Efficacy of Subthreshold Newborn Phototherapy During the Birth Hospitalization in Preventing Readmission for Phototherapy

Wickremasinghe, Andrea C.; Kuzniewicz, Michael W.; McCulloch, Charles E.; Newman, Thomas B.

doi:10.1001/jamapediatrics.2017.5630

Cited by 34 publications

(35 citation statements)

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“…2 In logistic regression, cancers occurring shortly after birth are given the same weight as those with longer latency periods. [5][6][7] As our study and others raise questions about the role of phototherapy in cancer development, 8,9 we encourage further research in this field. 2 Furthermore, the efficiency of logistic regression estimates decreases with length of follow-up whereas efficiency improves with Cox regression.…”

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confidence: 73%

“…[5][6][7] Poor adherence to existing phototherapy guidelines, including those set out by the American Academy of Pediatrics, is widespread. [5][6][7] As our study and others raise questions about the role of phototherapy in cancer development, 8,9 we encourage further research in this field. Until the possibility of unmeasured confounding is ruled out, it seems prudent to avoid unnecessary exposure and follow recommended thresholds for the use of phototherapy.…”

Section: Dear Editormentioning

confidence: 99%

“…Logistic regression does not utilize information on the time at which events occur, and is generally considered less appropriate than Cox regression for the analysis of time to event data. [5][6][7] Poor adherence to existing phototherapy guidelines, including those set out by the American Academy of Pediatrics, is widespread. Studies have shown that the magnitude of the risks estimated by logistic regression can fluctuate depending on the length of follow-up and can deviate from Cox regression estimates when follow-up times are long.…”

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confidence: 99%

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Reply to: Phototherapy and childhood cancer: Shared risk factors?

Auger

Ayoub

et al. 2019

Intl Journal of Cancer

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Dear editor, We thank Heck et al. for their comment on our recent study of neonatal phototherapy and childhood cancer. 1 Heck et al. suggest that the association between phototherapy and the risk of childhood cancer may be explained by shared risk factors, such as preterm birth and low birth weight. To support this point, the authors performed a matched casecontrol study of Danish children with cancer between 1977 and 2013, and found that hyperbilirubinemia with or without phototherapy was not a risk factor for childhood cancer in analyses stratified by gestational age and birth weight. The authors use these findings as evidence that our results were most likely affected by unmeasured confounders.We commend Heck et al. for their attempt to clarify the relationship between neonatal phototherapy and childhood cancer. Confounding-by-indication is a well-recognized problem of observational studies in which factors associated with cancer cannot be measured or accounted for. The underlying problem is that these factors are an indication for phototherapy, raising the possibility that the increase in risk of childhood cancer attributed to phototherapy is in reality due to these other factors. The optimal way of eliminating confounding-byindication would be a randomized trial, but this approach is not possible due to the potential for harm from withholding phototherapy in patients with severe hyperbilirubinemia.While we appreciate Heck et al.'s attempt to address the role of confounding, we are compelled to point out that their results cannot be used to support their claim. The foremost problem is that the main exposure measure in Heck et al.'s analysis is a combination of phototherapy and untreated hyperbilirubinemia, rather than phototherapy specifically. As many jaundiced infants do not receive phototherapy, it is likely that their main exposure measure is heavily weighted by patients with untreated jaundice. Thus their results are representative of the effect of hyperbilirubinemia, not phototherapy which is the exposure of interest. It is essential to define the exposure as phototherapy specifically, otherwise the analysis merely reflects the association between jaundice overall and risk of cancer.To illustrate the impact of incorrectly defining the exposure, we reanalyzed our data combining phototherapy with untreated jaundice. Table 1 demonstrates that phototherapy is associated with childhood cancer between 4 and 11 years in our data, especially in term infants, but that untreated jaundice is not. When we combine the two exposures, the association with cancer disappears or weakens. The data behave in this manner due to the absence of a relationship between untreated jaundice and cancer. It is essential to analyze phototherapy separately in order to avoid attenuating the associations towards the null.Moreover, Heck et al. show that risk estimates for most cancers are greater in preterm infants than in term infants, a finding consistent with our results for untreated jaundice and phototherapy, or untreated jaundice a...

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Reply to: Phototherapy and childhood cancer: Shared risk factors?

Auger

Ayoub

et al. 2019

Intl Journal of Cancer

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“…Many such infants are treated prophylactically, in hopes of preventing a readmission for phototherapy. 2 The benefits of such treatment are unlikely to exceed the potential harm. In fact, with our results, we suggest the need to consider raising phototherapy thresholds, as some groups have already done.…”

Section: Figurementioning

confidence: 99%

“…Although the most important goal of phototherapy is to prevent a high total serum bilirubin (TSB) level from reaching a level that might be neurotoxic or require exchange transfusion, 1 phototherapy is also used at lower TSB levels, with a goal of preventing readmissions for phototherapy. 2 In some studies, authors have also linked more modest TSB elevations to subtle neurodevelopmental problems. 3 -6 Phototherapy might also be used with a goal of preventing these problems.…”

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Childhood Seizures After Phototherapy

Newman

Kuzniewicz

et al. 2018

Pediatrics

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BACKGROUND AND OBJECTIVES:In a recent Danish study, researchers found an increased risk of childhood epilepsy after phototherapy but only in boys. We investigated this association in a Kaiser Permanente Northern California cohort. METHODS:From 499 642 infants born at ≥35 weeks' gestation in 1995-2011 followed for ≥60 days, we excluded 1773 that exceeded exchange transfusion thresholds and 1237 with seizure diagnoses at <60 days. We ascertained phototherapy, covariates, and outcomes from electronic records and existing databases. Our primary outcome was ≥1 encounter with a seizure diagnosis plus ≥1 prescription for an antiepileptic drug. We used Cox and Poisson models to adjust for bilirubin levels and other confounding variables. RESULTS:A total of 37 683 (7.6%) infants received any phototherapy. The mean (SD) follow-up time was 8.1 (5.2) years. The crude incidence rate per 1000 person-years of the primary outcome was 1.24 among phototherapy-exposed children and 0.76 among those unexposed (rate ratio: 1.63; 95% confidence interval [CI]: 1.44 to 1.85). The adjusted hazard ratio (aHR) was 1.22 (95% CI: 1.05 to 1.42; P = .009). Boys were at higher risk of seizures overall (aHR = 1.18; 95% CI: 1.10 to 1.27) and had a higher aHR for phototherapy (1.33; 95% CI: 1.10 to 1.61) than girls (1.07; 95% CI: 0.84 to 1.37), although effect modification by sex was not statistically significant (P = .17). The adjusted 10-year excess risks per 1000 were 2.4 (95% CI: 0.6 to 4.1) overall, 3.7 (95% CI: 1.2 to 6.1) in boys, and 0.8 (95% CI: −1.7 to 3.2) in girls. CONCLUSIONS:Phototherapy in newborns is associated with a small increased risk of childhood seizures, even after adjusting for bilirubin values, and the risk is more significant in boys.

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Initiating Phototherapy at Subthreshold Levels

Taylor

Chang

2018

JAMA Pediatr

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The well-designed study by Tun et al 7 therefore has merits because of the addition of important information that supports the view that maternal BMI and cesarean delivery cooperate in shaping the microbial communities of early life, which are associated with the development of OWOB in their offspring. Nonetheless, their study has a number of limitations that should be taken into consideration by future confirmatory studies. In particular, a major limitation was the lack of maternal samples for IM analysis. Maternal vaginal and skin microbiota are also involved in the development of infant IM but were not studied. Infant stool samples were collected only once at a mean age of 3.7 months. Other stool samples collected at older ages (eg, age 12 months) might have allowed confirmation of the results, especially given the information that infant IM changes during the first year of life and that different factors affecting infant IM (eg, breastfeeding and early exposure to antibiotics) appear pivotal. Limited generalizability of the results (exclusive Canadian ethnicity) was also a limitation.Despite the limitations of the study by Tun et al, 7 its strengths include the large study population. They found that richness in Firmicutes species and increased abundance of Lachnospiraceae were important for the intergenerational transmission of OWOB. Future studies are needed to confirm these results and to understand more deeply the multiple factors implicated in a hitherto still complex interplay. Further clarification of the mechanisms leading to the development of childhood obesity may pave the way to novel strategies for obesity prevention that include the interruption of intergenerational transmission of OWOB from mother to offspring.

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Efficacy of Subthreshold Newborn Phototherapy During the Birth Hospitalization in Preventing Readmission for Phototherapy

Cited by 34 publications

References 30 publications

Reply to: Phototherapy and childhood cancer: Shared risk factors?

Reply to: Phototherapy and childhood cancer: Shared risk factors?

Childhood Seizures After Phototherapy

Initiating Phototherapy at Subthreshold Levels

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