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Development of necrotizing enterocolitis in neonatal patients treated with diazoxide
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Accepted: ,
How to cite this article: Cline JC, Rivera AM. Development of necrotizing enterocolitis in neonatal patients treated with diazoxide. J Pediatr Endocrinol Diabetes. doi: 10.25259/JPED_19_2026
Abstract
Neonatal hypoglycemia has a few possible underlying etiologies, the most common of which is hyperinsulinemia. Diazoxide is often used in the management of hypoglycemic hyperinsulinemia. It has been well-documented to cause potential fluid retention, pulmonary hypertension, and mild thrombocytopenia, although other adverse events have not been commonly reported. Here, we present two cases of necrotizing enterocolitis following diazoxide use in neonatal patients. Through these case studies, the authors describe an uncommon potential adverse effect of diazoxide and add to the limited reported data surrounding its use to further inform decision-making in this vulnerable population.
Keywords
Diazoxide
Hyperinsulinemia
Hypoglycemia
Necrotizing enterocolitis
Neonate
INTRODUCTION
Transient neonatal hypoglycemia is a common issue after birth, often related to the transition from a continuous supply of glucose from the placenta to intermittent enteral feeding. Persistent hypoglycemia may be due to inadequate glycogen stores related to prematurity or fetal growth restriction, impaired glucose production secondary to inborn errors of metabolism, endocrine disorders, and/or increased glucose utilization because of hyperinsulinemia.[1]
Diazoxide is used to treat hypoglycemic hyperinsulinemia (HH) due to its ability to inhibit insulin release from pancreatic beta cells through its effect on adenosine triphosphate-sensitive potassium channels. While diazoxide has been proven to be an effective first-line option for the underlying causes of hyperinsulinemia, it does not come without potential adverse effects (AEs).[1] The antidiuretic properties may lead to significant fluid retention and respiratory decompensation, so thiazide diuretics are often co-prescribed.[2] In the past decade, cases of severe AEs, including pulmonary hypertension and congestive heart failure, have been reported, leading the Food and Drug Administration (FDA) to release a black box warning for its use.[3-5] As one of the few pharmacologic options for hyperinsulinemia in neonates, diazoxide is utilized despite the potential of these high-risk, though uncommon, effects.
In addition to these known AEs, there have been a handful of case studies reporting incidents of necrotizing enterocolitis (NEC) following administration of diazoxide. Diazoxide hyperpolarizes smooth muscle cells and closes the L-type calcium channels to cause smooth muscle relaxation. This has been theorized to result in cessation of spontaneous and rhythmic intestinal activity and may potentially be a mechanism for gut dysmotility in diazoxide-treated patients.[2,4]
This case series aims to add to the limited body of data surrounding diazoxide-exposed neonates who developed NEC and further inform decision-making surrounding its use.
CASE SERIES
After an instance of NEC following diazoxide exposure, an internal report was run to identify neonatal patients who received diazoxide while admitted to the neonatal intensive care unit (NICU) from 2015 to 2025. Of the six patients identified, two (33%) developed NEC.
Patient A
A male infant born at 36 weeks and 0 days (2810 g) due to non-reassuring fetal heart tracing (NRFHT) was admitted to the NICU for intermittent apnea. The birth history was complicated by reversed end-diastolic flow on the umbilical artery Doppler study and a fetal diagnosis of trisomy 21 (T21) confirmed with postnatal karyotype. An echocardiogram on admission showed a moderate to large patent ductus arteriosus (PDA), which remained pharmacologically untreated, and signs of persistent pulmonary hypertension, though the patient remained hemodynamically stable in room air.
While in the NICU, the patient experienced hypoglycemia initially managed with 12.5% dextrose in water intravenous (IV) fluid and a transition from bolus orogastric tube feedings to a continuous infusion of maternal breastmilk fortified to 30 kcal/oz. He remained hypoglycemic despite administrations of glucose gel and IV boluses of 10% dextrose in water, ultimately requiring increased IV dextrose to a glucose infusion rate of >15 mg/kg/min (up to 21 mg/kg/min) for 5 days. Critical laboratory tests, including insulin levels, were not obtained due to continued glucose exposure, despite suspicion of HH. Because of ongoing glucose requirements, diazoxide was initiated on day of life (DOL) 4 at 10 mg/kg/day, divided every 8 h, along with chlorothiazide.
Hematochezia developed 3 days after initiation of diazoxide. Imaging confirmed Bell’s Stage IIA NEC with thrombocytopenia (platelet count 34,000/µL) without acidosis or presence of pneumoperitoneum. NEC was treated with antibiotics, a Replogle drain to suction, and bowel rest, at which time all enteral therapies, including diazoxide, were discontinued. Hematochezia and associated thrombocytopenia resolved within 24 h of bowel rest, and pneumatosis resolved within 48 h. The Replogle drain was removed after 7 days, and trophic feeds were initiated. Antibiotic therapy was continued for 10 days. Following completion of NEC management, the patient maintained euglycemia without diazoxide and gradually increased enteral feeds, suggesting that, if present, hyperinsulinism (HI) was transient. He was discharged on DOL 42 with ad lib feedings of a mix of 22 kcal/oz fortified maternal breastmilk and formula.
Patient B
A male infant born at 27 weeks and 4 days (1220 g) through emergent cesarean section due to maternal hypertensive crisis, cardiomyopathy, and NRFHT was admitted to the NICU. The antenatal course was also complicated by maternal class 3 obesity without the presence of diabetes. He had pancytopenia and hypoglycemia at delivery, consistent with intrauterine conditions, but he continued to have intermittent hypoglycemia requiring continuous orogastric tube feeds of donor breastmilk fortified to 27 kcal/oz.
Feeds were held to obtain critical sample laboratories on DOL 34 with a serum glucose level of 44 mg/dL, resulting in an insulin level of 10.3 µIU/mL, beta-hydroxybutyric acid of 0.24 mmol/L, and ammonia level of 148 µmol/L, biochemical features suggestive of hyperinsulinemia/hyperammonemia (HI/HA). Cortisol was within normal limits, and growth hormone was 4.1 ng/mL.
With a pediatric endocrinologist’s recommendation, the patient was placed on a leucine-restricted diet and supplemented with medium-chain triglyceride oil, in addition to unfortified donor breastmilk. Diazoxide was initiated at 10 mg/kg/day, divided every 8 h on DOL 36 and increased to 15 mg/kg/day on DOL 39. Chlorothiazide was started concomitantly. Eight days after initiation of diazoxide, the patient developed abdominal distention. An abdominal ultrasound confirmed Bell’s Stage IIA NEC with extensive pneumatosis throughout the bowels, which continued to worsen despite initiation of antibiotics, bowel rest, and the placement of a Replogle drain. Due to an abrupt worsening of pneumatosis on serial ultrasounds, the patient was transferred to a tertiary center for surgical management.
At the outside hospital, he received 10 days of medical management before requiring an ileocecal resection and primary end-to-end ileocolonic anastomosis. Following surgery, the patient remained off diazoxide and received parenteral nutrition as he worked up to full feeds, indicating that hyperinsulinemia was possibly transient. On DOL 101, he was discharged home on ad lib feedings of 22 kcal/oz of elemental formula without the need for endocrinology follow-up.
Table 1 summarizes the clinical profile of patients A and B, compared with other patients treated with diazoxide who did not develop NEC.
| Patient | A | B | C | D | E | F |
|---|---|---|---|---|---|---|
| Gestational age | 36 weeks 0 days |
27 weeks 4 days |
39 weeks 0 days |
36 weeks 0 days |
37 Weeks 1 day |
37 weeks 0 days |
| Birth weight | 2810 g | 1220 g | 3390 g | 2855 g | 3700 g | 1895 g |
| Diazoxide total daily dose (Maximum) | 10 mg/kg | 15 mg/kg | 9 mg/kg | 10.5 mg/kg | 8 mg/kg | 15 mg/kg |
| Concomitant chlorothiazide | Yes | Yes | Yes | No | No | No |
| Feeds† | 26 kcal/oz MBM with HMF and/or term formula | 27 kcal/oz MBM/DBM with HMF; Leucine restriction | 24 kcal/oz term formula | 30 kcal/oz term formula | 27 kcal/oz MBM/DBM with HMF and/or term formula | 27 kcal/oz term formula |
| Comorbidities | REDF; PDA; T21; RDS | VLBW; RDS | MAS; PPHN; PDA; RDS | Beckwith- Wiedemann Syndrome | RDS; VUR | SGA; PDA; PPHN; cholestasis; RDS |
| NEC Onset (DOL) | 7 | 44 | N/A | N/A | N/A | N/A |
DISCUSSION
Diazoxide remains the first-line agent and only FDA-approved option for hyperinsulinemia in neonatal patients, and although rare, AEs must be considered before initiation. Proposed mechanisms that increase the risk of NEC include decreased gut motility and reduced anti-inflammatory vagal tone, resulting from inhibition of acetylcholine release.[3,6] In addition to decreased gut motility, another explanation is a possible decrease in splanchnic perfusion, a mechanism described in patients with HH who received octreotide.[3] There is no definitive association between diazoxide and NEC, though three prior publications describe NEC in 16 patients in total.[2-4]
The first report of a potential association was a 2020 case report by Theodorou and Hirose who described a neonate delivered at 35 weeks and 3 days by cesarean section who experienced IV dextrose-dependent hypoglycemia. The patient was started on diazoxide at 3 mg/kg/day on DOL 17 and gradually increased to 16 mg/kg/day over the following 11 days. On DOL 32, the patient developed abdominal distention with imaging revealing pneumatosis intestinalis, requiring bowel rest and 10 days of antimicrobial therapy.[3]
Prado et al. reported that seven (13%) patients developed NEC after initiation of diazoxide in their multicenter retrospective cohort study (n = 55). During the 5-year study period, the institutional protocol recommended initiating diazoxide 10 mg/kg/day for persistent hypoglycemia.[4] The average time from diazoxide initiation to NEC development was approximately 5 days. Of the patients who developed NEC, four were medically managed, one was treated surgically, and the final two patients died from fulminant NEC. NEC was more common in diazoxide-treated neonates when compared to those who did not receive diazoxide (odds ratio [OR] 5.07, 95% confidence interval [CI] 2.27–11.27; p < 0.001) and with the highest OR seen in patients 33–36 weeks of gestation (OR 13.76, 95% CI 3.77–50.23; p < 0.001).[4]
Finally, a 2021 retrospective cohort study by Keyes et al. reported that 5 patients (20%) who received diazoxide for the management of neonatal HH developed NEC. These patients were born at a younger gestation (36.6 weeks vs. 37.1 weeks, p = 0.03), had lower birthweight (2080 g vs. 2930 g, p = 0.04), and received formula less frequently (60% vs. 100%, p = 0.04) than those who did not. They found no difference in NEC risk factors or etiology of HH between groups, though the dose of diazoxide was not reported.[2]
Summaries of previously reported incidents mirror what was observed in our patients. Among the four patients exposed to diazoxide who did not develop NEC, no distinctive risk factors were identified [Table 1]. Causality assessment using the Naranjo adverse drug reaction scale yielded a score of 3, indicating NEC is a possible adverse drug reaction of diazoxide in neonates.[7]
One limitation of our review was the potential impact of prompt escalation of both caloric density and feeding volumes. Escalation of feeding support to mitigate hypoglycemia may have confounded the association between diazoxide and NEC development. Similarly, additional risk factors for NEC, including the presence of PDA, reverse-end diastolic flow, and confirmed T21, cannot be stratified due to the scope of this report, which may have led to overinterpretation attributed solely to diazoxide exposure.
CONCLUSION
We report two instances of NEC following initiation of diazoxide in neonatal patients. Although this case series cannot confirm an association between diazoxide and the development of NEC in neonatal patients, it adds to the previously reported cases with similar outcomes. This information should be considered when evaluating comparable symptoms in patients exposed to diazoxide. Further research is needed to better inform decision-making surrounding diazoxide use in neonatal patients.
Acknowledgment:
Colette Meehan, MD, Christopher Zimmerman, MD
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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