Meconium abnormalities in neonates may cause intestinal obstructions that vary widely in severity, ranging from transient functional ileus to meconium ileus with cystic fibrosis, and meconium plug syndrome (MPS). MPS is characterized by a low-level intestinal obstruction. The course is typically benign, and the plug is eliminated via rectal stimulation or contrast enema [1-4]. MPS can be associated with motility disorders including Hirschsprung’s disease and cystic fibrosis [5,6]. Meconium obstruction of prematurity (MOP) is a clinical entity distinct from meconium ileus and MPS in term neonates [1-4]. The number of extremely low-birth-weight (LBW) neonates with MOP and intestinal perforation has been increasing because more extremely LBW neonates survive and the live-birth rate of such infants has increased [7,8]. MOP develops in very LBW infants who develop obstructive symptoms several days after initially passing some meconium [3,7,9]. MOP is not associated with any underlying disease such as congenital bowel obstruction, necrotizing enterocolitis (NEC), or hypothyroidism [3,7,9,10]. MOP in preterm infants is caused by the high viscousness of the meconium and poor bowel motility associated with ganglion immaturity [8-11]. If the sticky meconium fails to progress, it causes bowel obstruction and feeding cannot be ensued [7]. MOP can be complicated by bowel ischemia or increased mucosal permeability, progressing to perforation, NEC, or sepsis [9,10,12,13]. MOP is associated with high-level morbidity or mortality, associated with prolonged hospitalization if not diagnosed and treated appropriately [1].

The modalities used to diagnose bowel obstruction, follow-up, and treat meconium plugs and uncomplicated meconium ileus include plain radiography and contrast enema [2,3,14-17]; these are based principally on low-quality evidence and expert opinion [18]. Water-soluble contrast media are hyperosmolar and can loosen a tenacious meconium by drawing large volumes of fluid into the bowel, freeing the meconium and allowing it to pass through the rectum [14]. This also promotes bowel peristalsis [19]. Although water-soluble contrast enemas are increasingly given to preterm infants, the overall success rate is only 36% to 54.5%, and large amounts of contrast media are required [15-17,20,21]. If medical treatments fail or a bowel perforation develops, surgery is needed. In surgically managed patients, 50% to 83% of all perforations were in the distal ileum. Standard medical therapy is less effective in such infants because the enema may not attain the obstructed area [1,7].

We speculate that oral nonionic water-soluble contrast media loosen the meconium and promote peristalsis. We administered oral contrast media to seven clinically diagnosed MOP patients whose obstructions were not relieved via conventional management, to avoid risky surgery. We retrospectively evaluated whether oral nonionic water-soluble contrast media relieve MOP.

Our Institutional Review Board approved this retrospective study. A total of 385 LBW premature infants were admitted to the neonatal intensive care unit from June 2015 to January 2019. Of these, 67 (17.4%) were clinically and radiologically diagnosed with MOP [3,7,9,10,15]. All the infants had no NEC and weighed less than 1,500 g. Fifty-four patients improved on medical treatment, two underwent surgery due to bowel perforation or unresolved bowel distention. Nine underwent contrast enema (four successful and five failure to treat MOP). Seven (7/67, 10.4%; five failed contrast enema and two oral contrast media only) were managed using oral contrast media (Omnipaque350, GE Healthcare, Shanghai, China; 844 mOsm/kg water).

Premature infants in the neonatal intensive care unit were managed using glycerin and warm saline enemas to prevent the development of meconium-related disease. Abdominal ultrasonography (US) and plain radiography were performed for all MOP patients. Prior to administration of oral contrast media, five patients received sonography-guided water-soluble contrast enemas (cases 1–3, 6, 7) (Iomeron 300, Bracco, BIPSO GmbH, Germany; 521 mOsmol/kg water) to ensure that the contrast media reaches the ileum. This was not effective in all five patients; therefore, contrast media were administrated orally via a gavage tube. Two patients with gasless abdomens received oral contrast enemas as initial treatment.

Prior to contrast administration, all patients underwent US to rule out NEC and any other bowel abnormality. To ensure that the contrast medium reached the loops of the distal small bowel, the contrast medium was injected manually via a gavage tube in the right anterior oblique position of the infant. The amount of contrast media was equivalent to a feed. Follow-up radiographs were routinely taken 6 and 24 hours after the procedure to evaluate bowel distention and evacuation of the contrast media. We recorded the intervals from birth to initial symptom onset, from birth to the procedure, and from the procedure to radiographic improvement, meconium evacuation, and commencement of enteral feeding. We obtained demographic data, maternal histories (presence of pre-eclampsia/eclampsia, gestational diabetes mellitus [GDM], premature rupture of membranes, chorioamnionitis, oligohydramnios, MgSO₄, or steroid administration during pregnancy, and mode of delivery), and neonatal clinical data (small for gestational age [SGA], patent ductus arteriosus [PDA], and respiratory distress syndrome [RDS]) from medical records.

Patient demographics and outcomes of oral contrast media treatment are listed in Table 1. MOP presented as abdominal distention, poor passage of meconium, and feeding intolerance. MOP was diagnosed when a persistent or progressive gaseous bowel distension was noted on plain radiography, together with hypoechoic meconium-filled bowel loops and distended proximal bowel loops on US without NEC (n=5). Two infants had gasless abdomens, in which only the stomach gas was visible, and US showed meconium- filled bowel loops (n=2). Included patients did not exhibit NEC clinically and radiologically.

We administered the oral contrast media to five male and two female infants. The gestational ages and body weights (median [interquartile range, IQR]) at birth versus at the time of oral contrast media administration were 27⁺⁵ weeks (IQR, 24⁺⁶ to 29⁺²) and 890 g (IQR, 660 to 1,055) versus 28⁺¹ weeks (IQR, 26⁺¹ to 29⁺⁵) and 822 g (IQR, 610 to 1,040), respectively. The median age of MOP diagnosis was 7 days (IQR, 3.5 to 8.5). Two (28.6%) infants were SGA. RDS (7/7), PDA (6/7), grade 4 germinal matrix hemorrhage (2/7), and pneumothorax (3/7) were associated with the perinatal period. Pre-eclampsia (4/7) was the most common maternal risk factor; GDM, chorioamnionitis, and oligohydramnios were also associated with MOP. Five of the seven (71.4%) infants had maternal risk factors and one a history of both maternal GDM and pre-eclampsia.

Two mothers had received MgSO₄, and five mothers had received antenatal corticosteroids. Six (85.7%) infants were born via emergency cesarean section, and one via premature spontaneous vaginal delivery.

Radiography revealed multiple distended intestinal loops without air-fluid interfaces in five cases (cases 1–3, 6, 7) (Figure 1). Two exhibited gasless abdomens, in which only stomach gas was visible (cases 4, 5) (Figure 2). Oral contrast medium (median, 2.5 mL [IQR, 2.25 to 4]) was administrated at a median age of 8 days (IQR, 6 to 9). MOP was relieved in five patients (71.4%). Two infants developed vomiting without contrast media progression to the distal bowel loops and were managed surgically. Two infants were diagnosed as having ileal stenosis with microperforation (patient 6) or hypoganglionosis (patient 7). Meconium was evacuated within 1 day in three patients, 2 days in one, and 4 days in one. Feeding commenced within 1 day in two patients, 2 days in two, and 7 days later in one. Radiographic improvements were apparent within 1 day in three patients, 3 days in one, and 5 days in one.

Meconium obstruction in a LBW infant ranges from mild functional ileus to a perforation. The incidence of MOP is unclear but is increasing [1,15,21]. We found that MOP occurred in 17.4% of LBW infants.

The differential diagnosis of MOP includes NEC, meconium ileus, Hirschsprung’s disease, and intestinal atresia. NEC may clinically resemble MOP. The former is triggered by ischemia due to inspissated meconium syndrome, which is a severe prolonged distention proximal to the meconium obstruction. Meanwhile, the pathophysiology of MOP is unclear. Apart from immaturity of the ganglia, weak peristalsis and excessive water absorption in a hypoperistaltic bowel before birth may render the meconium inspissated [1,8-11]. Pre- and perinatal risk factors include any condition causing perinatal intestinal hypoperfusion and factors associated with intestinal dysmotility and stasis [2,9]. Fetal hypoglycemia causes excess glucagon production, in turn decreasing bowel motility [1]. Maternal hypertension and preeclampsia/eclampsia may trigger prenatal intestinal hypoperfusion [2,9]. GDM and hypermagnesemia are associated with functional obstruction in premature infants, attributed to depression of intestinal smooth muscle activity and delayed peristalsis [1,2,9]. Having a lower body weight at birth or at the time of the contrast enema (SGA) reduces the success rate of contrast enema [17]. Five of the seven (71.4%) infants exhibited maternal risk factors, one of which had a combination of maternal GDM and pre-eclampsia. However, the relationship between risk factors and MOP and the optimal treatment remain to be investigated.

MOP should be clinically suspected when a preterm infant ineffectively passes a meconium and exhibits progressive abdominal distention and feeding intolerance despite administration of a glycerine enema [1,15]. Prompt recognition and early aggressive medical treatment are essential to prevent surgical intervention. Perforation develops if the obstruction is not relieved. Delayed diagnosis and an inspissated meconium in the distal ileum are common in infants who develop perforations [1].

The use of plain radiography to diagnose large bowel obstruction, followed by hyperosmolar contrast enema for follow-up and treatment, is acceptable. Treatment of meconium-related disease is based principally on consensus opinion of low-quality evidence [18]. A sonography-guided water-soluble contrast enema remains the treatment of choice to relieve the obstructions in meconium-related diseases including MPS, MOP, and meconium ileus [1-3,14-17]. This treatment is both non-invasive and effective. Success depends on the reflux of contrast media into the distal ileum, where an inspissated meconium is located most frequently [1,17]. Garza-Cox et al. [1] reported that 38% of obstruction sites were in the distal ileum and 10% in both the distal ileum and colon. Reflux of contrast medium into the distal ileum is a significant predictor of success but does not occur in all cases [15-17,20,21], requiring repeat enemas. Although water-soluble contrast enemas are increasingly used to treat preterm infants, the overall success rate is only 36% to 54.5%, and a large amount of contrast medium is required [15-20]. If medical treatments fail or a bowel perforation develops, surgery is required. Of MOP patients, 9% to 50% require surgery, and 50% to 83% of obstructions occur in the distal ileum [1,2,17]. Standard medical therapy is less effective in such infants because the enema may not reach the obstructed area [1,7]. Apart from the ileum, surgically managed patients had obstructions in other small bowel loops and the associated microcolon, which are not resolved via repeated contrast enemas; 38% to 43% exhibit an abnormal bowel histopathology [1,2,5-7]. In this study, two patients (28.6%) who were surgically managed had abnormal bowel histopathology.

Oral agents are potential adjuncts to enemas. Greenholz et al. [2] administered 10% oral acetylcysteine for 2 weeks to an infant who underwent a gastrografin enema. N-acetylcysteine given via an orogastric tube, as advocated by Noblett [14], reduced stool viscosity by 99% after 6 hours [22]. Water-soluble contrast media are hyperosmolar;they pull fluid into the intestinal lumen, which hydrates and softens the meconium mass [20,23] and promotes bowel peristalsis [19]. We used an undiluted contrast media with an osmolarity higher than that of normal plasma. We speculate that oral contrast media can assist patients with MOP who do not respond to conventional contrast enemas or in whom the meconium is located in small bowel loops. In an effort to avoid the need for surgery, we tested small amounts (median, 2.5 mL, equivalent to a feed) of oral contrast media and found that 71.4% of patients improved, and 42.9% of patients evacuated meconium within 1 day and 57.1% within 2 days. Enteral feeding commenced within 2 days in 57.1% of responding patients. Oral contrast administration is simple and useful in treating patients with a meconium in the small bowel.

Our study had limitations. It was a single-center, non-controlled retrospective study with a small number of patients. Therefore, a multicenter prospective study with a large number of patients is needed. The contrast media in this study was hyperosmolar. So far, there has been no consensus on the dose and concentration of contrast media in premature infants, requiring further studies.

In conclusion, oral water-soluble contrast media are useful to treat premature infants with meconium obstructions. The procedure has a very low-risk, and we used much less contrast medium than employed for a contrast enema.