Association between hypertensive disorders of pregnancy and disease progression in preterm infants with necrotizing enterocolitis: a retrospective cohort study

Abstract

Introduction

The aim of this study was to investigate the association between hypertensive disorders of pregnancy (HDP) and disease progression in preterm infants with necrotizing enterocolitis (NEC), providing a basis for risk-stratified monitoring.

Methods

We conducted a retrospective cohort study of 237 preterm neonates diagnosed with Bell stage II NEC at a tertiary level teaching hospital in China between January 2015 and January 2025. Statistical analyses included univariate analysis, multivariate logistic regression, smooth curve fitting, and threshold effect analysis.

Results

Among the 237 mothers included, 54 (22.78%) presented HDP. Disease progression (to Bell stage III or death) occurred in 71 NEC patients (29.96% of the cohort). Infants in the HDP group presented a significantly lower progression rate compared to the non-HDP group (16.67% vs. 33.88%; OR, 0.36 [95% CI 0.14–0.92]). Furthermore, systolic blood pressure (SBP) was negatively correlated with NEC progression when the mean SBP was less than 171.20 mmHg, with each 1 mmHg increase associated with a 2% reduction in progression risk (95% CI, 0.96–0.99).

Conclusions

Maternal HDP and a SBP < 171.2 mmHg were associated with a decreased risk of NEC progression in preterm infants with Bell stage II NEC. These findings suggest that maternal blood pressure monitoring and hypertensive status may inform clinical decision-making in NEC management.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40001-025-03159-1.

Introduction

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease that primarily affects preterm infants, with survivors often developing long-term gastrointestinal sequelae and neurodevelopmental impairment [1]. Despite advances in neonatal care, such as prompt feeding cessation and antibiotic therapy, disease progression remains a significant clinical challenge [2].

Hypertensive disorders of pregnancy (HDP) represent a major cause of maternal and perinatal morbidity and mortality worldwide and frequently necessitate iatrogenic preterm delivery. The association between HDP and NEC remains controversial, with inconsistent results reported in the few available studies [3–8]. Notably, the specific relationship between HDP and NEC progression (Bell stage II NEC at diagnosis) remains poorly characterized. Given these knowledge gaps, we conducted a 10-year retrospective cohort study at a tertiary-level teaching hospital in China to examine this association.

The global incidence of HDP continues to increase, paralleling the increasing prevalence of risk factors such as assisted reproductive technologies, advanced maternal age, maternal obesity, and diabetes mellitus [9]. A population-based cohort study using the United States National Inpatient Sample revealed that, of 15,714,940 obstetric deliveries, 2,045,089 (13.02%) were complicated by HDP [10]. In clinical practice, cautious feeding advancement strategies are typically employed for preterm infants born to mothers with HDP. We hypothesized that NEC progression in preterm neonates was associated with HDP. The aim of this investigation was to elucidate the relationship between HDP and disease progression in patients with NEC, potentially informing novel clinical management approaches.

Methods

Study design and study population

Preterm neonates diagnosed with Bell stage II NEC between January 2015 and January 2025 at our institution were enrolled in this retrospective observational study (Fig. 1). Data reviewers were blinded to exposure status and outcome. The inclusion criteria were (1) postnatal age < 28 days at admission and (2) meeting modified Bell's staging criteria for NEC in preterm infants. The exclusion criteria were isolated intestinal perforation confirmed after surgery, viral enteritis, enterocolitis associated with Hirschsprung's disease, immunodeficiency diseases, severe congenital malformations, food allergies, inherited metabolic diseases and chromosomal anomalies. A total of 251 newborns born during the study period had confirmed stage II NEC at diagnosis. After applying exclusion criteria, such as isolated spontaneous intestinal perforation or intestinal malformation (n = 4), Bell stage III disease at diagnosis (n = 8), and incomplete medical records (n = 2), 237 neonates were included in the final analysis.

Fig. 1.

Research flow chart. NEC necrotizing enterocolitis

Definitions

HDP encompass chronic hypertension, gestational hypertension, preeclampsia/eclampsia, and preeclampsia superimposed on chronic hypertension. Chronic hypertension was diagnosed before pregnancy or before 20 weeks of gestation and persisted after delivery. Gestational hypertension is defined as a systolic blood pressure ≥ 140 mmHg and/or a diastolic pressure ≥ 90 mmHg after week 20 of gestation [9]. Small for gestational age (SGA) is defined as a birth weight and/or length < −2 standard deviations [11]. Meconium-stained amniotic fluid results from either foetal colonic evacuation (meconium passage) or intraamniotic haemorrhage with haematolysis products [12]. Early-onset sepsis (EOS) is defined as a blood or cerebrospinal fluid culture obtained during the first 72 h of life that indicates the presence of a pathogenic bacterial species [13]. Late-onset sepsis (LOS) is defined as the isolation of pathogenic bacteria from blood and/or cerebrospinal fluid or fungi from blood obtained > 3 days after birth [14]. Hypoalbuminaemia is defined as a serum albumin concentration < 35 g/L [15].

Diagnosis and treatment of NEC

Once diagnosed with NEC [1], all newborns underwent the same treatment protocol, including bowel rest, nasogastric suction, intravenous nutrition, parenteral antibiotics, and intensive care therapy. The mainstay of treatment for neonatal sepsis is broad-spectrum intravenous antibiotics, although a tailored therapy is administered once the pathogen and its antibiotic susceptibility have been characterized.

Common initial empirical antibiotic combinations include ampicillin plus gentamicin to cover common causes of EOS or vancomycin plus an aminoglycoside or third-generation cephalosporin to cover common causes of LOS [16]. Aminoglycosides are not routinely used for treating neonatal sepsis in China due to nephrotoxicity and ototoxicity [17]. Although resistance to glycopeptides, such as vancomycin and Linezolid, is rare in China, methicillin resistance has been reported in 60% to 70% of gram-positive Staphylococcus spp. [18, 19]. In our neonatal intensive care unit, common initial empirical antibiotic combinations are piperacillin sodium and cefoperazone/sulbactam to cover common causes of EOS. Vancomycin or linezolid plus a third-generation cephalosporin or carbapenem antibiotic are used to cover common causes of LOS. Antimicrobial therapy was subsequently tailored according to the culture results and clinical evidence of infection resolution. Antibiotic selection was consistent throughout the study period.

Data collection

This retrospective observational study utilized data extracted from electronic medical records by two independent investigators. The inter-rater reliability was greater than 90%. The collected variables included (1) maternal antepartum characteristics (hypertensive disorders, premature rupture of membranes, amniotic fluid status, antenatal corticosteroid administration, and antibiotic exposure); (2) neonatal parameters (gestational age, birth weight, sex, Apgar scores, small-for-gestational-age status, and feeding regimen); and (3) clinical interventions (early antibiotic therapy, ibuprofen exposure, blood product transfusions, age at NEC onset, and enteral feeding advancement rate). The study protocol received approval from the Institutional Review Board of Affiliated Suzhou Hospital of Nanjing Medical University (Ethics Approval No: KL901537).

Statistical analysis

Data normality was assessed using the Shapiro–Wilk test. Continuous variables with a normal distribution are expressed as the means ± standard deviations (SDs), while non-normally distributed variables are presented as the medians (interquartile ranges [IQRs]). Categorical variables are described using frequencies and percentages. Intergroup comparisons were performed using (1) the independent samples t-test for normally distributed continuous variables, (2) the Mann–Whitney U test for non-normally distributed continuous variables, and (3) Pearson's χ² test or Fisher's exact test for categorical variables, as appropriate. Initial comparative analyses were used to examine covariate distributions between the HDP and non-HDP groups (Table 1). Univariate logistic regression (Table 2) followed by multivariable logistic regression analysis. (Table 3) were employed to evaluate the independent associations between HDP/other covariates and NEC progression. Nonlinear relationships were investigated using generalized additive models with smooth functions (Fig. 2). A generalized additive model helps to discover nonlinear relationships and determine whether there is a threshold effect. It also helps determine if linear regression is appropriate. To identify nonlinear associations, inflection points were objectively calculated, and piecewise linear regression models were constructed on either side of these thresholds (Table 4). Finally, post hoc exploratory analyses were performed to understand the results in certain subgroups (Supplement Fig. 1 and Table 2). The subgroup analyses were conducted as hypothesis-generating explorations to identify potential effect modifiers, with stratification criteria determined a priori based on previous research. Differences with a p value < 0.05 were considered statistically significant. After considering clinical significance, we adjusted for the covariates mentioned above. All analyses were performed using R (http://www.R-project.org) and EmpowerStats software (www.empowerstats.com, X&Y solutions, Inc. Boston MA). Power analysis was performed using PASS 15.0 software. The rate of progression to Bell stage III or death ranged from 33.88% to 16.67% in the non-HDP and HDP groups, respectively. A sample size of 237 (183 non-HDP and 54 HDP NEC patients) had a power of 0.86, with an alpha of 0.05 and a two-tailed test.

Table 1.

Demographic and clinical characteristics of the preterm neonates with necrotizing enterocolitis according to hypertensive disorders or pregnancy status (n = 237)

Variables	No HDP (n = 183)	HDP (n = 54)	Statistics	P-value
GA (weeks)	29.50 (28.00, 31.60)	30.35 (29.30, 32.18)	− 1.621	0.106
BW (grams)	1428.03 ± 489.27	1220.93 ± 368.06	2.880	0.004
Multiple pregnancy	57 (31.51%)	4 (6.98%)	10.408	0.001
Fetal distress	22 (12.33%)	22 (41.86%)	18.787	< 0.001
Membranes ruptured > 18 h before delivery	50 (27.32)	1 (1.85)	16.021	< 0.001
Antenatal MgSO4	111 (69.20)	53 (98.15)	27.501	< 0.001
GDM	39 (21.31)	11 (20.37)	0.020	0.882
Antenatal glucocorticoid use	137 (75.34%)	47 (88.37%)	3.320	0.068
Antenatal antibiotic use	97 (53.42%)	17 (32.56%)	5.789	0.016
Amniotic fluid contamination	15 (8.22%)	0 (0.00%)	2.518	0.113a
Male sex	100 (54.64)	28 (51.85)	0.131	0.717
SGA	18 (10.27%)	23 (44.19%)	25.893	< 0.001
One-minute Apgar score	9.00 (8.00, 9.00)	8.00 (8.00,9.00)	− 1.991	0.046
Five-minute Apgar score	9.00 (8.00,10.00)	9.00 (8.00,9.00)	− 1.151	0.251
Hypoproteinemia on admission	52 (28.42)	9 (16.67)	3.011	0.083
Formula feeding	72 (39.72%)	27 (51.16%)	1.780	0.182
Surfactant therapy	145 (79.45%)	37 (69.77%)	1.773	0.183
Ibuprofen use	24 (13.11%)	7 (12.96)	0.000	0.977
Red blood cell transfusion in the week before NEC	7 (18.92%)	3 (27.27%)	0.031	0.860
Speed of advancing enteral feeding volumes (mL/kg/day)	14.36 ± 5.82	12.75 ± 5.20	− 1.521	0.105
Age at onset of NEC (days)	15.00(11.00, 24.50)	17.50 (7.50, 25.00)	− 0.601	0.551
Progression to stage III NEC or death	62 (33.88)	9 (16.67)	5.897	0.015

Data are expressed as mean ± SD, median (interquartile range), or percentage

a Chi-squared continuity correction

NEC necrotizing enterocolitis, HDP hypertensive disorders or pregnancy, GA gestational age, BW birth weight, GDM gestational diabetes mellitus, SGA small for gestational age

Table 2.

Crude association of necrotizing enterocolitis progression to stage III or death with risk factors

Variables	Total	OR (95% CI)	P value
GA (weeks)	30.40 (28.50,32.55)	0.84 (0.76, 0.93)	0.001
BW (grams)	1380.84 ± 471.82	0.99 (0.99, 1.00)	0.024
Multiple pregnancy
No	140 (74.07%)	1.00
Yes	49 (25.93%)	1.46 (0.72, 2.96)	0.300
IVF
No	167 (88.36%)	1.00
Yes	22 (11.64%)	0.57 (0.18, 1.76)	0.328
Membranes ruptured > 18 h before delivery
No	186 (78.48%)	1.00
Yes	51 (21.52%)	0.85 (0.43, 1.71)	0.659
Antenatal MgSO4
No	73 (30.80%)	1.0
Yes	164 (69.19%)	0.85 (0.46,1.57)	0.611
GDM
No	187 (78.90%)	1.0
Yes	50 (21.09%)	1.09 (0.54, 2.20)	0.798
Antenatal glucocorticoid use
No	41 (21.69%)	1.00
Yes	148 (78.31%)	0.64 (0.30, 1.35)	0.245
Antenatal antibiotics use
No	97 (51.32%)	1.00
Yes	92 (48.68%)	1.26(0.66, 2.40)	0.476
Amniotic fluid contamination
No	177 (93.65%)	1.00
Yes	12 (6.35%)	0.90 (0.23, 3.45)	0.873
Sex
Female	109 (45.99%)	1.00
Male	128 (54.01%)	1.35 (0.76, 2.37)	0.299
SGA
No	155 (82.01%)	1.00
Yes	34 (17.99%)	0.41 (0.15, 1.12)	0.082
One-minute Apgar score
> 3	224 (94.51%)	1.0
≤ 3	13 (5.48%)	1.49 (0.47, 4.74)	0.493
Five-minute Apgar score
> 7	228 (96.20%)	1.0
≤ 7	9 (3.79%)	3.06 (0.79, 11.78)	0.102
Hypoproteinemia on admission
NO	176 (74.26%)	1.0
Yes	61 (25.73%)	1.96 (1.06, 3.61)	0.031
Type of enteral nutrition
Breast milk only	43 (22.75%)	1.00
Formula or breast milk	146 (77.25)	0.82 (0.37, 1.79)	0.615
Surfactant therapy
No	109 (57.67%)	1.00
Yes	80 (42.32%)	1.79 (0.91, 3.56)	0.094
Early antibiotic use
No	8 (4.23%)	1.00
Yes	181 (95.77%)	2.67 (0.32, 22.27)	0.364
Ibuprofen use
No	206 (86.92%)	1.0
Yes	31 (13.08%)	0.79 (0.33, 1.86)	0.589
Red blood cell transfusion in the week before NEC
No	38 (79.16%)	1.0
Yes	10 (20.83%)	0.92 (0.22, 3.79)	0.904
Speed of advancing enteral feeding volumes (mL/kg/day)	14.00 ± 5.72	1.01 (0.95,1.07)	0.792
Age at onset of NEC (days)	17.82 ± 12.98	1.01 (0.99,1.03)	0.278
HDP
No	146 (77.25%)	1.00
Yes	43 (22.75%)	0.36 (0.14, 0.92)	0.033
SBP
< 140	186 (78.48%)	1.0
≥ 140	51 (21.51%)	0.36 (0.16, 0.81)	0.014
DBP
< 90	185 (78.05%)	1.0
≥ 90	52 (21.94%)	0.48 (0.22, 1.02)	0.059

NEC necrotizing enterocolitis, GA gestational age, BW birth weight, IVF in vitro fertilization, SGA small for gestational age, GDM gestational diabetes mellitus, HDP hypertensive disorder of pregnancy, SBP systolic blood pressure, DBP diastolic blood pressure, OR odds ratio, CI confidence interval

Table 3.

Multivariate logistic regression models for risk factors associated with deterioration in premature infants with necrotizing enterocolitis

Variables	Model 1		Model 2		Model 3
	OR (95%CI)	P	OR (95%CI)	P	OR (95%CI)	P
HDP
NO	1.00		1.00		1.00
Yes	0.39 (0.17, 0.85)	0.018	0.42 (0.19, 0.93)	0.033	0.37 (0.15, 0.90)	0.030
DBP	0.97 (0.95, 0.99)	0.036	0.97 (0.95, 0.99)	0.044	0.98 (0.95, 0.99)	0.043

Model 1: Crude model

Model 2: Adjusted for sex and GA

Model 3: Adjusted for sex, GA, antenatal MgSO4, GDM, and hypoproteinemia on admission

HDP hypertensive disorders of pregnancy; DBP: diastolic blood pressure; GA: gestational age; GDM: gestational diabetes mellitus; OR: odds ratio; CI: confidence interval

Fig. 2.

Analysis of the relationship between systolic blood pressure and necrotizing enterocolitis progression by smoothing curve fitting. Adjusting variables: sex, GA, antenatal MgSO4, GDM, and hypoproteinemia on admission. NEC necrotizing enterocolitis; SBP systolic blood pressure, GA gestational age, GDM gestational diabetes mellitus

Table 4.

Independent correlation between systolic blood pressure and deterioration in premature infants with necrotizing enterocolitis by multiple segmented linear regression

Outcome	Effect (95% CI)	P value
Model 1 Fitting model by standard linear regression	0.99 (0.97—1.00)	0.053
Model 2 Fitting model by two-piecewise linear regression
Inflection point	171.20
< 171.20	0.98 (0.96—0.99)	0.014
≥ 171.20	1.39 (0.87—2.24)	0.170
P for likelihood test		0.030

CI confidence interval

Results

Baseline characteristics

The study included 237 neonates with a median GA of 30.2 weeks (IQR 28.1–32.0) and a mean BW of 1380 g (SD 471.8), of whom 128 (54.0%) were male. HDP was present in 54 patients and included chronic hypertension (1.8%), gestational hypertension (5.6%), preeclampsia (68.5%), chronic hypertension with superimposed preeclampsia (14.8%), and HELLP syndrome (9.3%).

The demographic characteristics of the patients are compared in Table 1. Compared with the non-HDP group, the HDP group had a significantly lower frequency of multiple gestation, membranes ruptured > 18 h before delivery, and antenatal antibiotic use (P < 0.05). Conversely, the HDP group had a higher incidence of foetal distress, antenatal MgSO4, and SGA (P < 0.05). Additionally, neonates in the HDP group had lower birth weights (1220.93 ± 368.06 g vs. 1428.03 ± 489.27 g, P = 0.004), lower one-minute Apgar scores (median 8 [IQR 8, 9] vs. 9 [8, 9], P = 0.046), and a lower proportion of patients progressing to stage III NEC or death than those in the control group. The significantly higher incidence of SGA (44.19% vs 10.27%, p < 0.001) and lower Apgar scores (median [IQR]: 8[8, 9] vs 9 [8, 9]) in HDP-exposed neonates may reflect placental insufficiency-related fetal compromise, suggesting these parameters could serve as early indicators for NEC. No significant differences in GA, GDM, antenatal glucocorticoid use, amniotic fluid contamination, infant sex, five-minute Apgar score, hypoproteinaemia at admission, formula feeding, surfactant therapy, ibuprofen treatment, red blood cell transfusion within the week before NEC, speed of advancing enteral feeding volume, or age at NEC onset were detected between the two groups.

Progression of stage II NEC

In our cohort, 54 of the 237 preterm infants with Bell stage II NEC (22.78%) progressed to stage III disease or death during hospitalization. Among these patients, 68.52% (37/54) underwent surgical intervention, excluding those who discontinued treatment. The progression rate to Bell stage III disease or death was significantly greater in the non-HDP group (33.88%) than in the HDP group (16.67%) (P < 0.05; Table 1).

Unadjusted association between baseline variables and clinical manifestations and the progression of stage II NEC or death

Univariate regression analysis revealed that HDP was significantly associated with the progression of Bell stage II NEC or death (OR 0.36, 95% CI 0.14–0.92; p = 0.033). Compared with that in the non-HDP group, the risk of NEC progression in the HDP group was reduced by 64% (OR = 0.36). GA, BW, and hypoproteinaemia at admission were also associated with disease progression (p < 0.05). However, the progression of stage II NEC or death was not affected by multiple pregnancy, IVF, membrane rupture > 18 h before delivery, antenatal glucocorticoid use, antenatal antibiotic use, amniotic fluid contamination, male sex, SGA, Apgar score, hypoproteinaemia on admission, type of milk, surfactant therapy, early antibiotic use, ibuprofen use, red blood cell transfusion in the week before NEC, speed of advancing enteral feeding volumes, and age at onset of NEC (Table 2).

Adjusted associations between baseline characteristics and Bell stage II NEC progression

We constructed three models to analyse the independent effects of HDP on the progression of stage II NEC or death (Table 3). HDP decreased the risk of progression of stage II NEC or death (OR 0.39, 95% CI 0.17–0.85; p = 0.018) according to the unadjusted model (Model 1). In the adjusted model (Model 2) (adjusted for sex and GA), HDP decreased the risk of the progression of stage II NEC (OR 0.42, 95% CI 0.19–0.93; p = 0.033). In Model 3 (adjusted for sex, GA and hypoproteinaemia on admission), we also found a similar correlation (OR = 0.43, 95% CI 0.19–0.96; p = 0.041). Compared with that in the non-HDP group, the risk of NEC progression in the HDP group was reduced by 57% (OR = 0.43) after controlling for confounding factors. Similarly, Models 1, 2, and 3 revealed a negative correlation between DBP and the progression of stage II NEC or death when DBP was modelled as a continuous variable. we specifically examined whether severe preeclampsia—the most prevalent subtype of HDP- influenced NEC progression. Both unadjusted and covariate-adjusted analyses yielded conclusions consistent with our primary findings (Supplementary Table 1).

Using generalized additive modelling with smooth curve fitting, we identified a nonlinear association between SBP and Bell stage II NEC progression (Fig. 2) after adjusting for sex, GA, and admission hypoproteinaemia. Specifically, a threshold effect was observed at 171.2 mmHg: below this value, each 1 mmHg increase in SBP was associated with a 2% reduction in progression risk (adjusted OR 0.98, 95% CI 0.96–0.99), whereas no significant association was observed above this threshold (p = 0.170) (Table 4).

Stratified analyses of the associations between HDP and NEC progression

Given the limited sample sizes in stratified analyses, these results should be interpreted as exploratory. Consistency was observed across all prespecified subgroups, including GA, BW, membranes ruptured > 18 h before delivery, sex, Apgar scores, admission hypoproteinaemia, and NEC onset age (Supplementary Table 2). No statistically significant differences were observed in GA, BW, membrane rupture > 18 h before delivery, sex, one-minute Apgar score, hypoproteinaemia at admission, or age at onset of NEC after the interaction (all p-interaction > 0.05).

Discussion

This retrospective cohort study demonstrated that HDP were significantly associated with a reduced risk of NEC progression in preterm infants with Bell stage II NEC. This protective association remained statistically significant after multivariable adjustment for potential confounders. Notably, an inverse relationship was observed between SBP and clinical deterioration when the SBP exceeded 171.2 mmHg. Subgroup analyses confirmed the consistency of these associations across diverse populations, further supporting the robustness of our findings.

Previous studies have investigated several factors related to the progression of NEC in preterm neonates. LOS and elevated CRP levels are independent prognostic factors for the clinical progression of NEC in preterm neonates [20]. Faecal HBD-2 and claudin-3 levels may be potential biomarkers for predicting the progression of NEC [21]. Hyponatremia and a decrease in plasma sodium levels at the onset of NEC are positively associated with the need for surgery and death within 2 weeks [22]. Low serum bicarbonate levels in the 3 days prior to clinical onset and patent ductus arteriosus for which ibuprofen was administered predict surgical NEC [23]. Targeting lower oxygen saturations may increase the risk of surgical NEC compared with targeting higher saturations [24]. Most research focuses on risk factors during the neonatal and postnatal periods, and prevention efforts may be more effective by focusing on protective factors during the prenatal and perinatal periods. The use of antenatal magnesium sulfate, which is recommended for the prevention and treatment of preeclampsia/eclampsia, appears to have a protective effect against intestinal morbidity requiring surgery in preterm infants (adjusted OR 0.766, 95% CI 0.589–0.997) [25]. A multicentre retrospective cohort study revealed that maternal HDP was not significantly associated with the incidence of Bell’s stage II or higher NEC. However, it was associated with a lower rate of NEC requiring surgery [26]. Increased mean arterial pressure was negatively associated with NEC [27]. These three conclusions are to some extent in accordance with our results.

Placental insufficiency, which occurs when nutrients are not properly transferred from the mother to the foetus, affects 10% to 15% of all pregnancies. This can lead to complications such as HDP, encompassing gestational hypertension, preeclampsia and eclampsia, as well as foetal growth restriction, preterm birth and stillbirth [28]. The pathophysiology of placental insufficiency involves many factors, such as antiangiogenic, proinflammatory and hypoxic factors [29]. Placental hypoxia is a key factor in the development of placental insufficiency. Hypoxia-inducible factor (HIF)-α is a transcription factor that plays a critical role in the cellular response to hypoxia or low oxygen levels. It regulates the expression of genes involved in various physiological processes, such as angiogenesis, metabolism, and cell survival [30]. HIF-1α increases the expression of the mitogen-activated protein kinase p38 and NOD-like receptor protein 3 inflammasomes, promoting placental inflammation and dysfunction [31]. A previous study [32] revealed that mice lacking HIF-1α exhibit increased intestinal damage severity; elevated oxidative stress, apoptosis and persistent inflammation in necrotizing enterocolitis (NEC); and upregulation of the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signalling pathway, specifically in the intestines of mice lacking HIF-1α in intestinal epithelial cells (IECs) with NEC. Murine models in which Hif1a is specifically knocked out in IECs or cell models in which Hif1a is knocked down exhibit mucosal barrier defects [33]. Collectively, these results highlight the crucial role of HIF-1α in protecting the intestinal barrier in NEC and provide a theoretical basis for our research. However, further experimental studies are needed to confirm our speculation about the pathological mechanisms involved.

HDP remains one of the leading causes of pregnancy-related maternal and foetal mortality worldwide. The management of HDP has been controversial, and new approaches for its management of are needed in the fields of obstetrics and neonatology [34]. In line with the neonatal outcomes of NEC, we provide a novel perspective to guide the control of HDP. Once Bell’s stage II NEC is diagnosed in a preterm infant whose mother does not have HDP, closer monitoring of clinical indicators such as blood counts, CRP levels, and repeated abdominal ultrasounds or X-rays may be necessary to assess disease progression. From the perspective of preterm neonatal complications such as NEC, maintaining systolic blood pressure below 171.2 mmHg in mothers with HDP may be beneficial. In contrast, preterm infants born to normotensive mothers who develop NEC require closer monitoring due to increased risk of NEC progression.

Strengths and limitations

First, this was a single-centre retrospective study, potentially limiting its generalizability to different geographic/ethnic populations. Second, we did not perform a classification analysis of several types of HDP and assess the exposure timing and treatment strategy of HDP because the sample size was small. Third, the blood pressure measurements used in our study were entered manually by healthcare providers into the electronic medical record during routine clinical practice, which may have resulted in errors or omissions. Measurement bias may also have arisen from differences in the blood pressure measurement techniques used by healthcare providers. Fourth, it is also worth noting that the blood pressure measurements used in our study were entered manually by healthcare providers into the electronic medical record during routine clinical practice, which may have resulted in errors or omissions. Measurement bias may also have arisen from differences in the blood pressure measurement techniques used by healthcare providers. Fifth, although we attempted to adjust for many confounders, other unmeasured or unknown confounders might have played a role.

The strengths of this study include the use of three statistical models controlling for various clinical factors. In addition, the cohort was rather homogeneous in terms of ethnicity, degree of prematurity, and clinical therapeutic strategies. Furthermore, we excluded neonates with a diagnosis of “suspected NEC”, as this condition is difficult to distinguish from septicemia, feeding intolerance and other conditions.

To gain a more comprehensive understanding of the importance of HDP in the treatment of NEC, the focus of future research in this area should be as follows: a) characterize other blood pressure components, such as diastolic blood pressure and mean arterial blood pressure, the effect of specific comorbid conditions, and the number of blood pressure measurements; b) design a test to detect the level of the same marker, such as HIF-a protein level, in NEC patients and their mothers to further confirm the protective effect of maternal HDP on NEC; and c) expand the scope of research to other multicentre prospective studies to eliminate regional differences.

Conclusions

Our main finding was that HDP was associated with a lower risk of NEC progression for preterm infants with Bell stage II NEC. From the perspective of preterm neonatal complications such as NEC, maintaining systolic blood pressure below 171.2 mmHg in mothers with HDP may be beneficial. Preterm infants born to normotensive mothers who develop NEC may require closer monitoring due to increased risk of NEC progression. Future studies examining the appropriate SBP target for people with HDP may wish to consider neonatal outcomes in a larger, prospective, multicenter study. For preterm infants with NEC, we could apply a maternal SBP-based stratification strategy.

Author contributions

Study conception and design: Lirong Shen, Jiajuan Lin, Zuming Yang. Data acquisition: Mingling Cui, Xuejie Zhang, Lili Li. Analysis and data interpretation: Lirong Shen, Mingling Cui, Yan Cai. Drafting of the manuscript: Lirong Shen, Jiajuan Lin. Critical revision: Zuming Yang. All authors reviewed the manuscript.

Funding

This research was supported by the Special Project of Scientific Research on Intestinal Flora, Gusu School, Nanjing Medical University [grant number GSKY20240808].

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was conducted according to the Declaration of 1964 Helsinki and approved by the Ethics Committee of the Affiliated Suzhou Hospital of Nanjing Medical University approved this retrospective study (approval number of ethical documents: KL901537). Waiving the requirement for written informed consent due to the retrospective study design and anonymized patient data.

Competing interests

The authors declare no competing interests.