Breakthrough Discovery Uncovers Preterm Infants Have Possible Exposure to Volatile Organic Compounds in Incubators

The neonatology team at University of Maryland Children’s Hospital has conducted the first-ever study examining preterm infants’ exposure to volatile organic compounds (VOCs) while receiving care in an isolette.

VOCs are ubiquitous gases emitted from some natural and man-made solids or liquids. They have low boiling point and high vapor pressure, causing them to evaporate at ordinary room temperature when used or stored. Their concentrations are 2-5 times higher indoors than outdoors.

VOCs may have adverse health effects as eye, nose and respiratory allergies, as well as possible injury to kidneys, liver and brain. Many VOCs are also classified by the U.S. Environmental Protection Agency (EPA) as 'air toxic pollutants,' which may cause cancer.

Sources of VOCs include household products, such as fragrance, paint, wood preservatives, cleansers, disinfectants, pesticide, and dry cleaned clothes. Other products outside the home include tobacco smoking, nicotine, gasoline, industrial chemicals, building materials, plastics, and furnishing.

Study Details

The study hypothesized that preterm infants are contained in closed plastic incubators, which are a potential source of VOCs and a microenvironment for entrapment of potentially harmful gases secondary to the limited air circulation compared with open-air cribs. The primary question this study wanted to uncover is, “do preterm babies in the incubators have higher urinary concentrations of VOC metabolites compared to babies in the open beds (bassinettes/cribs)?”

The study was conducted at the University of Maryland Children's Hospital. The collected samples were analyzed by collaborators from the Centers for the Disease Control and Prevention (CDC).

A non-randomized study of 40 preterm infants in incubators and 40 infants in open cribs were enrolled who met inclusion criteria: The incubator infants had to be in an incubator for a minimum of 3 days prior to obtaining the urine sample. They had to be on no respiratory support and/or nasal cannula  1.5 LPM. The control infants in the open-crib group were breathing room air, without respiratory assistance, for a minimum of 3 days before sample collection. None of the study group infants had vascular access.

The urine samples were collected by placing a cotton gauze pad in the infant’s diaper and was squeezed at the end of 3 hours and stored within 1 hour of collection at –80 °C. Samples were shipped in dry ice to the CDC for analysis. The electronic medical record was reviewed for demographic data.

The study included 28 VOC metabolites from 18 parent chemicals. This specific panel of VOCs metabolites was studied in urine and published by the CDC (Alwis KU et al., 2012). The National Health and Nutrition Examination Survey (NHANES) utilized urinary metabolites as quantifiable biomarkers to report the exposure of U.S. populations to a variety of VOCs (CDC, 2017).

Ultra-high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI/MSMS) was used to quantify the VOC metabolites in urine.

Findings

The isolette infants were of smaller gestational age, birth weight, and weight at the time of sample collection. They had more feeding tubes and nasal cannula. The differences between the isolette and crib groups were statistically significant. There was no difference between groups regarding sex, race, and disclosure of tobacco smoking by pregnant women.

Out of the 28, VOC metabolites studied, 22 VOC metabolites were detected in urine samples regardless of groups. All urine samples had measurable levels of six VOC metabolites corresponding to parent compounds acrylamide, acrolein, 1,3- butadiene, and toluene. The geometric means of five VOC metabolites were 2-fold higher than those reported for NHANES children 6–11 years of age in one or both of the groups.

Incubator Group

Twelve VOC biomarkers were higher in the incubator compared to the open crib infants; acrolein, acrylonitrile, carbon disulfide, cyanide, N-dimethyl- formamide, ethylbenzene, ethylene oxide, propylene oxide, styrene, toluene/benzyl alcohol, vinyl chloride, and xylene.

Plasticizers, acrylics, and synthetic rubber are known common sources for acrylonitrile, carbon disulfide, cyanide, N-dimethyl- formamide, propylene oxide, styrene, vinyl chloride, and xylene. Plasticizers are common materials in the NICU. Plastics are an integral constituent of incubators and medical devices (nasal cannulas and feeding tubes). Also, VOCs may be emitted from polyurethane foam in bedding materials.

Another potential source of VOC metabolites in the incubators is the cleaning and sterilizing agents used to clean the cribs and incubators, as agents including ethylene oxide and propylene oxide. Ethylene oxide, which is commonly used as a disinfectant for respiratory equipment, had a geometric mean seven times higher in the isolette compared with the crib infants. The cleaning and medical care products can become a part of the enclosed breathable air, thus posing an entrapped source of VOC metabolites in isolettes.

The Crib Group

Two urinary metabolites were elevated in the open-crib group, consistent with a higher 1,3-Butadiene as the parent chemical. Those metabolites are emitted from cigarette smoking, among other sources. Infants in open cribs may have more physical contact with parents and caregivers, likely increasing exposure to cigarette smoke on the clothing of handlers.

A common source of VOC: Tobacco smoking exposure

The 12 VOC metabolites identified in infants in the incubators were also measurable in the open crib group and most share cigarette smoke as a common source. In this study, the reported rate of maternal cigarette smoking was only 10%. There was no statistical difference between both study groups. Prenatal exposure from maternal cigarette smoking is unlikely since the median days of life of the urine sample collection were 11 and 16 days for infants in the incubators and cribs, respectively. The source is probably a third- and fourth-hand tobacco smoke from the clothing, hair, and entrapment after off-gassing by smoking parents/caregivers/visitors.

Toluene: A known teratogen

The geometric means for the toluene metabolites; N-acetyl-S-(benzyl)-L-cysteine (BMA) were 12 and 7 times higher than those reported for NHANES in 6–11-year old children in the isolette and crib groups, respectively. Toluene is associated with embryopathy in infants of solvent abuser pregnant women.

Moreover, BMA is a nonselective biomarker. It can be emitted from more than one VOC source, of relevance to the NICU is benzyl alcohol, which is also metabolized to BMA. Benzyl alcohol is used as an excipient in medications given to infants in the NICU as ranitidine, chlorothiazides, dexamethasone, potassium chloride, and ferrous sulfate.

Study Limitations

The significantly lower gestational and post-conceptual age of the incubator group could have contributed to the differences in the VOC metabolites levels due to functional immaturity of the renal excretion system compared to more mature infants in cribs. There are unmeasured variables that impact the VOC levels; as the type of feeding, hydration status, exposure to medications, complications of prematurity, smoking habits of caregivers and parents, and the time interval between sanitization of the incubators and cribs and placement of an infant inside. Also, several measured VOC metabolites are not unique and result from different parent compounds. Last, some of the measured VOCs could be derived from endogenous metabolism.

Finding Implications

There is widespread exposure of infants in the NICU to some VOCs, which were feasible to quantify. The exposure was maybe dependent on whether the infant is placed in an incubator or a crib.

Future Direction

A larger sample size validating study to control for the variability in exposure and different confounders is warranted. The following study could also identify hospital practices that reduce VOC exposure. An example is increasing the airflow ventilation rate inside the incubators and prolonging the off-gassing period after sanitation of incubators and cribs. Further studies are also needed to understand the impact on long-term health and neurodevelopmental outcomes.

References

Alwis KU, Blount BC, Britt AS, Patel D, Ashley DL. Simultaneous analysis of 28 urinary VOC metabolites using ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI/MSMS). Anal Chim Acta 2012;750:152–60.

CDC. National Report on Human Exposure to Environmental Chemicals, 2017 https://www.cdc.gov/exposurereport/ (Accessed 16 February 2020).

El-Metwally D, Chain K, Stefanak MP, Alwis U, Blount B, LaKind JS, Bearer CF. Urinary metabolites of volatile organic compounds of infants in the neonatal intensive care unit. Pediatr Res. 2018 May 16. DOI: 10.1038/pr.2018.52