progressing to surgical intervention, persistently elevated inflammatory markers and progressive metabolic acidosis have been observed^(18,19). However, no biomarker currently demonstrates sufficient predictive value to decisively guide surgical timing.

Early differentiation between forms that will progress to surgical necrotizing enterocolitis and those responsive to conservative treatment is a major clinical challenge, and predictive biomarkers are still insufficiently validated^(18,19).

NEC in twins

In twin pregnancies, necrotizing enterocolitis may occur concordantly or discordantly. The literature suggests that discordant involvement is more frequent, particularly in dichorionic pregnancies, where each fetus has an independent placental circulation^(8,11). This reduces the risk of inter-fetal hemodynamic complications characteristic of monochorionic pregnancies, but does not entirely exclude differences in perfusion or vascular development.

In monochorionic pregnancies, complications such as twin-to-twin transfusion syndrome may contribute to hemodynamic imbalances, influencing the NEC risk. In contrast, in dichorionic pregnancies, the mechanisms appear predominantly individual^(8,9). Birth weight discordance, differences in immediate cardiorespiratory adaptation and distinct microbial colonization patterns may explain the differential susceptibility. Even in seemingly identical environments, intestinal microbiota may rapidly diverge during the first days of life, leading to different inflammatory responses, influenced by feeding type, antibiotic exposure and contact with medical personnel^(12,15,20).

Materials and method

The following presents a retrospective observational study conducted in the Neonatology Department of the „Elias” Emergency University Hospital, Bucharest, Romania, on a sample of 26 neonates originating from twin pregnancies (13 pairs), carried out over the period 2015-2025.

The analyzed neonatal variables included gestational age, sex, mode of delivery, type of chorionicity, birth weight, growth status (SGA/AGA/LGA), the Apgar score at 1 minute, admission to the neonatal intensive care unit (NICU), neonatal antibiotic therapy, as well as the presence of digestive pathology (Table 1).

In the comparative analysis of data within twin pairs, no significant differences were identified in either the distribution of birth weight, or the rate of admission to neonatal intensive care, suggesting a relatively similar neonatal course within each pair (Figures 1 and 2).

Of the 26 neonates, three (11.5%) presented with digestive pathology. The cases were discordant within twin pairs. Admission to the NICU and neonatal antibiotic therapy were more frequently associated with digestive pathology (Table 2). Although neonatal antibiotic therapy was statistically associated with digestive pathology, antibiotics were administered in response to the clinical condition rather than preceding disease onset, thus reflecting neonatal severity rather than causation. Maternal factors such as maternal age, hospitalization duration, antibiotic therapy and maternal-fetal infection risk did not reach the statistical significance. However, trends toward longer maternal hospitalization and higher antibiotic exposure in the pathology group were observed (Figure 3), which may reflect more complex pregnancies or perinatal conditions that could indirectly influence neonatal adaptation.

The statistical analysis of the cohort demonstrated predominantly homogeneous neonatal outcomes within twin pairs, with no significant differences in birth weight distribution or NICU admission rates. In contrast, three cases exhibited a distinct clinical course, characterized by digestive pathology in only one twin. Given their unique characteristics and potential implications for understanding individual susceptibility mechanisms, each of these three discordant cases will be presented in detail.

Case 1

A 30-year-old G2P2 woman delivered diamniotic, dichorionic term twins at 38 weeks of gestation by caesarean section. The pregnancy was uneventful, with no significant maternal risk factors. Antenatal ultrasound revealed a thin layer of ascitic fluid in Twin 1.

Twin 1. A female neonate, with birth weight of 2580 g (small for gestational age; SGA), cephalic presentation, with an Apgar score of 9 at 1 minute, exhibited a good initial neonatal transition. At 36 hours of life, she developed an altered clinical status characterized by progressive abdominal distension, decreased reactivity and passage of meconium. Her condition deteriorated, with marked abdominal distension, visible venous collateral circulation, abdominal tenderness and diminished bowel sounds. Abdominal radiography demonstrated pneumoperitoneum. The neonate was transferred to a tertiary pediatric surgical center, where exploratory surgery confirmed meconium peritonitis secondary to a congenital intestinal anomaly. An ileostomy was performed. The case evolved as a surgical abdominal emergency, initially mimicking necrotizing enterocolitis.

Twin 2. A male neonate, with birth weight of 2490 g (SGA), breech presentation, with an Apgar score of 8 at 1 minute, had an uncomplicated postnatal adaptation. He developed physiological neonatal jaundice requiring phototherapy. The infant was discharged on the seventh day of life in good clinical condition.

Case 2

A 34-year-old G2P2 woman delivered diamniotic, dichorionic preterm twins at 36 weeks of gestation by caesarean section. The pregnancy was complicated by chronic arterial hypertension and hypothyroidism. Antenatal corticosteroid therapy (dexamethasone) for fetal lung maturation was administered at 28 weeks of gestation.

Twin 1. A male neonate, with birth weight of 2720 g (appropriate for gestational age; AGA), with an Apgar score of 9 at 1 minute, initially demonstrated good adaptation. At 72 hours of life, he developed abdominal distension and tenderness, absence of stool and gas passage and episodes of reversible apnea. Multiple episodes of bilious vomiting were noted. Laboratory investigations revealed severe leukopenia with neutropenia and markedly elevated procalcitonin levels (42 ng/mL), denoting a severe inflammatory response. Abdominal ultrasonography showed gastric and intestinal distension with thickened, edematous bowel walls. Pediatric surgical consultation raised the suspicion of intestinal obstruction, and the infant was transferred to a surgical center for further management. This presentation was highly suggestive of complicated NEC with potential surgical evolution, given the systemic inflammatory response and imaging findings.

Twin 2. A female neonate, with birth weight of 2120 g (AGA), with an Apgar score of 8 at 1 minute, required positive pressure ventilation with a T-piece resuscitator and brief inotropic support immediately after birth. She was subsequently stabilized, without the requirement for continuing respiratory or cardiovascular support. Enteral feeding was well tolerated. She developed neonatal jaundice treated with phototherapy, being discharged on day 13 of life in good clinical condition.

Case 3

A 28-year-old G2P2 woman delivered diamniotic, dichorionic term twins at 38 weeks of gestation vaginally. The pregnancy was complicated by gestational diabetes mellitus, well controlled with dietary measures.

Twin 1. A male neonate, with birth weight of 2950 g (SGA), in cephalic presentation, with an Apgar score of 8 at 1 minute, developed neonatal hypoglycemia within the first 30 minutes of life. At 24 hours of life, he presented with progressive abdominal distension, audible bowel sounds, poor tolerance to enteral feeding, minimal meconium passage and metabolic acidosis. Pediatric surgical consultation excluded an acute surgical abdomen. The clinical course worsened, and blood cultures were positive for Klebsiella pneumoniae, consistent with early-onset neonatal sepsis. Point-of-care abdominal ultrasonography confirmed necrotizing enterocolitis, Bell stage II. The infant experienced a severe but non-surgical evolution, defined by persistent inflammatory marker elevation, recurrent positive blood cultures, cholestatic jaundice and neurological involvement. Conservative management was pursued. He was discharged after 38 days of hospitalization.

Twin 2. A male neonate, with birth weight of 2640 g (SGA), in breech presentation, with an Apgar score of 9 at 1 minute, had an uncomplicated neonatal course. He developed physiological jaundice requiring phototherapy, being discharged on the fourth day of life in good condition.

Discussion

The presented cases demonstrate a consistent pattern of discordant gastrointestinal involvement in dichorionic twin pregnancies. Despite comparable maternal factors and gestational age, only one twin in each case developed severe intestinal pathology.

In Cases 1 and 2, only one twin developed severe gastrointestinal disease necessitating surgical evaluation, whereas the co-twin experienced an uncomplicated neonatal course. This discordant progression indicates that, in addition to shared prenatal influences, personal susceptibility – such as differences in intestinal perfusion, microbiome colonization, immune response variability and subtle hemodynamic imbalances – plays a central role in NEC pathogenesis.

Even in dichorionic, diamniotic twins with separate placental circulations, intrauterine growth restriction (SGA status observed in several neonates) may indicate placental insufficiency and chronic fetal hypoxia, both recognized contributors to intestinal mucosal vulnerability. The absence of NEC in the co-twin further emphasizes the multifactorial and individualized nature of the disease.

In Case 3, early-onset neonatal infection with Klebsie­lla pneumoniae preceded the NEC presentation, suggesting that bacteremia may serve as a triggering factor in a vulnerable intestine. In other cases, minor differences in hemodynamic adaptation or early intestinal colonization may have contributed to disease development.

These observations support the hypothesis that necrotizing enterocolitis arises not only from shared maternal or placental exposures, but also from a complex interplay between personal susceptibility and postnatal surrounding factors. In dichorionic pregnancies, independent placental circulation further substantiates the existence of distinct pathogenic mechanisms for each fetus.

Prognosis and long-term
complications

Survivors of NEC – particularly those with surgical forms – are at increased risk of long-term complications. Short bowel syndrome may require prolonged parenteral nutrition, associated with cholestasis and liver dysfunction^(4,6).

Furthermore, severe systemic inflammation during the neonatal period has been associated with an increased risk of neurodevelopmental impairment, including cognitive and motor deficits⁽¹⁵⁾. This under­scores that necrotizing enterocolitis is not solely an intestinal disorder but a systemic condition with widespread impact.

Consequences for clinical practice

When necrotizing enterocolitis occurs in one twin, careful monitoring of the apparently healthy co-twin is justified, although the literature does not support automatic concordant involvement. Repeated clinical evaluation, surveillance of feeding tolerance and monitoring of inflammatory markers may facilitate the early detection of potential disease onset.

Preventive approaches are important, including promoting human milk feeding, judicious antibiotic use and optimizing circulatory stability.

Conclusions

Necrotizing enterocolitis is still a complex, multifactorial disease with mechanisms that are not yet fully understood. It results from the interplay among intestinal immaturity, dysbiosis, excessive immune activation and ischemic factors. In dichorionic twin pregnancies, discordant evolution underscores the critical role of personal susceptibility.

This study was limited by a relatively small sample size, which constrained the detection of multiple statistically significant associations. However, the results indicate that, even within a shared intrauterine environment, neonatal digestive pathology may develop along distinct individual trajectories, as demonstrated by discordant twin cases. Additional prospective multicenter studies examining inflammatory markers, microbiota profiles and potential genetic differences between twins are required to elucidate these mechanisms and inform the development of personalized preventive and therapeutic strategies to reduce NEC-associated morbidity and mortality.

Autor corespondent:  Smit Bharat Solanki E-mail: drsmitbharat@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.