Zygomycosis in Neonates: An Uncommon but Life-threatening Infection

Abstract

We systematically reviewed all published cases of zygomycosis, an increasingly important infection with high mortality, in neonates. We searched PubMed and individual references for English publications of single cases or case series of neonatal (0 to 1 month) zygomycosis. Cases were included if they fulfilled prespecified criteria. Fifty-nine cases were published through July 2007. Most of the infants (77%) were premature. The most common sites of zygomycosis were gastrointestinal (54%) and cutaneous (36%) diseases. This pattern differs from sinopulmonary and rhinocerebral patterns of older children. Fifty-six percent of cases were diagnosed by histology only and 44% by histology and culture. Rhizopus spp. were isolated from 18/25 (72%) cases. Thirty-seven percent of patients received no antifungal therapy. Thirty-two (54%) neonates underwent surgery with (39%) or without (15%) antifungal agents. Overall mortality was 64%. A higher fraction of neonates treated with amphotericin B and surgery survived than those who received no therapy (70% versus 5%). Zygomycosis is a life-threatening infection in neonates with a distinct pattern of gastrointestinal and cutaneous involvement and high mortality. Combination of amphotericin B and surgery was common management strategy in survivors.

Neonates, especially those born prematurely, have important deficiencies in their innate immune response, leading to increased susceptibility to opportunistic bacteria and fungi.¹ Although Candida spp. are the most frequent fungi causing invasive infection in neonates,² filamentous fungi may also cause infections that can be life-threatening.³

Zygomycosis refers to a group of uncommon but frequently fatal mycoses caused by fungi of the class Zygomycetes.⁴ These include human pathogens from classes of both Mucorales and Entomophthorales. Zygomycosis has emerged as an increasingly important fungal infection during the past decade. This increase has been particularly evident in hematopoietic stem cell transplant recipients and patients with hematologic malignancies.⁵ Other populations at risk for zygomycosis include patients with diabetes, burns, and trauma as well as those undergoing surgery or deferoxamine therapy. Neonates also have been described in individual case reports as a population at risk for zygomycosis.^6–8

To date, however, there has not been a comprehensive review of zygomycosis in neonates to guide our understanding of the epidemiology, management, and outcome of this devastating infection. We therefore systematically reviewed the English-language literature for all cases of neonatal zygomycosis. In this review, we sought to describe demographic and clinical characteristics as well as outcome of invasive zygomycosis in neonates and to compare them with those of older children and adults.^9,10 This may lead to improvement of management of neonatal invasive zygomycosis.

METHODS

Literature Search

Case reports and series of neonatal zygomycosis published in the English literature were retrieved by use of “zygomycosis,” “mucormycosis,” “phycomycosis,” “Rhizopus,” “Mucor,” “Rhizomucor,” “Cunninghamella,” “Absidia,” “Apophysomyces,” “Syncephalastrum,” “Sakse-naea,” “Cokeromyces,” “Entomophthoral,” “Conidiobolus,” and “Basidiobolus” as keywords with the limitation “less than 1 month of age” in searches of the PubMed bibliographic database (U.S. National Library of Medicine, Bethesda, MD) from 1950 through July 2007. After this initial series of reports was reviewed, the references cited in the above articles were screened for additional cases of neonatal zygomycosis. In addition, all references from major book chapters written on the subject of zygomycosis were reviewed. Their references were carefully scrutinized for single case reports or case series.

Criteria for Inclusion of Cases

Only those cases that contained the following five variables were included in our review:

1. Age: Cases of patients less than 1 month of age were included.

2. Documentation of infection: Zygomycosis was confirmed either histologically or by culture. Information as to whether the infection was documented premortem or postmortem also was required.

3. Anatomic location of infection: Documentation of the primary site of infection at time of diagnosis and whether the infection remained localized or disseminated was required. Disseminated infection was defined as two or more noncontiguous sites. Those patients with disseminated infection at the time of diagnosis where the primary site of infection was impossible to identify were classified as having “generalized disseminated” infection. Patients with cutaneous infection were subcategorized into three groups. Those patients in whom the infection was confined to the cutaneous or subcutaneous tissue were defined as having localized disease. Patients with invasion into muscle, tendon, or bone were classified as “deep extension.” Patients with cutaneous disease involving another noncontiguous site were considered disseminated. Patients with pulmonary infection were subcategorized in a similar manner. Those with disease confined to the lungs were classified as localized. Those with disease that extended to the chest wall, pulmonary artery, aorta, or heart were considered “deep extension.” Those cases that demonstrated involvement of a noncontiguous site were classified as disseminated.

4. Therapeutic intervention: Only those cases that specified presence or absence of both surgery and antifungal therapy were included.

5. Outcome: Mortality was assessed as “all-cause mortality” during the course of zygomycosis.

Database Development

Filemaker Pro 5.5 software (Santa Clara, CA) was used to develop an initial database of categorical and continuous variables. The categorical variables included gender, underlying diagnosis, organism, diagnostic method used for recovery of organism, premortem or postmortem diagnosis, infection site (focal or disseminated disease), surgery, and outcome. The continuous variables included year of diagnosis, year of publication, gestational age, birth weight, postnatal age of patient, and dose/duration of antifungal therapy. From there, the data were transferred to a Microsoft Excel (XP Professional) software (Redmond, WA) for further analysis and presentation.

Statistical Analysis

Descriptive statistics were conducted using the Statistical Package for the Social Sciences for Windows (version 11.5; SPSS Inc., Chicago, IL). Categorical variables are reported as percentages and continuous variables (except for years of diagnosis and publication) as median and interquartile range (IQR).

RESULTS

Fifty-nine cases of zygomycosis were identified in neonates.^{6–8,11–51} The main demographic, clinical, therapeutic, and outcome data of these cases are shown in Table 1. The earliest case of neonatal zygomycosis included in this study was published in 1956.⁵¹ There was a clear increase in the number of neonatal zygomycosis cases reported over time, with 71% of all cases published after 1990 (Table 2). Although the mortality of reported zygomycosis cases remained high through the years of reporting, there were fewer deaths in cases published after 2000 (41%) (Table 2).

Table 1.

Cases of Neonatal Zygomycosis Published

Year and Reference	Sex/Age (d)	GA (wk)	BW (g)	Factors Preceding Zygomycosis				Sites of Infection (Extension)	Organism and Method	Treatment (Duration, d)†	Survival
				Steroids	Antb	Surgery	Other Risk Factors*
195651	M/20		2830		Yes	No	Malnutrition	Gl (D)	Zygomycete, T (postmortem)	None	No
195950	F/4				Yes	No		Gl (D)	Zygomycete, T (postmortem)	None	No
196049	M/6	<38			Yes	No		Gl (D)	Zygomycete, T (postmortem)	None	No
196048	M/9	<38	3175		Yes	No		Gl (L)	Zygomycete, T (postmortem)	None	No
196141	M/9		1360		Yes	No		Gl (L)	Zygomycete, T (postmortem)	None	No
196141,44	F/10		3200		No	No	Malnutrition, diarrhea, acidosis	Gl (L)	Zygomycete, T (postmortem)	None	No
196747	M/15		1250			No	Diarrhea	Gl (D)	Zygomycete, T (postmortem)	None	No
1980/’7737	M/5	32		No	Yes	Yes	Gastric trauma, colonized bandage	CU (DE)	R. oryzae, T & C	AMB-D (10) & surgery	Yes
198039	M/7	32	2560		Yes	Yes	Nasogastric intubation	Gl (D)	R. oryzae, T & C	AMB-D (14) & surgery	Yes
198035	M/31	≥38	3200	No	Yes	No		Palate, maxilla, orbit, CE (D)	Zygomycete, T	AMB-D (7) & surgery	Yes
198111	M/11		1600	No	Yes	Yes	Acidosis	CU (D)	Zygomycete, T & C (postmortem)	None	No
198443	F/11	25	910	No	Yes	No	Acidosis, ↑GIu, renal insufficiency	CU & PU (D)	Zygomycete, T (postmortem)	None	No
1986/’5221	F/28	≥38		No	No	No		PU (D)	Zygomycete, T (postmortem)	None	No
1986/’5821	M/4	≥38		No		Yes		Gl (L)	Zygomycete, T (postmortem)	Surgery	No
1986/’8121	M/30	≥38		No		Yes		CU (L)	Zygomycete, T	None	Yes
198942	F/9	≥38			No	No	Diarrhea, acidosis	RC (L)	Zygomycete, T (postmortem)	None	No
198915	M/15	26	1100		Yes	No	Acidosis, prolonged adhesive strapping	CU (L)	Rhizopus spp., T & C	AMB-D & 5FC (28) & surgery	Yes
199013	M/16		430		Yes	No	Metabolic disorder, nasogastric tube	Gl (D)	Rhizopus spp., T & C	AMB-D (51) & surgery	No
199234	M/neonate			No		Yes		PU, MO (D)	Rhizopus spp., T & C (postmortem)	None	No
199220	F/21	27	1190	Yes	No	Yes		Gl (D)	R. microsporus, T & C	Surgery	No
199220	F/21	24	660	Yes	No	Yes		Gl (L)	Zygomycete, T	Surgery	No
199311	F/26	38		No	Yes	No		Gl (L)	Zygomycete, T (postmortem)	None	No
199438	M/5	28	1131	No		Yes		Gl (D)	Zygomycete, T	Surgery	No
199414	M/16	28	1245	Yes	Yes	No	Colonized adhesive to endotracheal tube	CU (D)	R. arrhizus, T & C	AMB-D & rifampicin (5) & surgery	No
199418	M/20	26			Yes	No		Gl (D)	Mucor spp., T&C	None	No
199546	M/9	≥38	2365	No	No	Yes	Early feeding	Gl (L)	Zygomycete, T (postmortem)	None	No
199546	M/9	29	1080	No	Yes	No	Early feeding	Limb, part of abdomen, Gl, kidney, ureter, thrombus in aorta (D)	Zygomycete, T (postmortem)	None	No
199546	F/1	36	1980	No	Yes	Yes	Early feeding	Gl (L)	Rhizopus spp., T& microscopy	AMB-D (15) & surgery	Yes
199517	F/24	26	670	Yes	No	No	Hyperglycemia	CU (DE)	Rhizopus spp., T&C	AMB-D (51) & surgery	Yes
199616	F/4	24	680	Yes	Yes	No	Wooden tongue depressors	CU (L)	R. microsporus, T&C	LAMB & ITC (23)	Yes
199616	F/7	25	525	No	Yes	No	Wooden tongue depressors	CU (D)	R. microsporus, T&C	LAMB & ITC (2)	No
199616	F/20	25	750	Yes	Yes	No	Wooden tongue depressors	CU (DE)	R. microsporus, T&C	LAMB & ITC (14) & surgery	Yes
199616	M/22	25	850	Yes	Yes	No	Wooden tongue depressors	CU (D)	R. microsporus, T&C	LAMB & ITC (2)	No
19976	M/8	24	430	Yes	Yes	No	Monitor lead	CU (D)	Rhizopus spp., T&C (postmortem)	None	No
199740	M/8	35	1100	Yes	Yes	No	Sepsis, renal failure, ↑Glu, suspected HIV infection	CU (DE)	Zygomycete, T (postmortem)	None	No
199733	9	29	1380		Yes	No	Impaired immunity	Gl (D)	Rhizomucor spp., T & C	AMB-D (49) & surgery	Yes
199812	F/14	31	1500	Yes	Yes	Yes	Umbilical catheter	CU (D)	Absidia corymbifera, T & C	AMB-D (14) & surgery	No
199819	M/21	26	915	Yes	No	No	Adhesive tape	CU (DE)	R. oryzae, T & C	AMB-D (16)	Yes
199812	M/25	≥38			Yes	No	Several chest tubes	PU (L)	A. corymbifera, T & C	None	No
199832	F/9					No		Gl (D)	Zygomycete, T postmortem)	None	No
199832	F/4					No		Gl (D)	Zygomycete, T	Surgery	No
199931	F/11	24	730		Yes	No		Gl (D)	R. microsporus, T & C	AMB-D (4) & surgery	No
200130	M/19	34	1810		Yes	No	Acidosis, nasogastric tube	Gl (D)	Zygomycete, T	AMB-D (32) & surgery	No
200229	F/12	37	3650	Yes	Yes	No	IV catheter	CU (L)	Rhizopus arrhizus, T & C	AMB-D (2) & surgery	No
200229	F/14	25	635		Yes	No	IV catheter	CU (L)	Rhizopus spp., T & C	AMB-D & surgery	Yes
200327	M/15	25	820	Yes	Yes	No	Infection site: IV site	CU (L)	Zygomycete, T	AMB-D (19) & surgery	Yes
200328	F/17	24	740	Yes	Yes	No	Hyperglycemia	CU (L)	A. corymbifera, T & C	AMB-D (14) & surgery	Yes
20047	F/12	25	704		Yes	No	Acidosis, hyperglycemia, nasogastric tube	Gl (D)	A. corymbifera, T & C	LAMB (29)	No
200425	F/15	32	2944	Yes	Yes	No		Gl (D)	Zygomycete, T & immunostaining	Surgery	Yes
20048	F/27	36	1600	No	Yes	No	Containment mesh-associated surgical wound	CU (L)	A. corymbifera, T & C	AMB-D (28) & surgery	Yes
200426	M/15	26	839	Yes	Yes	No	Nasogastric tube, intubation	Gl (D)	Zygomycete, T	AMB-D (42) & surgery	Yes
200523	M/10	35	1600		Yes	No		CU (L)	Zygomycete, T & C	AMB-D (90) & surgery	Yes
200524	M/4		SGA		No	No	Barium enema	Gl (D)	Zygomycete, T	AMB-D (14) & surgery	No
200524	F/7	≥38			No	No	Barium enema	Gl (D)	Zygomycete, T	FLC & surgery	Yes
200524	M/16	≥38			Yes	No		Gl (D)	Zygomycete, T	None	No
200622	M/3	34	2000	Yes	Yes	No		CU (L)	Zygomycete, T	AMB-D & surgery	Yes
200636	F/4	30	1380		Yes	No		Gl (D)	Zygomycete, T	Surgery	No
200636	M/2	33	1710		Yes	No		Gl (D)	Zygomycete, T	Surgery	No
200745	M/16	≥38	3200	No	No	No		Gl (L)	Zygomycete, T	Surgery	Yes

^*Other risk factors as indicated by the authors in each case.

BW, body weight; Glu, glucose; 5FC, 5-flucytosine; FLC, fluconazole; IV, intravenous; R. oryzae, Rhizopus oryzae; R. arrhizus, Rhizopus arrhizus’, R. microsporus, Rhizopus microsporus T, tissue; C, culture; SGA, small-for-gestational-age infant; CU, cutaneous; Gl, gastrointestinal; RC, rhinocerebral; PU, pulmonary; MO, multiple organs; CE, cerebral; Antb, antibiotics; AMB-D, amphotericin B deoxycholate; LAMB, liposomal amphotericin B; DE, deep extension; D, disseminated; L, localized.

Table 2.

Published Cases of Neonatal Zygomycosis since 1950 through July 2007

Time of Publication	All Patients Reported, n (%)	Reported Patients Who Died, n (%)
1950–1959	2 (3)	2 (100)
1960–1969	5 (8)	5 (100)
1970–1979	0 (0)	—
1980–1989	10 (17)	5 (50)
1990–1999	25 (42)	19 (76)
2000-July 2007	17 (29)	7 (41)
Total	59 (100)	38 (64)

The demographic and clinical characteristics of these patients are depicted in Table 3. Male infants had a median age 10 days (IQR, 8 to 16) and female infants 14 days (IQR, 9 to 20.5). Most of the neonates (77%) were born prematurely (gestational age <38 weeks). Zygomycosis developed in the setting of several conditions that may have increased risk of zygomycosis. These included prior administration of corticosteroids or antibiotics or prior surgery as well as extremity immobilization with wooden tongue depressors, intravenous catheter sites, acidosis, and hyperglycemia. However, none of them was found to lead to more deaths due to zygomycosis (Table 3).

Table 3.

Demographic Characteristics, Potential Risk Factors, and Disease Patterns in Reported Cases of Neonates with Zygomycosis

Characteristic	All Patients Reported, n (%)	Reported Patients Who Died, n (%)
Patients	59 (100)	38 (64)
Demographics
Male gender	33 (57)	22 (67)
Female gender	25 (43)	16 (64)
GA in wk, median (IQR)	28 (25–39)	28 (25–34)
BW in g, median (IQR)	1131 (745–1895)	1131 (730–1710)
Postnatal age in d, median (IQR)	12 (8–18)	11.5 ± 1.3 (2–22)
Potential risk factors for death
Prematurity (<38 wk)	37/48 (77)	20/37 (54)
Corticosteroids	18/34 (53)	8/18 (44)
Antibiotics	41/53 (77)	25/41 (61)
Major surgery prior to the infection	12/57 (21)	8/12 (67)
Impaired host defense*	3	2/3 (67)
Metabolic acidosis	7	6/7 (86)
Contaminated source†	20	10/20 (50)
Hyperglycemia	5	3/5 (60)
Disease pattern
GI tract	32 (54)	25/32 (78)
Cutaneous	21 (36)	8/21 (38)
Pulmonary‡	4 (7)	4/4 (100)
Rhino-orbital-cerebral	2 (3)	1/2 (50)
Extension of disease
Localized	21 (36)	10/21 (48)
Deeply extensive	5 (8)	1/5 (20)
Disseminated	33 (56)	28/33 (85)

^*Other than corticosteroid treatment.

^†Wooden tongue depressors, intravenous catheter sites, etc.

^‡One case with concomitant cutaneous infection; one case disseminated to multiple organs.

GA, gestationalage; BW, body weight, IQR, interquartile range; GI, gastrointestinal.

All neonates had infection documented by histopathology and/or culture. Thirty-three (56%) cases were diagnosed by means of histopathology only and 26 (44%) by histopathology and culture. The great majority of cases up to 1990 were diagnosed postmortem. The genera identified by culture are depicted in Fig. 1. Rhizopus spp. was by far the most frequent genus of Zygomycetes isolated. Among 16 isolates with species identification reported, six were identified as Rhizopus microsporus, five as Rhizopus oryzae/arrhizus, and five as Absidia corymbifera.

Figure 1.

Zygomycete genus identification by culture in neonates with zygomycosis.

The distribution of infection sites is shown in Table 3. The most common patterns of zygomycosis in neonates were gastrointestinal (GI; 52%) and cutaneous (36%) forms. Pulmonary and rhinocerebral infections as well as infections of other sites were found in a total of 6 (10%) cases. Localized disease was present in 36% of patients, deeply extensive disease in 8%, and disseminated disease in 56% of them (Table 3).

Among the 59 patients with zygomycosis, there were 38 (64%) deaths reported. Reported mortality was lower (38%) for cutaneous disease than for all the other forms of zygomycosis (> 66%). This was especially high in neonates who developed GI disease (the most frequent form reported), in which mortality was 78%. Of reported cases of disseminated disease 85% died (Table 3).

Twenty-two (37%) neonates did not receive any form of therapy (Table 4). Of the 28 neonates who received antifungal agents, 27 received amphotericin B (22 deoxycholate amphotericin B, five liposomal ampohotericin B). Among the patients who received antifungal treatment, four received amphotericin B in combination with itraconazole and one with flucytosine. The median duration of antifungal treatment was 14 (IQR, 8.5 to 28.5) days. Twenty-three (39%) patients underwent surgery in combination with antifungal chemotherapy, and 9 (15%) underwent surgery without antifungal agents.

Table 4.

Treatment and Outcome of Reported Cases of Neonatal Zygomycosis

Treatment	All Patients Reported, n (%)	Reported Patients Who Died, n (%)
Total of patients	59 (100)	38 (64)
Surgery combined with antifungal chemotherapy	23 (39)	7 (30)
Surgery alone	9 (15)	7 (78)
Antifungal chemotherapy alone	5 (8)	3 (60)
No therapy	22 (37)	21 (95)
Antifungal agents
AMB-D	20	6
LAMB	1	1
LAMB + itraconazole	4	2
AMB-D + flucytosine	1	0
AMB-D + rifampicin	1	1
Fluconazole	1	0

AMB-D, amphotericin B deoxycholate; LAMB, liposomalamphoter-icin B.

Although neonates with no therapy showed a mortality of 95%, those who underwent surgery and were treated with antifungal agents had the lowest reported mortality (30%). Thirty-two neonates underwent surgery alone or as part of their treatment and 14 (56%) survived. Both cutaneous (13/21, 62%) and GI (17/31, 55%) zygomycosis cases were frequently treated with surgery. Among neonates who underwent surgery, 10/13 (77%) neonates with cutaneous infections survived, whereas only 7/18 (39%) neonates with GI infections survived.

DISCUSSION

This is the first reported comprehensive analysis of zygomycosis in neonates. This study underscores that prematurity is a distinctive underlying condition in developing zygomycosis independent of the well-known classical risk factors such as diabetes mellitus and hematologic malignancies. GI, disseminated, and cutaneous diseases appear to occur more often in neonates compared with older patients. Mortality is high especially for GI infections.

Of all cases of zygomycosis reported in the different age groups, GI zygomycosis is more commonly encountered in neonates than in pediatric patients and adults. Thus, among a total of 59 cases of zygomycosis reported in neonates, 32 (54%) were GI cases as compared with 17/124 (14%) of pediatric patients beyond age of 1 month and 33/772 (4%) of all patients above 18 years.^9,10 Most of the cases of GI disease happened in premature babies, some occurring in association with progressive necrotizing skin lesions,⁶ some of them even mimicking the presentation of necrotizing enterocolitis only without the pathognomonic sign of pneumatosis intestinalis.⁵² Furthermore, although ileum and large bowel are by far the most frequently involved sites in necrotizing enterocolitis,⁵² a more extensive involvement of the GI tract from esophagus to large bowel may be observed in premature neonates with either disease.^20,39

The mortality of GI zygomycosis was high, particularly in premature neonates (24/31, 77%) perhaps due to the delay in diagnosis and the underlying immunodeficiency of these babies.¹ Although patients with cutaneous zygomycosis were similarly managed with surgical resection, GI infection still carried a worse postoperative prognosis. There was a tendency that, in contrast to cutaneous zygomycosis, performance of surgery did not appear to increase survival among patients with GI zygomycosis. Exploratory laparotomy and bowel resection was performed in 18 patients, and 11 (61%) of them died. Despite resection of infected bowel, the histopathologic diagnosis of zygomycosis was considerably delayed postoperatively. An increased awareness of this pattern of zygomycosis among neo-natologists is needed to facilitate timely diagnosis and management. In virtually all cases, the preoperative diagnosis was necrotizing enterocolitis. GI zygomycosis should be considered as an uncommon cause of disease in infants who present with signs of necrotizing enterocolitis. A tissue biopsy specimen should be obtained to diagnose these right-angle-branched, nonseptated hyphae, and specific culture should be performed.

Similarly, of all cases of zygomycosis reported in the different age groups, disseminated zygomycosis is more commonly encountered in neonates than in pediatric patients and adults. Specifically, among a total of 59 cases of zygomycosis in neonates, 33 (56%) cases were disseminated as compared with 16/124 (13%) cases in pediatric patients beyond age of 1 month and 164/772 (21%) cases among all patients above 18 years.^9,10 Thus, neonates are most vulnerable to dissemination of zygomycosis, and early diagnosis and attempt to treat this devastating disease are very important.

Overall mortality of zygomycosis in neonates is 38/59 (64%) as compared with 70/124 (56%) for pediatric patients >1 month to 18 years⁹ and 408/772 (53%) for adults above 18 years.¹⁰ In a previous analysis of all pediatric patients including neonates up to 2003, disseminated infection and young age (< 12 months) were found to be independent risk factors of increased mortality as compared with localized disease and older age, respectively.⁹ This trend may be due to the high incidence of prematurity among neonates, other host differences that make zygomycosis more likely to be fatal in these patients, or other age-dependent differences in difficulties in diagnosis, management, and reporting of zygomycosis in pediatric and adult patients.

Amphotericin B continues to be the mainstay of medical treatment for both suspected and proven zygomycosis and most other invasive fungal infections in neonates. Deoxycholate amphotericin B appears to be well tolerated without significant nephrotoxicity in most neonates.^3,53 The lipid formulations of amphotericin B were introduced for clinical care in the mid-1990s. Among newer antifungal agents, such as voriconazole, posaconazole, and echinocandins, with activity against filamentous fungi, posaconazole appears to have greater activity against Zygomycetes⁵⁴; however, the pharmacokinetics and clinical efficacy of posaconazole are not known in neonates.⁵⁵

Because of the nature of the systematic reviews of reported cases as case reports or small series of cases, our results may be biased if the included cases are a biased sample of cases. Our review, however, is descriptive and summarizes the experience of a rare disease for which no large studies have been published, and therefore it is hoped to be helpful in better understanding this life-threatening infection. Future approaches to study this devastating and rarely diagnosed disease that is likely to be often missed could involve large research networks or clinical databases to prospectively collect incidence information. In addition, other studies could prospectively examine all necrotizing skin lesions and/or all medical (stool culture) and surgical necrotizing enterocolitis cases (biopsy) over a specified time period (1 to 2 years).

In this study, we included only infants up to 1 month of life. Because it was possible that there may be cases of zygomycosis in infants who had stayed in the NICU for time longer than 1 month, we also searched PubMed for any additional cases in young infants up to 3 months of age. There were no more cases that we could find according to our prespecified criteria. Thus, to be consistent with our neonatal terminology, we restricted our analysis to the infants up to 1 month of age. It seems that there are only few cases reported during infancy beyond neonatal age.^56,57

The results of this comprehensive review of published neonatal cases of zygomycosis demonstrate that neonatal zygomycosis has a high mortality and strong propensity to disseminate. Early diagnosis and amphotericin B formulations combined with surgery may improve the otherwise dismal outcome.