Spontaneous intestinal perforation associated with premature twin infants

Abstract

OBJECTIVE:

Identify perinatal risk factors associated with SIP

STUDY DESIGN:

This was a retrospective case-control study of SIP in infants born at ≤28 weeks of gestation and admitted between 1995 and 2016 at a tertiary care NICU. Infants with NEC or other GI abnormalities were excluded. Cases of SIP were matched with gestational age-matched controls with the closest birth date. Maternal, infant and birth related factors were evaluated using univariate analyses and significant factors were evaluated using multiple logistic regression.

RESULT:

25 cases of SIP were matched with 25 controls. No maternal factors reached statistical significance. Being one of twins increased the odds of SIP 29-fold. Birth-order or weight-discrepancy in twin had no association of SIP within twin pairs.

CONCLUSION:

Twins are at significantly higher risk for SIP. The association of SIP and twin gestation was independent of previously reported risk factors of perinatal indomethacin or magnesium sulfate and merits further study.

Keywords

Spontaneous intestinal perforation ELBW infants twin gestation

Abbreviations

NEC

Necrotizing enterocolitis

ELBW

Extremely low birth weight

VLBW

Very low birth weight

NICU

Neonatal intensive care unit

SIP

Spontaneous intestinal perforation

1. Introduction

Spontaneous intestinal perforation (SIP) of the newborn is defined as the sudden occurrence of perforation of the intestine during the first 14 days of life involving less than five centimeters of bowel and not associated with any concomitant signs of NEC or other intestinal pathology [1 –3]. SIP incidence is reported to be two to three percent in very low birth weight infants (VLBW) and five percent in extremely low birth weight (ELBW) infants [2 , 4–5]. The incidence is likely under-reported because in some cases it is misdiagnosed or classified as NEC [3 –5]. Low birth weight and prematurity are the well-characterized risk factors for SIP. The average gestational age at birth of infants that develop SIP ranges from 25–27 weeks, and the average birth weight is between 670 and 970 grams [6]. SIP is more commonly seen in males [7]. Early administration of post-natal steroids, such as dexamethasone [8 –10], and the use of early postnatal indomethacin [6 , 10–12] are well established risk factors for SIP. The combination of postnatal steroids and postnatal indomethacin was found to be additive in predisposing to SIP [13, 14]. The contribution of prenatal obstetric factors to SIP such as chorioamnionitis, placental abruption, pregnancy-induced hypertension, and medications such as antenatal steroids, magnesium sulfate, and indomethacin have been reported but evidence has been inconsistent [6 , 12–14]. The aim of the current study is to evaluate the association of perinatal factors with the development of SIP in premature infants born at ≤28 weeks’ gestation.

2. Methods

This was a retrospective case-control study done at a single tertiary care NICU in Farmington, CT. Infants born at ≤28 weeks gestational age and admitted to the NICU between January 1, 1995 and December 31, 2016 were studied. Infants who developed perforations during their NICU stay were identified using a prospectively collected neonatal patient database (Neonatal Information Systems Version 5, Medical Data Systems, Philadelphia, PA).

2.1 Definition of SIP

SIP was defined as presence of intraperitoneal air in non-anomalous bowel without clinical or laboratory signs of NEC such as pneumatosis intestinalis, portal venous air or hematological changes, such as thrombocytopenia, anemia and increased or decreased neutrophil counts. Patients with perforation associated with NEC, congenital intestinal anomalies or other genetic conditions were excluded. Each case of SIP was matched with a control of the same gestational age at birth that was born within six months of the case. The clinical database (NIS-5) included items that were prospectively collected from daily input of data elements. The fidelity of these data elements was verified at time of discharge by a dedicated information management team to conform to pre-determined definitions of terms mostly derived from the Vermont-Oxford Handbook of definitions [15]. Medical records of all cases and controls were reviewed for demographic factors as well as information regarding putative perinatal risk factors for SIP.

2.2 Antenatal data collection

Antenatal data included dosage and use of antenatal medications (steroids, magnesium sulfate, and indomethacin), maternal conditions (presence of preterm labor, premature prolonged rupture of membranes, pregnancy-induced hypertension, and placental abruption), maternal substance use and group B streptococcal (GBS) infection status at delivery. Intrapartum data included mode of delivery, Apgar scores, and resuscitative procedures in the delivery room (chest compressions, epinephrine and volume use).

2.3 Postnatal risk data collection

Postnatal risk data included gestational age, birth weight, growth classification (small for gestational age - SGA, appropriate for gestational age - AGA, or large for gestational age - LGA), multiple gestation, infant sex, umbilical arterial line use and dose and timing of indomethacin and dexamethasone administration. Additional postnatal risk factors investigated were postnatal age at diagnosis of bowel perforation, need for surgery with details of type and timing of surgical intervention and the outcomes at discharge. Approval for the study was obtained from the Institutional Review Board of Connecticut Children’s Medical Center.

2.4 Statistical analysis

All analyses were performed using IBM SPSS version 25. Demographic and clinical characteristics of the study group were described using median and interquartile ranges as appropriate. Univariate comparisons of risk factors and outcomes were performed using Chi square test, Student’s t-test or Mann-Whitney-U test as appropriate. Multivariate logistic regression modeling strategies were used to identify factors significantly associated with SIP after accounting for confounding variables.

3 Results

During the 21-year study period there were 9349 neonates admitted to the Connecticut Children’s Medical Center NICU in Farmington, CT. Of these, 1387 infants were born at ≤28 weeks of gestation. Among these patients, 62 (4.5%) were diagnosed with intestinal perforations. After excluding other causes of intestinal perforations (NEC, anomalies, etc.), 25 infants met the criteria for diagnosis of a spontaneous intestinal perforation (SIP), and they were matched with 25 controls based on gestational age, birth weight, and birth within six months of the corresponding case.

3.1 Maternal and obstetric characteristics

Table 1 shows the maternal and obstetric characteristics of the cases and controls. The two groups did not differ significantly in maternal age, gravidity or parity status. There were no differences in GBS colonization or use of tobacco, alcohol or illicit drugs. The occurrence of preterm labor, placental abruption, chorioamnionitis, pregnancy-induced hypertension or the mode of delivery were not statistically different between SIP cases and controls. Maternal medications such as steroids, indomethacin and magnesium sulfate used prior to birth of the infant were also not statistically different in the two groups.

Table 1
Maternal Factors in SIP

Variable SIP Cases N= 25 Controls N= 25 p Value

Maternal Age (yr) 29.9±6.0 27.5±6.2 0.170

Gravida 2.5±1.6 2.7±2.0 0.696

Para 0.64±0.81 0.76±0.97 0.637

Tobacco 1 (4%) 4 (16%) 0.349

Cocaine 0 (0%) 1 (4%) 1.000

Marijuana 0 (0%) 3 (12%) 0.235

Chorioamnionitis^a 7 (28%) 8 (32%) 0.755

PPROM^b 10 (40%) 13 (52%) 0.387

Preterm Labor 21 (84%) 22 (88%) 1.000

PIH 1 (4%) 2 (8%) 1.000

Placental Abruption 1 (4%) 6 (24%) 0.098

Received antenatal steroids 23 (92%) 20 (80%) 0.417

Received antenatal magnesium sulfate 18 (72%) 15 (53%) 0.551

Received antenatal indomethacin 12 (40%) 6 (23%) 0.140

Variable	SIP Cases N= 25	Controls N= 25	p Value
Maternal Age (yr)	29.9±6.0	27.5±6.2	0.170
Gravida	2.5±1.6	2.7±2.0	0.696
Para	0.64±0.81	0.76±0.97	0.637
Tobacco	1 (4%)	4 (16%)	0.349
Cocaine	0 (0%)	1 (4%)	1.000
Marijuana	0 (0%)	3 (12%)	0.235
Chorioamnionitis^a	7 (28%)	8 (32%)	0.755
PPROM^b	10 (40%)	13 (52%)	0.387
Preterm Labor	21 (84%)	22 (88%)	1.000
PIH	1 (4%)	2 (8%)	1.000
Placental Abruption	1 (4%)	6 (24%)	0.098
Received antenatal steroids	23 (92%)	20 (80%)	0.417
Received antenatal magnesium sulfate	18 (72%)	15 (53%)	0.551
Received antenatal indomethacin	12 (40%)	6 (23%)	0.140

Statistical analysis based on Fisher’s Exact Test. ^aMissing data 3, ^bMissing data 3.

3.2 Patient description

Table 2 shows the infant factors associated with SIP. There were no differences in GA and birthweight in the two groups as they were matched for these variables. Twenty-five cases of SIP were noted, of which 11 cases were of singleton gestation and 14 were one of twin gestations. Twin gestations were significantly associated with SIP cases compared to controls (56%vs 4%; p < 0.0001). However, twin birth order or birthweight discrepancy between twins were not significant risk factors. The mean time of onset of SIP was 6.35 days with a range of 2–16 days. Of the infants with SIP, three died and 22 survived to discharge from the NICU. The location of perforation was in the small intestine in all patients studied. For three infants, perforation was noted in the terminal ileum and four infants had perforation in the jejunum. Twelve infants were managed by placement of peritoneal drain and seven required laparotomy. Of the seven infants requiring laparotomy, bowel was resected in six infants. Two infants with SIP developed NEC at a later date in the NICU.

Table 2
Infants Factors in SIP

SIP Cases N= 25 Controls N= 25 p Value

Gestational age (wk) 25.0±1.5 25.2±1.6 Matched

Birth Weight (gm) 822±234 891±249 0.8104

Twin birth 14 (56%) 1 (4%) <0.0001^*

Male Sex 18 (72%) 12 (48%) 0.148

White race 21 (84%) 16 (64%) 0.1960

Vaginal Delivery 5 (20%) 9 (36%) 0.345

Vertex Presentation 10 (40%) 9 (36%) 0.931

Apgar at 5 mins <5 7 (28%) 8 (32%) 0.769

Chest Compressions 9 (36%) 6 (24%) 0.538

Volume resuscitation done 1 (4%) 5 (20%) 0.1890

Epinephrine use for Resuscitation 4 (16%) 1 (4%) 0.349

Postnatal Indomethacin within 16d of birth 11 (44%) 13 (64%) 0.778

Postnatal dexamethasone within 16 d of birth 0 (0%) 3 (12%) 0.490

IVH Grade > 3 7 (28%) 5 (20%) 0.742

	SIP Cases N= 25	Controls N= 25	p Value
Gestational age (wk)	25.0±1.5	25.2±1.6	Matched
Birth Weight (gm)	822±234	891±249	0.8104
Twin birth	14 (56%)	1 (4%)	<0.0001^*
Male Sex	18 (72%)	12 (48%)	0.148
White race	21 (84%)	16 (64%)	0.1960
Vaginal Delivery	5 (20%)	9 (36%)	0.345
Vertex Presentation	10 (40%)	9 (36%)	0.931
Apgar at 5 mins <5	7 (28%)	8 (32%)	0.769
Chest Compressions	9 (36%)	6 (24%)	0.538
Volume resuscitation done	1 (4%)	5 (20%)	0.1890
Epinephrine use for Resuscitation	4 (16%)	1 (4%)	0.349
Postnatal Indomethacin within 16d of birth	11 (44%)	13 (64%)	0.778
Postnatal dexamethasone within 16 d of birth	0 (0%)	3 (12%)	0.490
IVH Grade > 3	7 (28%)	5 (20%)	0.742

All analyses based on T-test or Fischer’s Exact Test; Values expressed as N (%) or Mean (SD). ^*Statistically significant.

3.3 Postnatal infant characteristics

Table 2 shows post-natal risk factors in cases and controls. There was no difference between the two groups for race and sex. Need for resuscitation at delivery, including need for chest compressions, epinephrine, and volume bolus with normal saline were not significantly different. Apgar scores at 1 and 5 minutes and use of postnatal indomethacin or ibuprofen use were statistically similar between both groups. Interestingly, postnatal dexamethasone was not noted in any of the SIP cases but 9%in the control group had received postnatal dexamethasone within 16 days postnatal age. Postnatal usage of hydrocortisone in the first 14 days was studied but not found to be statistically significant.

3.4 Multivariate analyses

Table 3 shows the Wald statistics and odds ratios from a multiple logistic regression analysis done using SPSS version 25.0. After meeting all assumptions for this analysis, the logistic regression model was found to be statistically significant, χ² (8) = 23.15 and p < 0.001. The model explained 51.6%(Nagelkerke R²) of the variance in SIP. Twins were 29.6 times more likely to develop SIP than singletons. None of the other putative factors including race, antenatal steroid use, postnatal steroid use, epinephrine use in delivery room, or use of antenatal magnesium sulfate had any significant effect in the model.

Table 3
Multiple Logistic Regression Analysis of Variables implicated in SIP

Perforation_YN^a B Std. Error Wald P-Value. Odds Ratio for Exp(B) 95%Confidence Interval Exp(B)

Lower Bound Upper Bound

Perf Intercept –2.144 1.031 4.326 0.038

Twin gestation 3.90 1.187 8.159 0.004 29.6 2.9 303.5

Male Sex 1.396 0.8.6 2.999 0.083 4.0 0.8 19.6

White Race 0.817 0.871 0.880 0.348 2.3 0.4 12.5

Antenatal Indomethacin 0.426 0.812 0.276 0.600 1.5 0.3 7.5

Postnatal Indomethacin –0.479 0.776 0.381 0.537 0.6 0.1 2.8

Perforation_YN^a	B	Std. Error	Wald	P-Value.	Odds Ratio for Exp(B)	95%Confidence Interval Exp(B)
Perf	Intercept	–2.144	1.031	4.326	0.038
	Twin gestation	3.90	1.187	8.159	0.004	29.6	2.9	303.5
	Male Sex	1.396	0.8.6	2.999	0.083	4.0	0.8	19.6
	White Race	0.817	0.871	0.880	0.348	2.3	0.4	12.5
	Antenatal Indomethacin	0.426	0.812	0.276	0.600	1.5	0.3	7.5
	Postnatal Indomethacin	–0.479	0.776	0.381	0.537	0.6	0.1	2.8

a. The reference category is: Non-perforation; b. Coefficient showing positive or negative association.

3.5 Characteristics of affected twins

14 of the 25 cases were from a set of twins allowing us to perform within pair comparisons as shown in Table 4. All twin pairs were di-chorionic and di-amniotic and did not share a common vascular supply in the placenta. The average weight difference among twin pairs was 91.8 gm (range 0–330 gm) and the average percent difference in birth weight was 9.67%(range 0%–30.6%). Of the 12 twins, 8 with higher birth weight developed SIP and 4 with lower birth weight developed SIP. The occurrence of SIP in the larger twin was statistically significant (p < 0.005). In one set of twins, both had the same birth weight. In two sets of twins, both developed SIP and in three sets of twins, the non-SIP twin was stillborn. In total mortality was 8%in the SIP group.

Table 4
Twin-Pair Comparisons

SIP/No Sequence GA birth (wk) BW Sex Rel BW Δ BW %Diff.

1A SIP First 27 970 F Smaller 20 2..0%

1B No Second 27 990 F Larger

2A No First 25 813 F Smaller 77 8.7%

2B SIP Second 25 890 M Larger

3A SIP First 27 1220 M Larger 250 20.5%

3B No Second 27 970 F Smaller

4A SIP First 25 950 M Larger 201 21.2%

4B No Second 25 749 M Smaller

5A^* SIP First 23 570 M Larger 96 16.8%

5B^* SIP Second 23 474 F Smaller

6A No First 23 750 M Larger 30 4.0%

6B SIP Second 23 720 M Smaller

7A^^ No First 26 920 M Smaller 40 4.2%

7B SIP Second 26 960 F Larger

8A SIP First 23 610 M Larger 30 4.9%

9B No Second 23 580 F Smaller

9A SIP First 23 540 M Smaller 10 1.9%

9B No Second 23 550 M Larger

10A^* SIP First 26 1020 M Same 0 0%

10B^* SIP Second 26 1020 M Same

11A SIP First 26 1080 M Larger 100 9.3%

11B No Second 26 980 M Smaller

12A^^ SIP Second 24 660 F Larger

12B^^ UK First 24 UK UK Smaller

	SIP/No	Sequence	GA birth (wk)	BW	Sex	Rel BW	Δ BW	%Diff.
1A	SIP	First	27	970	F	Smaller	20	2..0%
1B	No	Second	27	990	F	Larger
2A	No	First	25	813	F	Smaller	77	8.7%
2B	SIP	Second	25	890	M	Larger
3A	SIP	First	27	1220	M	Larger	250	20.5%
3B	No	Second	27	970	F	Smaller
4A	SIP	First	25	950	M	Larger	201	21.2%
4B	No	Second	25	749	M	Smaller
5A^*	SIP	First	23	570	M	Larger	96	16.8%
5B^*	SIP	Second	23	474	F	Smaller
6A	No	First	23	750	M	Larger	30	4.0%
6B	SIP	Second	23	720	M	Smaller
7A^^	No	First	26	920	M	Smaller	40	4.2%
7B	SIP	Second	26	960	F	Larger
8A	SIP	First	23	610	M	Larger	30	4.9%
9B	No	Second	23	580	F	Smaller
9A	SIP	First	23	540	M	Smaller	10	1.9%
9B	No	Second	23	550	M	Larger
10A^*	SIP	First	26	1020	M	Same	0	0%
10B^*	SIP	Second	26	1020	M	Same
11A	SIP	First	26	1080	M	Larger	100	9.3%
11B	No	Second	26	980	M	Smaller
12A^^	SIP	Second	24	660	F	Larger
12B^^	UK	First	24	UK	UK	Smaller

P < 0.005. BW- Birth Weight in grams; GA –gestational age in completed weeks; Rel. BW- Relative difference in birth weight; %Diff.–Percent Difference in birth weight, UK-unknown. ^*In this twin set, both developed SIP; ^*^*In this twin set one twin was delivered deceased.

4. Discussion

This retrospective case control study suggests that infants of twin gestation are at a significantly higher risk of developing SIP. Within twin pairs, the one with higher birth weight was more at risk but sex, and birth order were not significant factors.

The influence of gestational age and birth weight on SIP is well reported in the literature and these factors were controlled for in this report to focus on other lesser-recognized risk factors [16 –19]. No racial or ethnic differences have been noted in previous studies on SIP [20, 21]. Our study also found no significant association.

Previous studies have not shown a consistent association of male sex with SIP [17 , 22]. In our study, there were more males with SIP but there was no significant association either on univariate or on multivariate analysis. A larger sample size is needed for a more definitive analysis.

The use of antenatal indomethacin as a tocolytic prior to delivery was noted to be a risk factor in previous reports [23, 24]. We were not able to detect a statistically significant association in this case-control study. An association of SIP with antenatal steroid use or magnesium sulfate use previously suspected in SIP was not detected in our study [14].

Postnatal indomethacin use was found to be an important risk factor for SIP in a study of hydrocortisone use in the first week after birth for the prevention of BPD [21 , 26]. Further, use of prophylactic indomethacin was associated with increased odds of SIP independent of early enteral feeding shown in a study by Stavel et al. [11]. We do not use hydrocortisone in the first week of life and prophylactic indomethacin is not a routine practice at our center. Therefore, this specific association could not be studied. In general, we found no association between postnatal indomethacin use and SIP.

Some studies have shown an association of SIP with use of inotropes in premature infants [24, 27]. In addition, there is indirect evidence from a report from Singh et al who reported a higher incidence of SIP in infants who were acidotic at birth [28]. It is possible that circumstances related to perinatal distress and acidosis may have an effect on gut perfusion and predispose premature infants to SIP. However, both the use of epinephrine in the delivery room and the use of dopamine infusion in the first postnatal week were not associated with SIP in our study.

The mortality rate of SIP in our study was 8%, which is relatively low compared to the mortality in infants who develop perforation due to NEC. A similar finding was recently reported by Clyman et al. [29]. The finding of a higher risk of SIP in one of a pair of twins is intriguing. In a review of previous reports evaluating risk factors for SIP, there has always been a trend for a higher rate of occurrence in twins [16, 29]. Case reports of spontaneous ileal perforation in a pair of twins have been published [30]. In another case series, Hay et al. described SIP in three pairs of identical male twins [31]. SIP has been reported in the donor twin after twin-twin transfusion syndrome [32]. In one report by Suply et al., the adjusted odds ratio was 2.9 times higher risk of SIP in multiple pregnancies, although twin pregnancies were not specified [19]. Also, in a large cohort studied by Attridge et al., there is a slightly higher but non-significant increased incidence of SIP in multiple gestations [8, 24]. From data published by Singh et al. it is notable that twins had twice the rate of SIP compared to singletons but this finding was not elaborated in that paper [28]. In a retrospective analysis of putative risk factors for intestinal perforation in premature infants, twin births was noted to be one of the risk factors by Holland et al. [22]. Despite accumulating evidence from previous case reports and retrospective review of risk factors, we believe that this may be one of the first case-control studies describing the association of SIP in twins.

We also studied factors within the twin pairs that could increase the risk for SIP. Interestingly, when only one of the twins developed SIP, it was usually the larger twin that was at increased risk. No previous reports of this observation have been published. There were a few cases in our study in which both twins developed SIP and a similar phenomenon was noted in a published case report [33].

Two infants in our study who had developed SIP early in life later developed ≥stage 2 NEC. Similar to our experience, Drewett et al. described NEC and other gastrointestinal pathology in nine infants who developed SIP initially [34]. This highlights the fact that infants who developed SIP are at higher risk of developing further intestinal pathology and thus should be monitored closely. It is reasonable to speculate that one of the reasons for higher risk of SIP in twins may be a compromise of intestinal blood supply due to placental or other factors. The fact that both twins had developed SIP in some cases and the association with a stillborn twin is some other cases raises the possibility that there may be a role of the in-utero environment in the etiology of this condition. In relation to the relative blood and nutrient flow to the uterus and placenta, it is important to note that at any given week of gestation, the total body weight of twins exceeds that of the singleton infant. Therefore, unlike in a singleton, where only the ipsilateral uterine artery (on the placental side) undergoes changes in pulsatility, in twin gestation both uterine arteries need to undergo similar changes. This makes it more likely that the uterine and placental blood flow may be compromised in twin gestation. Volume flow rates in the uterine arteries in twin pregnancies need to exceed those in singleton pregnancies. Differences in pulsatility index have been noted in uterine arteries in twin versus singleton gestations and this factor may play a role in the higher risk of gut compromise and SIP in twins [35].

Given the limitations of a single center, retrospective, case-control study, our findings need to be interpreted with caution. Multiple gestation pregnancies are prone to preterm labor, so the potential risk of SIP is not insignificant. There is an urgent need for larger studies and corroboration of our findings from other centers to help confirm our findings of increased risk of spontaneous intestinal perforation among multiple gestation births.

Footnotes

Acknowledgments

The authors would like to thank the database management team at Connecticut Children’s Medical Center in Farmington, especially Vicki Pehmoeller, Lisa Dion and Shari Galvin, for their invaluable help in authenticating the data and helping in its collection and retrieval. We are grateful to Dr. Aaftab Husain for his help with collecting data from the charts.

Conflict of interest

The authors declare no conflict of interest.

Author contribution statement

NH was involved in development of the protocol. AM and UP were involved in data collection and statistical analyses. NH, AM and UP were involved in writing the manuscript. NH was the principal investigator.

Funding information

No funding was received for this project.

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