Carnitine deficiency in preterm infants: A national survey of knowledge and practices

1 Introduction

Nearly a half million premature infants are born in the United States each year and are at risk for neurodevelopmental problems, including developmental delay, cerebral palsy and hearing and vision impairment [1, 2]. There has been great interest in the role of nutrition in improving the neurodevelopmental outcomes of preterm infants. Long chain polyunsaturated fatty acids (LCPUFA) play a well-known role in central nervous system development, and literature supporting LCPUFA supplementation has been growing steadily. Supplementation with docosahexaenoic acid (DHA), a LCPUFA, at amounts available in term breast milk, has been associated with improved visual acuity, better light sensitivity, and better global developmental outcomes at 6–18 months [3, 4]. At higher doses, DHA supplementation has been associated with better outcomes in growth, visual acuity, and developmental testing [5–8].

The focus on enhancing delivery of LCPUFA to very preterm infants highlights the importance of a micronutrient essential for lipid metabolism: carnitine. Carnitine is necessary for the transport of long chain fatty acids across membranes, including into the mitochondria, and is involved in beta-oxidation, peroxidation, and detoxification processes. Very preterm infants are born with limited tissue reserves and are at risk of developing carnitine deficiency postnatally if not given external supplementation. A deficiency in precursors and decreased enzyme activity lead to a reduced ability to synthesize carnitine. Since placental transfer and biosynthesis of carnitine seems to occur primarily during the third trimester, preterm infants also begin with lower carnitine stores than infants born at later gestational ages [9]. After birth, carnitine levels in very preterm infants decline more rapidly over the first one to two weeks of life, compared with infants born at later gestational ages [10]. These factors make exogenous sources of carnitine important in order to prevent deficiency in the very preterm infant.

The goal of preterm infant total parenteral nutrition (TPN) is to mimic the intrauterine environment of the fetus. Most micronutrients are routinely added to TPN, but no recommendations exist for the inclusion of carnitine. Breast milk contains carnitine, and both cow’s milk and soy-based infant formulas are supplemented with carnitine [11]. However, the most stressed infants often receive prolonged parenteral nutrition, which does not routinely contain supplemental carnitine [12]. Carnitine supplementation for very preterm infants has been shown to enhance lipid tolerance and fatty acid oxidation and to increase nitrogen balance [13–21]. Studies assessing the impact of supplementation on weight gain have had mixed results [22]. Of note, studies focusing on short-term weight gain showed better early weight gain at two weeks of life [20, 23].

We previously conducted a national survey of American neonatal intensive care units (NICUs) in 2001 and found that carnitine was routinely supplemented by only one-third of respondents [24]. Little is known about whether use of carnitine supplementation in NICUs in the United States has changed, given new research underscoring the role of fatty acids on brain functioning, as well as carnitine derivatives on neuroprotection [25]. The goal of the current study was to assess neonatal practitioners’ knowledge, beliefs and practices regarding carnitine supplementation in very preterm infants among neonatal practitioners.

2 Methods

We conducted an electronic survey of members of the American Academy of Pediatrics Section on Perinatal Pediatrics (AAP SOPPe). The AAP SOPPe is a professional organization devoted to pediatricians with a special interest in neonatology, whose members consist primarily of board-certified neonatologists and a small proportion of nurse practitioners, physician assistants, trainees and general pediatricians. At the time of survey administration, there were nearly 2,900 members of the AAP SOPPe. The section maintains an electronic listserv that serves as a platform for distribution of informational emails and surveys. Not all members of the section are members of the electronic listserv.

3 Results

We received responses from 492 participants. The estimated number of listserv participants at the time of survey administration was 2,990, however, we are unable to calculate an accurate response rate, as we are not aware how many listserv members actually received the email. 361 participants completed all 18 survey items. Ninety-seven percent of the respondents were in active practice, and 63% had more than 10 years of experience. Attending neonatologists comprised 88% of respondents. Most respondents (91.8%) identified their unit as a Level III NICU. Respondents reported a median number of 550 admissions (range 2 – 3,000) admissions each year [average = 678]. The majority of respondents (66%) reported availability of expanded newborn screens identifying carnitine deficiency in their state of practice, and 24% of respondents did not know whether their state had an expanded screen.

3.1 Knowledge

Most respondents (67%) correctly recognized that carnitine is present in breast milk and infant formula. Fewer respondents (21%) correctly identified that the placenta secretes carnitine (Fig. 1).

OPEN IN VIEWER

Fig.1

Respondents’ Knowledge.

3.2 Beliefs

The percent of respondents who agreed that carnitine supplementation remains controversial was 42%, and 44% agreed that carnitine might be neuroprotective. Of all respondents, 29% believed that carnitine deficiency was rare, while 60% agreed that carnitine deficiency has potentially serious consequences (Fig. 2). More than half of the respondents were neutral when asked about the cost and availability of screening (53%) and the potential side effects of carnitine administration (57%).

OPEN IN VIEWER

Fig.2

Respondents’ Beliefs.

3.3 Practices

Among respondents, 29% had diagnosed and treated at least one infant with carnitine deficiency. Only 5% routinely screened for carnitine deficiency. When asked how many of the last 4 preterm infants under their care were supplemented with carnitine, 40% of respondents indicated that they had supplemented 4 of the last 4 preterm infants, and 42% had not supplemented any of the 4 newborns. An additional 20% indicated they had treated 1 – 3 of the last 4 infants (Fig. 3). Based upon these responses, we estimated that that less than half of infants were supplemented.

OPEN IN VIEWER

Fig.3

Percentage of responses regarding carnitine supplementation in each category for the following question: “Of the last 4 very preterm infants exclusively on TPN under your direct care/supervision, how many received carnitine supplementation?”.

Respondents were asked about possible barriers to screening and supplementation. 20% of respondents agreed that screening for deficiency is expensive, and 27% agreed that screening is not easily available at their institution. Lastly, 66% of the respondents were aware that they practiced in a state that had implemented an expanded newborn screen with carnitine deficiency included.

4 Discussion

In our survey, most of the respondents were aware that carnitine deficiency is common in very preterm infants and most believed carnitine deficiency could have serious consequences. Few correctly identified the placental secretion of carnitine, while 2/3 recognized its presence in breast milk. In addition, less than half of the respondents routinely supplemented TPN with carnitine, and even fewer screened for carnitine deficiency.

Neonatologists appeared familiar with the consequences of carnitine deficiency: two-thirds agreed that the consequences of carnitine deficiency are potentially serious. Indeed, carnitine deficiency in infants and children can result in encephalopathy, cardiomyopathy, muscle weakness, gastrointestinal symptoms, and hypoglycemia. There is reason to believe that carnitine deficiency may also create a vulnerability to neuronal injury. Pre-treatment with l-carnitine during hypoxia-ischemia has been shown to reduce neurologic injury in the immature rat and to reduce apoptotic cell death due to neonatal hypoxic ischemic brain injury [25, 26]. Many of the neonatologists who completed our survey appeared familiar with this literature. Since the majority recognized the prevalence of carnitine deficiency and possible role in neuroprotection, it is surprising that only 40% provided routine supplementation and even fewer, 5%, routinely screened for carnitine deficiency.

We hypothesize that our results may be partly a reflection of the mixed findings of trials investigating carnitine supplementation on weight gain in very preterm infants. In light of these conflicting results, one can understand why definitive recommendations on carnitine’s inclusion in parenteral nutrition have not been endorsed yet. However, a closer inspection of the literature on weight gain shows a consistent trend in the impact of carnitine supplementation on short-term weight gain, when the infants are most at-risk [20, 27]. We saw a similar trend in the study we previously conducted (data not previously reported) [28]. While weight gain is of unquestionable importance in the postnatal period, optimal brain development and neurological outcomes are also crucial. To our knowledge, the potential neuroprotective effects of L-carnitine supplementation have not been studied in preterm infants. Currently, we are completing a randomized clinical trial assessing the effect of L-carnitine on neurological and developmental outcomes in very preterm infants, which should guide practice if proven beneficial.

Other potential barriers to carnitine supplementation may include cost and availability. However, the majority of respondents did not identify these as barriers, likely consistent with increased affordability and availability of the tests. Most of the respondents did practice in a state that had implemented an expanded newborn screen, including carnitine deficiency. Results of the expanded newborn screens are typically received by providers two weeks after, so it is unlikely that results would be received early enough during an infant’s hospital course to begin supplementation while the infant is still receiving primarily parenteral nutrition. The timing of screening must be balanced with the knowledge that maternal carnitine levels are reflected in levels measured shortly after birth, and therefore such levels may be falsely reassuring.

Of note, more experienced neonatologists were significantly more likely to provide supplementation. The fact that few respondents screened for deficiency inhibited our ability to determine whether experience was associated with screening practices. It is possible that more experienced neonatologists are more familiar with the literature or have an increased focus on mimicking the intrauterine environment when deciding how to supplement. To our knowledge, there are no published guidelines that provide guidance on supplementation of carnitine in the very preterm infant. It is likely that practitioners at various institutions have interpreted the literature to create internal guidelines. However, the variability in practice noted in this study urges contemplation of the potential need for a more universal practice guideline.

A limitation of our study is the relatively low response rate. This rate may be an underestimate, as it is unclear how many of the total reported listserv participants received the survey link. However, survey response rates in our range have been shown to provide accurate representation [29, 30]. In addition, a comparison of the first 50 respondents with the total respondents showed no significant differences. Our survey was distributed only to members of the AAP-SOPPe email listserv. It is possible that section members who do not participate in the listserv have other views.

At a time when there is increased emphasis on lipid supplementation and neurodevelopmental outcomes, few respondents routinely supplemented TPN with carnitine and even fewer screened for carnitine deficiency, leaving most very preterm infants still at risk for unrecognized carnitine deficiency and its potential consequences. Further research is needed to better understand the impact of carnitine deficiency and supplementation on short- and long-term outcomes, including developmental outcomes in preterm infants.

Disclosures

None.