Community health worker-led household screening and management of neonatal hyperbilirubinemia in rural Bangladesh: a cluster randomized control trial protocol

Background Extreme hyperbilirubinemia leading to neurologic disability and death is disproportionately higher in low- and middle-income countries (LMIC) such as Bangladesh, and is largely preventable through timely treatment. In LMICs, an estimated half of all newborns are born at home and few receive screening or treatment for hyperbilirubinemia, leading to 6 million newborns per year who need phototherapy treatment for hyperbilirubinemia but are untreated. Household screening and treatment for neonatal hyperbilirubinemia with phototherapy administered by a trained community health worker (CHW) may increase indicated treatment for neonatal hyperbilirubinemia in comparison to the existing care system in Bangladesh. Methods 530 Bangladeshi women in their second or third trimester of pregnancy from the rural community of Sakhipur, Bangladesh will be recruited for a cluster randomized trial and randomized to the intervention arm — home screening and treatment for neonatal hyperbilirubinemia — or the comparison arm to receive usual care. In the intervention arm, CHWs will provide mothers with two prenatal visits, visit newborns by 2 days of age and then daily for 3 days to measure transcutaneous bilirubin (TcB) and monitor for clinical danger signs. Newborns without danger signs but with a TcB above the treatment threshold, but >15 mg/dL will be treated with light-emitting diode (LED) phototherapy at home. Newborns with danger signs or TcB ≥15 mg/dL will be referred to a hospital for treatment. Treatment rates for neonatal hyperbilirubinemia in each arm will be compared. Conclusion This study will evaluate the effectiveness of CHW-led home phototherapy to increase neonatal hyperbilirubinemia treatment rates in rural Bangladesh. LMICs are expanding access to postnatal care by using CHWs, and our work will give CHWs a curative treatment option for neonatal hyperbilirubinemia. Similar projects in other LMICs can be pursued to dramatically extend healthcare access to vulnerable newborns with hyperbilirubinemia.

(CHW) may increase indicated treatment for neonatal hyperbilirubinemia in comparison to the existing care system in Bangladesh.

Methods
530 Bangladeshi women in their second or third trimester of pregnancy from the rural community of Sakhipur, Bangladesh will be recruited for a cluster randomized trial and randomized to the intervention arm -home screening and treatment for neonatal hyperbilirubinemia -or the comparison arm to receive usual care.In the intervention arm, CHWs will provide mothers with two prenatal visits, visit newborns by 2 days of age and then daily for 3 days to measure transcutaneous bilirubin (TcB) and monitor for clinical danger signs.Newborns without danger signs but with a TcB above the treatment threshold, but >15 mg/dL will be treated with lightemitting diode (LED) phototherapy at home.Newborns with danger signs or TcB ≥15 mg/dL will be referred to a hospital for treatment.Treatment rates for neonatal hyperbilirubinemia in each arm will be compared.

Conclusion
This study will evaluate the effectiveness of CHW-led home phototherapy to increase neonatal hyperbilirubinemia treatment rates in rural Bangladesh.LMICs are expanding access to postnatal care by using CHWs, and our work will give CHWs a curative treatment option for neonatal hyperbilirubinemia.Similar projects in other LMICs can be pursued to dramatically extend healthcare access to vulnerable newborns with hyperbilirubinemia.

Background
Approximately 18% of all infants, including approximately 14 million infants per year in low-and middle-income countries (LMIC), are at risk of neonatal hyperbilirubinemia progressing to extreme hyperbilirubinemia and brain damage 1 .Of the 481,000 yearly cases of extreme hyperbilirubinemia, 80% occur in LMICs 1 .The highest burdens of extreme hyperbilirubinemia are in sub-Saharan Africa and South Asia, where the mortality rate of extreme hyperbilirubinemia and rhesus disease is about one hundred times higher and rates of neurologic disability are about eight times higher than rates in high income countries 1 .
Too often, newborns in LMICs present at hospitals for treatment too late, having already developed brain damage from extreme hyperbilirubinemia, when phototherapy is no longer effective 2 .It is estimated that 6 million newborns in LMICs need treatment yearly yet do not receive it 3 .There are a cascading series of delays in diagnosis and treatment that occur, resulting in preventable disability and deaths of this time-dependent condition 4 .In many LMICs, more than half of newborns are born at home, where postnatal visits and physical examination screenings or laboratory screening for neonatal hyperbilirubinemia are rarely performed 5 .The World Health Organization (WHO) in the Integrated Management of Childhood Illness (IMCI) guidelines, recommend neonates in LMICs receive home or clinic-based physical examination screenings followed by a referral to a hospital if there is concern for hyperbilirubinemia 6,7 .Physical examination-based screening by physicians prior to hospital discharge has been shown in one LMIC to be less effective in reducing cases of severe hyperbilirubinemia than transcutaneous bilirubin (TcB) screening 8 .In LMICs, infants born in health facilities by vaginal delivery are often discharged without bilirubin screening after less than 24 hours leading to missed cases of severe hyperbilirubinemia 8 .Parents often only realize that their child is sick when their newborn develops symptoms from brain damage.
Even if newborns are diagnosed in a timely fashion, hospital-based treatment for newborns in LMICs is difficult to access and expensive for families.In a study on neonatal sepsis in rural Bangladesh, only one-third of newborns that were referred to the hospital from home for physical examination findings concerning for sepsis went to the hospital 9 .
The costs of bringing the newborn to the hospital and obtaining care were found to be major barriers 9,10 .However, families were willing to have their newborns treated at home.Approximately 65% of parents who refused referral for neonatal sepsis evaluation in hospitals consented to home care by CHWs with intramuscular injection with antibiotics, increasing access to care and reducing neonatal mortality by 34% 9 .By providing household treatment for neonatal hyperbilirubinemia, essential care can be expanded to families that would otherwise not have access to treatment, potentially reducing disability and death from neonatal hyperbilirubinemia.Families will not have to travel to hospitals, wages will not be lost from taking days off from work, the cost of nurses and physicians will be replaced with less expensive and easier-to-train CHWs, and hospital bed costs will be eliminated.The risk of newborn exposure to hospital borne infections would also be eliminated.Home screening and treatment for neonatal hyperbilirubinemia has the promise to increase access to treatment and reduce cases of extreme hyperbilirubinemia 11 .

Study aims and hypothesis
We hypothesize that CHW-led household screening and treatment for neonatal hyperbilirubinemia will increase the rate of indicated treatment for neonatal hyperbilirubinemia when compared to current practices in rural Bangladesh.

Aim 1 (Treatment)
Assess the impact of CHW-administered home screening and neonatal hyperbilirubinemia treatment on treatment rates in comparison to the current postnatal care system in Bangladesh.
• The percentage of newborns that receive treatment for neonatal hyperbilirubinemia in the intervention and comparison clusters will be compared.
• We will evaluate the safety of CHW-administered LED phototherapy.We will measure the number of referrals for danger signs after starting home phototherapy, the need for exchange transfusion after starting home phototherapy, the development of extreme hyperbilirubinemia after starting home phototherapy (total serum bilirubin, TSB) ≥25 mg/dL, the development of severe hyperbilirubinemia (TSB ≥20 mg/dL) after starting home phototherapy, sepsis diagnosed after starting home phototherapy, and newborns diagnosed with hypoglycemia after starting home phototherapy.
• The acceptability of home and hospital hyperbilirubinemia screening and phototherapy treatment will be assessed qualitatively.

Aim 2 (Screening)
During appropriately timed home visits, CHWs will screen infants for neonatal hyperbilirubinemia.
We will demonstrate: • At least 80% of newborns born vaginally in intervention households are screened for neonatal hyperbilirubinemia by two days of age.

Amendments from Version 1
The new version of paper contains additional clarifying information requested by reviewers of the paper, notably including a change in the order of the study aims, additional detail on community health worker recruitment and training, and clarification of use of the phototherapy device and bilirubin thresholds for phototherapy.
Any further responses from the reviewers can be found at the end of the article

Aim 3 (Prevention)
Develop and conduct two maternal prenatal educational sessions supervised by CHWs in intervention households to encourage breastfeeding initiation within one hour of birth and exclusive breastfeeding through six months of age and help mothers to develop a plan for how to get to the nearest hospital with newborn services if their newborn is sick.
We will demonstrate: An absolute increase of at least 20% in breastfeeding rates by one hour of age and exclusive breastfeeding rates through four weeks of age in intervention families.

Trial design
We will conduct a prospective cluster randomized controlled trial to evaluate the impact of CHW-led home screening and treatment for neonatal hyperbilirubinemia on the percentage of newborns treated for hyperbilirubinemia.
In the intervention arm, CHWs will provide home hyperbilirubinemia screening and home treatment with phototherapy or referral for hospital treatment.In the comparison arm, newborns will receive treatment based on the current postnatal care system in rural Bangladesh, where newborns are referred for evaluation for hyperbilirubinemia based on parental concern and physical examination findings during postnatal visits.

Study setting
This study will enroll pregnant mothers in Sakhipur, Bangladesh, which is a rural agrarian community with a population of 300,000.It is 429 square kilometers in area, includes 132 villages, and is a part of the Tangail District.There are approximately 7,000 births in this community per year and approximately half of births occur at home 12 .There is a government hospital with 50 beds that provides caesarean section, vaginal birthing services, and emergency services 12 .Poverty, crowding, unstable housing, food insecurity, and poor hygiene and sanitation are common throughout the region.

Study population
About 98% of pregnant women in Sakhipur sub-district receive at least one antenatal care visit from a trained medical provider, and 66% of women receive four antenatal care visits 12 .
Approximately half of the mothers deliver at home 12 .Approximately 60% of newborns are seen by a health care provider within the first 48 hours after birth 12 .If neonatal hyperbilirubinemia is diagnosed and phototherapy is needed, newborns are referred for phototherapy treatment to the nearest hospital, which is more than two hours away.

Sample size
Approximately 18% of infants need treatment for neonatal jaundice 1 .We estimate that of the neonates born in facilities, half of those in need of treatment actually receive the indicated treatment and for home births, none receive the indicated treatment 1 .The indicated treatment rate in the comparison arm will be 25%, or 4.5% of infants.In the intervention arm, we expect that we can provide home phototherapy in 60% of cases of neonatal hyperbilirubinemia that need treatment.Of the other 40% of infants that we identified and referred to the hospital for treatment, we estimate that 33% will receive treatment 9 .The total indicated treatment rate is estimated at 80%, or 14.4% of infants.With a type 1 error rate of 5% and type 2 error rate of 20%, and a design effect of 1.6 due to cluster sampling and a loss to follow-up of 5%, the sample size is 262 in each arm.We aim to enroll 530 pregnant mothers from the Sakhipur sub-district.

Participant recruitment
The trial will receive oversight from the steering committee composed of eight investigators from icddr,b, three investigators from Stanford University, one investigator from Dhaka Children's Hospital, and one investigator from Bangabandhu Sheikh Mujib Medical University.
Trained fieldworkers from icddr,b will travel to the eligible communities and ask community leaders for permission to conduct research within their community.If the community leaders agree, then the team will proceed with recruitment.The prospect of participation in the study will be discussed with adults in the communities, including the pregnant mothers.
The scientific field team will go house-to-house to list all the pregnant women on the basis of documentation of their pregnancy (i.e., possession of an antenatal care (ANC) card and/or prescription from the selected unions of the sub-district) to enroll them as study participants if they meet the eligibility criteria.If any pregnant mother does not have an ANC card, but is willing to participate in the study, she will be sent to local health facilities to register for an ANC card.Before recruitment, we will reach out to local government workers to identify pregnant women in the second or third trimester.They maintain a register of all newlyweds and update new pregnancies to encourage ANC, safe delivery and postnatal care services.In addition, the trained fieldworkers will travel to the eligible communities to create an enabling environment to conduct the research in their community.Field workers will confirm that participants have access to a mobile phone.
Written informed consent will be obtained from interested participants prior to beginning the study.

Inclusion criteria
Study participants will be pregnant women 18 years of age or older in their second or third trimester of pregnancy and who consent to enroll as study participants.

Exclusion criteria
Study participants will be excluded if there is a multiple gestation pregnancy, future plans to leave the area within the next 12 months (e.g., if a mother is planning to give birth at her natal home and then return later to the study area, she will not be a candidate for enrollment), if maternal danger signs are present, if there is a history of severe mental health condition, defined as any mental condition either medically diagnosed or reported by family to affect activities of daily living.
There are no inclusion or exclusion criteria for newborns born to study participants.All newborns born to enrolled mothers will be enrolled.A timeline of the study period is described in Table 1.

Cluster randomization and intervention allocation
Amongst eligible participants, we will form clusters of 25-29 expectant mothers who live close enough to participate in the study based on the geographical proximity (Figure 1).There will be a minimum distance of one hundred meters between households.There will be a minimum distance of one kilometer between clusters.Households that do not form a cluster according to geographical proximity will not be included in the cluster.A statistician not involved in the study will randomly assign 20 clusters using a random number generator.Clusters will be divided equally across intervention and comparison arms.
Given the nature of treatment in the intervention group, masking of participants and caretakers will not be feasible in the intervention group.CHWs will know if they are delivering the intervention.However, care will be taken to ensure that the outcome assessors are not aware of the interventions allocated to specific clusters.Individuals involved in delivering the intervention and the evaluation will have minimal contact to minimize bias.

Community health workers recruitment and training
CHWs will be recruited through local advertisements and supervised by the Bangladesh-based scientific team. .Bedside training will include danger sign assessment of neonates and using the transcutaneous bilimeter and phototherapy device.CHWs will be trained to make newborn danger sign and lactation assessments in the hospital under the supervision of physicians and receive feedback on their assessment of five newborns in the hospital.There will also be a pre-test and post-test assessment on the content of the second phase of training.Then, the CHWs will be observed performing physical examinations and using equipment in the field for three days under supervision from the study physician.The ten CHWs that performed best on the assessments will be invited to participate in the study.
The study physician will observe CHWs' neonatal danger sign assessments over the course of the study to evaluate the sensitivity and specificity of CHW newborn danger sign assessments in comparison to a physician examination.The study physician will repeat the newborn danger sign assessment independently within 4 hours of the CHW assessment.The study physician will repeat 20% of the newborn danger sign assessments conducted by each CHW.The sensitivity and specificity of CHW physical newborn examination in identifying newborns with clinical danger signs will be determined in comparison to a physician's physical examination.Feedback will be given to CHWs based on their danger sign assessments.
In addition, the study physician and field staff will observe CHWs administering home phototherapy and provide feedback as necessary.
CHWs will be taught how to operate the phototherapy device during training at Dhaka Children's Hospital and in the field.They will be trained to measure the irradiance of the phototherapy unit and that it should measure at least >50 μW/cm2/nm prior to initiating treatment.They will be taught to educate parents on how the newborn should be treated with phototherapy in their absence, and to call the CHW if they need additional help.CHWs will be trained to complete the following operational and educational checklist with caregivers prior to initiating phototherapy.The operational checklist will also be completed at each follow-up visit.

CHW Phototherapy Operational Checklist
• Measured temperature between 25°C -27°C within the bassinet; if the temperature could not be maintained between 25°C -27°C, an electric heater will be provided to maintain the temperature between 25°C -27°C within the bassinet.If this fails, the infant will be referred to the hospital for treatment.
• Bassinet is covered by a white blanket.
• Phototherapy device is placed in a safe place on a flat surface.
• Phototherapy device has a household power source and would turn on.
• Infant is in a bassinet face-up with eye cover and diaper and no other clothes on.
• Review of parental log on daily number of breastfeeding attempts, urination, and defecation and if the phototherapy unit was turned off overnight from 0000-0600.
CHW Educational Checklist for mothers and caregivers whose newborn will be treated with home phototherapy.
• CHW to explain the need to treat the newborn with phototherapy for neonatal hyperbilirubinemia.
• CHW explains that newborns will be treated for 2 days with phototherapy with two 6-hours breaks at night from midnight to 6 am, for approximately 36 hours of phototherapy treatment.
• CHW explains that mothers should take newborns out from under the phototherapy lights to breastfeed their newborns every two to three hours for approximately twenty to thirty minutes.
• CHW will return in four to six hours and then daily until phototherapy treatment and post-treatment monitoring was completed.
• CHW explains how the phototherapy device works and how to operate the phototherapy device in the absence of CHWs.
o The phototherapy device should be in a safe space on a flat surface.
o How to cover the newborn's eyes with a mask when the newborn was being treated with phototherapy.
o Infant to be placed in phototherapy bassinet face-up with eye cover and diaper and no other clothes on during treatment.
o Phototherapy unit covered by a white blanket.
o Instruction on how to use a provided chart to record the daily number of breastfeeding attempts, urination, and defecation and if the phototherapy unit was turned off overnight from 0000-0600.
o How to use diapers during phototherapy, to clean and dry the bassinet if it gets soiled.
o Monitor the newborn for danger signs and contact the designated CHW if any issue arose, 14 and to bring their newborn to the hospital if concerned.
o If the phototherapy device is turned off for more than 2 hours and unable to turn back on due to power loss, bring the newborn to the hospital.
• Call the CHW if there were issues or questions.
We will also conduct a training session with the staff nurses and medical officers of the referral hospital to orient them to the study intervention and ensure proper management of referred newborns.Field staff along with the training team will review performance (knowledge, skill, and attitude) of CHWs every two weeks and provide advice and trainings to maintain skills.
Each CHW will manage the care of approximately twenty newborns per month over the course of the study.On average each CHW will perform three home visits per day.Study households will be within one-hour travel time for the CHWs.

Intervention arm Intervention 1: Breastfeeding and neonatal hyperbilirubinemia module development
We will develop a CHW-led prenatal education module to encourage early and frequent breastfeeding, including initiation within one hour after birth and exclusive breastfeeding through six months of age, and to educate mothers on the neonatal and maternal danger signs as well as the dangers of severe neonatal hyperbilirubinemia 14 .The module will help mothers develop a plan to bring their newborn to an appropriate health facility, if necessary, after birth.We will adapt the guideline from Bangladesh Ministry of Health Comprehensive Newborn Care package 15 .We will share the guideline with our key stakeholders to incorporate their recommendations to make the modules more feasible for CHWs.CHWs will visit enrolled pregnant mothers and conduct two prenatal education sessions which will increase awareness among mothers and other household members about exclusive breastfeeding and risk of neonatal hyperbilirubinemia.The sessions will include education on the importance of attending recommended antenatal and postnatal newborn and maternal care visits, delivery preparation, ante partum, intrapartum and postpartum danger signs, neonatal danger signs, exclusive breastfeeding, and neonatal hyperbilirubinemia (including signs, symptoms, screening via transcutaneous bilimeter and possible need for treatment in the hospital or at home with phototherapy).Newborns in the intervention arm are not restricted from receiving neonatal hyperbilirubinemia care through the existing postnatal care system.

Intervention 2: Blood and rhesus typing, noninvasive TcB screening newborns for neonatal hyperbilirubinemia and evaluation of newborn danger signs
The mother's blood and rhesus type will be determined at the birth survey visit, if it was not already determined during antenatal visits, by a medical technologist.Newborn blood grouping and rhesus typing will be determined at the birth survey visit by a medical technologist.Three drops of blood will be collected using a lancet needle.For newborns, the specimen will be taken by heel prick and for mothers it will be taken by the finger prick.The slide test method will use antimonoclonal blood type antibodies for each blood type and anti-D monoclonal antibodies.We define rhesus incompatibility to be when the mother is rhesus negative and the newborn is rhesus positive, and we define blood type incompatibility to be when the mother is blood group O, and the newborn does not have blood group O.If rhesus incompatibility is present, we will refer the mother for rho(D) immune globulin treatment at a local health facility if she has not already received treatment.
We will follow the neonatal hyperbilirubinemia management algorithm in Figure 2a that we developed following the 2004 American Academy of Pediatrics (AAP) guidelines (Figure 2b), using intensive >30 μW/cm2/nm irradiance, clinically approved, LED phototherapy (Firefly, Figure 3) 16 .CHWs will be supported by an electronic tablet that guides them through the clinical management algorithm (Figure 2a) step-by-step.
Total bilirubin will be measured using a transcutaneous bilimeter (Draeger JM-105).Transcutaneous bilimeters tend to overestimate the serum bilirubin concentration at TcB levels <15 mg/dL by 0.84 mg/dL 17 .This provides a safety margin as transcutaneous bilimeters tend to measure higher than the serum bilirubin.At levels of bilirubin >15 mg/dL, transcutaneous bilimeters do not approximate the serum concentration as well, which is why we will refer all newborns with a TcB >15 mg/dL to the hospital to obtain a serum bilirubin and evaluation by a medical provider 18,19 .
The assigned CHW will visit each newborn born vaginally within two days after birth and newborns born via caesarean section will be visited the day after hospital discharge then daily for three consecutive days to assess for hyperbilirubinemia and evaluate breastfeeding and institute phototherapy if indicated.During CHW visits, if any danger signs are observed, CHWs will refer newborns to an appropriate medical  facility.The phototherapy treatment level is the 2004 AAP phototherapy threshold adjusted for gestational age, and presence of rhesus or blood type incompatibility or if the bilirubin is rising ≥0.2 mg/dL/hour on consecutive visits (Figure 2b).Newborns eligible for home treatment will be treated with CHW-led LED phototherapy.
The following neonatal and maternal danger signs were adopted from the National Neonatal Health Strategy 2009 and research done in Bangladesh to validate neonatal danger signs to predict need for hospital-based care [19][20][21][22] .If any of the following neonatal danger signs are present on CHW assessment, the newborn will be referred to the nearest appropriate medical facility for treatment.CHWs will make a lactation assessment of the feeding of the newborn and offer the mother tips to improve breastfeeding.

Intervention 3: Home management of neonatal hyperbilirubinemia by LED phototherapy
The following are the inclusion criteria for newborn home phototherapy.At least one must be present: a) TcB above the AAP phototherapy threshold adjusting for gestational age and presence of rhesus or blood type incompatibility (Figure 2b) 16  All newborns will be treated with phototherapy for a 48-hour period.Newborns will be recommended to be placed under the phototherapy lights unless they are feeding, which we estimate to be 30 minutes every three hours and there will be a six-hour phototherapy break overnight.The total treatment duration will be approximately 36 hours of phototherapy, 18 hours per day.The phototherapy device will be checked by the CHW before each use in the home using the manufacturer recommended irradiance meter (Lightmeter V7.0) to ensure that the irradiance is at recommended levels of at least 50 μW/cm 2 /nm.The phototherapy unit will be covered by a white blanket to maintain the temperature and to enhance phototherapy effectiveness.The CHW will measure the temperature inside the phototherapy unit on initiation and during each subsequent visit with a target of 25°C-27°C under the blanket inside the unit.A portable room heater will be available to maintain the room temperature during phototherapy treatment.
After diagnosing the need for home phototherapy, the CHW will initiate phototherapy within four hours.
CHWs will perform the operational checklist at each phototherapy visit and educate parents following the educational checklist.Parents will be instructed when to seek emergency care.The CHW will survey mothers during phototherapy to explore potential issues with treatment.
During home phototherapy treatment, newborns will be evaluated by a CHW daily.If any maternal or newborn danger signs are present, home phototherapy will be stopped, and the newborn or mother will be referred to the nearest appropriate health facility.CHWs will answer any questions parents have about the treatment.CHWs will be able to consult the study physician by phone if there are concerns or questions.

Monitoring after home phototherapy
CHWs will visit the household daily for two days beginning the day after phototherapy completion and measure the TcB on consecutive days and assess for danger signs (Figure 2a).We will consider any newborn that has a TcB <15 mg/dL for two consecutive days after treatment and rising <0.2mg/dL/hour to have resolved hyperbilirubinemia.If the TcB is ≥15 mg/dL or rising ≥0.2mg/dL/hour on the second follow up visit, we will refer the newborn to the hospital for evaluation.If the newborn requires subsequent hospital admission after initial qualification for phototherapy, we will define that as unresolved hyperbilirubinemia.
Transcutaneous bilimeters are not as reliable to measure the progress of phototherapy during treatment, as TcB values are less than the serum value while phototherapy is occurring.After 16-24 hours after phototherapy treatment is completed, their reliability is similar to before phototherapy 28,29 .We will perform TcB measurements on consecutive days beginning 24 hours after phototherapy to ensure that the transcutaneous bilirubin remains below the treatment threshold and is not rising rapidly.
If the family refuses treatment at home, the newborn will be referred to the hospital for treatment.If they refuse home and hospital treatment, CHWs will continue to follow up with the newborn and make three consecutive daily visits in each household and refer the newborn to the hospital if indicated.

Mobile health (mHealth) data collection and decision support
CHWs will use a program that we developed on CommCare (Dimagi, Cambridge, USA) that is uploaded on electronic handheld tablets to guide CHWs through each task during each encounter with participants (Figure 4).The program will   2b) 14 .
The data on the blood and rhesus type will be entered and stored in CommCare at the time of collection.The rate of rise of TcB will be calculated by CommCare by subtracting the TcB measured the previous day from the current day's TcB and dividing by the hours that elapsed between the two measurements.
On completion of newborn danger sign assessment, transcutaneous bilirubin measurement, and maternal danger sign assessment, CommCare will help the CHW decide if the newborn needs to be referred to the hospital for care or can be treated at home with phototherapy for neonatal hyperbilirubinemia.
CHWs will be encouraged to consult the study physician by phone or in person if there are concerns or questions.

Laboratory evaluation of all newborns referred for danger signs or TcB ≥15
We will obtain the following laboratory studies for any newborn referred for hospital evaluation for danger signs or TcB ≥15 mg/dL: blood glucose, total serum bilirubin and blood culture.Blood glucose will be tested using a rapid field test kit.Hypoglycemia will be defined as serum glucose <50 mg/dL.Serum bilirubin will be tested in Sakhipur Health Complex using a Garnier G-3000 semi-auto analyzer and end point, kinetics, fixed-time, 2-point kinetic, absorbance coagulation method.
Blood cultures will be collected by a trained medical technologist from icddr,b with assistance of trained staff nurses of Sakhipur Health Complex.At least 1 mL of blood will be collected, and the specimen will be transferred to icddr,b laboratory within 12 hours of collection.If Candida or multiple bacterial species are identified, the case will be discussed with the study physician and blood cultures will be repeated as indicated to verify the growth as an infection versus the result of contamination.Coagulase-negative Staphylococcus, Diptheroids, and Bacillus species will always be considered to be contaminants.Culture reports of growth or no growth will be provided to the clinical care team within 24 hours.
Blood culture measurement will help validate CHW danger sign assessments and to determine if infection may have been a cause for neonatal hyperbilirubinemia.
There will be a study physician who will coordinate with hospital and district level managers for any referral issues.Both secondary and tertiary level facility service providers will receive orientation on the study protocol and referral processes.Any newborn who requires exchange transfusion will be referred to Dhaka Children's Hospital in Dhaka, Bangladesh.
During trial implementation, a field monitoring team consisting of a field research officer, a study physician, and a field coordination manager will regularly visit the field to monitor the intervention delivery.The primary responsibility of this team is to monitor if the intervention has been delivered following guidelines, identify, and solve problems regarding field implementation and report to the investigators.

Equipment
Transcutaneous bilirubin will be measured by Draeger JM-105.Draeger JM-105 is a non-invasive transcutaneous bilirubinometer which has demonstrated high accuracy when compared to total serum bilirubin 30 .Phototherapy treatment will be provided by a double surface portable LED phototherapy device with battery backup, Firefly (Figure 3).Peak wavelength is 455 to 470 nm, lamp duration is 44,000 hours to 30% degradation.Top light: irradiance 34.8 μW/cm 2 /nm, surface area: 53 cm × 25 cm, irradiance uniformity ratio 0.51 (IEC Compliant > 0.4).Bottom light: irradiance 50.4 μW/cm 2 /nm, surface area 50 cm × 20 cm irradiance uniformity 0.72.The overhead light position is fixed at 49.5 cm above the bottom of the device.The dimensions of the bottom of the unit are 66 cm by 38 cm and it weighs 13 kilograms.The LED phototherapy device has an internal battery backup that can maintain operation for 12 hours in case of power outages.The irradiance of the device will be measured using the manufacturer recommended irradiance meter (Lightmeter V7.0).A portable room heater will be available if needed to maintain the temperature between 25°C and 27°C within the bassinet at home during phototherapy.

Comparison arm (Existing postnatal care system)
In the comparison arm, newborns will receive treatment for neonatal hyperbilirubinemia based on the current postnatal care system in rural Bangladesh.Approximately 7% of newborns born at home have a postnatal visit within 48 hours and are unlikely to be evaluated for neonatal hyperbilirubinemia in a time frame that would result in timely treatment.Infants born vaginally in a hospital delivery often spend 4-8 hours in the hospital prior to discharge.Infants born by vaginal delivery in the hospital or by caesarean section typically have a postnatal care visit by two days of age.If the mother has a concern about the health of their newborn, including concern for jaundice, they may bring the child to the healthcare system, leading to physician assessment, and recommendation for testing.

Baseline survey
A group of field research assistants will conduct a baseline survey of all mothers at the time of enrollment.The survey will assess each mother's previous medical history, family history of treatment for hyperbilirubinemia, family history of disability from hyperbilirubinemia, and family history of hearing loss.The survey will also collect information on parental socioeconomic factors, knowledge of breastfeeding and neonatal hyperbilirubinemia, delivery plans, and plans for emergency neonatal and maternal care.Figure 1 illustrates the various steps for each arm in the study.

Birth survey
We will establish a direct contact system to inform the research team about a study participant's delivery.The mother and the head of the household will be given the emergency contact number of the research team.They will be instructed to inform the research team once the mother is in labor.The survey will occur approximately one day after discharge of the hospital or by two days of age for home births in intervention households and by seven days of age in comparison households.The assigned field worker will go to the home and survey the family on the circumstances of the birth, inquire on how long after birth breastfeeding was initiated, measure the birth weight, and calculate the gestational age based on last menstrual period and birth date with the assistance of an electronic tablet.

Endline survey
We will carry out a household survey in each study arm at infant age four weeks to evaluate the health status of the newborns.We will survey for newborn hospitalizations, maternal hospitalizations, presence of neonatal hyperbilirubinemia, screening for neonatal hyperbilirubinemia with blood or TcB measurement, phototherapy treatment for hyperbilirubinemia, neonatal sepsis, exclusive breastfeeding percentage, and maternal depression.The endline survey data will be used to evaluate if the newborn received phototherapy treatment for hyperbilirubinemia.

Primary outcome
The primary outcome will be the proportion of neonates that receive phototherapy treatment, either at home or in a facility in each study arm.
At the end of this intervention period, we will compare the primary outcomes between the intervention and comparison newborns using a chi-square test while adjusting for cluster study design.The significance level will be p <0.05.The quantitative analysis will be conducted by the original assigned groups in an intention-to-treat analysis.Investigators will have no access to outcome data until field activities are complete.CONSORT guidelines will be followed to conduct the analysis 31 .This analysis will be conducted by the scientific team using a variety of software including R Project for Statistical Computing (RRID:SCR_001905) and STATA RRID:SCR_012763).We are not planning an interim analysis.

Secondary outcomes
Secondary outcomes include the proportion of mothers who initiated breastfeeding within one hour of childbirth in each study arm, the percentage of mothers exclusively breastfeeding at four weeks in each study arm, the proportion of neonates born vaginally that are screened for neonatal hyperbilirubinemia by 48 hours of age in each study arm, and any neonatal deaths during that period in each study arm.At the end of this intervention period, we will compare these secondary outcomes between intervention and comparison group newborns using chi-square test while adjusting for cluster study design.The significance level will be p <0.05.The quantitative analysis will be conducted by the original assigned groups in an intention-to-treat analysis.
We will also evaluate for safety measures in Table 2.This includes the number of referrals for danger signs after starting home phototherapy, the need for exchange transfusion after starting home phototherapy, the development of extreme hyperbilirubinemia (total serum bilirubin ≥25 mg/dL) after starting home phototherapy and severe hyperbilirubinemia (total serum bilirubin ≥20 mg/dL) after starting home phototherapy.We will measure the number of newborns with sepsis (positive blood culture) diagnosed after starting home phototherapy, and the number of newborns diagnosed with hypoglycemia (serum blood glucose <50 mg/dL) after starting home phototherapy.

Missing data
CHWs will communicate with the participants throughout the study over the phone to monitor their health condition.This will build a sense of trust and reliability between study participants and CHWs.The research team will also arrange community meetings to gain overall community and community leader support on neonatal hyperbilirubinemia screening and management.This outreach will be integral to encouraging protocol adherence.However, in the case of protocol non-adherence we will use an intention to treat analysis to assess the main study outcome.For any other missing data, we will document the cause of missing data.For analysis, we will not count the missing data and will set the denominator excluding the missing data Data and safety monitoring board (DSMB) and safety review plan An independent five-member DSMB will be assembled in Bangladesh to monitor adverse events and to advise investigators.The board will be composed of two neonatologists, two epidemiologists, and one demographer.
We will collect data on treatment progress, side effects of treatment, and adverse events during the study.Any cases of acute bilirubin encephalopathy, exchange transfusion, or death during the trial will be considered a serious adverse event and reported to the DSMB.The investigators will report serious adverse events to the DSMB within 24 hours of the event.For any serious adverse event, a follow-up report will be submitted withing 48 hours and a final report will be submitted within 72 hours of first report submission.The DSMB will be responsible for evaluating the event and decide if the principal investigator's report is satisfactory or not.If the event is not a serious adverse event but determined by the principal investigator to be reportable, an initial report will be submitted to the DSMB as soon as possible, but no later than seven days after the investigators learns of the event.The DSMB will disseminate the outcome of the review to the principal investigator of the study.
Side effects from phototherapy treatment are rare and the AAP regards the treatment as safe 16 .A rare complication of phototherapy, bronze baby syndrome, occurs in some infants with cholestatic jaundice when treated with phototherapy 32 .With exposure to phototherapy, infants develop a dark, gray-brown discoloration of skin, urine, and serum.For newborns with a bilirubin above the phototherapy threshold, it is recommended to treat infants with cholestatic jaundice with phototherapy.The incidence of cholestatic jaundice in newborns is 1 in 2500 33 .Not all newborns with cholestatic jaundice need phototherapy and the long terms effects of bronze baby syndrome are not thought to be deleterious and resolve over time.CHWs will screen and monitor to determine the possibility of the development of this complication.
Another possibility is the development of purpura or bullae in infants with cholestatic jaundice or congenital erythropoietic porphyria 34 .There are approximately 200 cases of congenital erythropoietic porphyria reported.Because the photosensitivity and blistering can be severe in infants with porphyria, infants who have this diagnosis or a positive family history for this disorder have an absolute contraindication for phototherapy.CHWs will screen and monitor neonates to determine the possibility of the development of this complication.

Qualitative analysis
We will use focus group discussions (FGD) and in-depth interviews (IDI) to assess barriers and facilitators of home treatment and hospital treatment amongst the implementers and the participants.Discussions will assess for challenges with using the phototherapy device and explore mothers' concerns with the treatment and whether they felt they could ask for help in using the device.We will explore if mothers felt like using the device made breastfeeding more difficult.Facilitators will query if CHWs provided adequate explanations for why treatment was necessary and if they educated the mother sufficiently on how to do the treatment.
For mothers whose newborns were referred to the hospital for treatment, we will assess if there was difficulty breastfeeding due to treatment, if there was difficulty traveling to the hospital, and if the hospital provided adequate resources for treatment.We will discuss barriers and facilitators of a successful referral to the hospital.Facilitators will query if CHWs provided adequate explanations for why referral was needed.
Facilitators will explore mothers' comfort with CHWs and their trust in their recommendations.We will explore if diagnosis of hyperbilirubinemia needing treatment with the transcutaneous bilimeter was more likely to result in successful referral in comparison to diagnosis with danger signs by CHW physical examination.

Data collection plan for qualitative analysis
The qualitative data will be collected by qualitative researchers, and they will be trained on the proposed guideline before going to the field.The collection plan is outlined in Table 3.
All the IDIs and FGDs will be recorded using audio recorders.
The research team will take field notes of informal discussions, observations on the tone and attitudes of the respondents during data collection.
Audio recorded data of IDIs and FGDs will be transcribed into Bengali and then translated to English.Some portions of the interviews that contain local terms and expressions will be highlighted to understand the tone of the interviewees.
Code lists for each of the tool, i.e., FGD, IDI will be prepared separately.All the data will be coded accordingly using ATLAS.tiversion no.5.2.Coded data will be summarized according to the study objectives and relevant themes.All data will be analyzed considering the content and context analysis, followed by comparison and triangulation.It is a common phenomenon to have different findings when applying different tools for the same issue with the same unit of analysis.If this occurs, we will conduct additional exploration.
One assistant program manager will regularly check the data and will identify any inconsistency, missing data and quality of the data and will report to the investigators.
and benefits, confidentiality and future use of information will be explained to the participants.For the collection and use of biological specimens, additional informed consent will be taken from the participants.
Trial data will be collected in the CommCare database, which is a secure, web-based application designed to support data capture for research studies.All pregnant women and newborns will have an anonymous study identification number.Any documents linking patient identifiers to the anonymous study identification number will be stored in CommCare.
Both icddr,b and Stanford research teams will have access to final trial data and there are no contractual agreements that limit access to investigators.Only aggregate analyses without patient identifiers will be published.The study data will be stored by the principal and co-investigators during the study period and will be stored in the icddr,b data repository under the icddr,b Data Repository committee at the end of the study period.Data from the icddr,b Data Repository (icddr,b Datasets) will be provided upon request for purposes of secondary data analyses upon approval of a Data Licensing Application & Agreement.The Spirit 2013 Checklist and CONSORT 2010 checklist were uploaded to Zenodo 31 .To maintain participants' anonymity and confidentiality, the data set generated during the study will not be publicly available but are available from the principal investigator on reasonable request.We plan to disseminate the results of this trial in peer-reviewed journals and international conferences.Our target audience are those involved in newborn health management in low-resource settings as well as those who develop and advise on policy, especially the Ministry of Health and Family Welfare, Bangladesh.
We will periodically share the progress and challenges of the study to keep the stakeholders updated and seek their support as and when needed.At the end of intervention, we will convene a national level stakeholders' meeting to disseminate study findings with government and non-government organizations.This convening will also be an opportunity to influence implementers based on the result generated by the project.We will develop an agenda for the convening meeting that addresses key themes that emerge from household-level interventions.

Study status
The study has completed data collection, and the results are being analyzed.No changes were made to the protocol after the trial commenced.

Discussion
In this study, we will evaluate the impact of CHW-led home screening and household phototherapy treatment for neonatal hyperbilirubinemia on access to phototherapy treatment in a rural community in Bangladesh where timely postnatal care is limited.The treatment arm will employ improved household screening with a point-of-care TcB measurement, a mHealth platform to extend the capabilities of CHWs, and a phototherapy device that can be used to treat newborns at home.This study leverages relationships with Bangladeshi communities, the government, and health providers.
The results of the study will be clinically relevant by developing evidence to show how to successfully expand access to neonatal hyperbilirubinemia care to the most vulnerable newborns in LMICs.It will provide evidence on how to safely extend the capabilities of CHWs through mHealth with a validated treatment algorithm to provide quality postnatal care and curative neonatal hyperbilirubinemia care.LMICs are expanding access to postnatal care by using CHWs, and our work will give CHWs a curative treatment option in the immediate postnatal period.Caring for newborns at home instead of in the hospital offers potential benefits including improved access and acceptability which may lead to improved health outcomes as well as decreased risk of obtaining hospital acquired infections, which could drive widespread adoption and reduce morbidity and mortality from neonatal hyperbilirubinemia care amongst those that are most vulnerable.Similar projects in other LMICs can be pursued to evaluate their effectiveness and dramatically extend healthcare access to the most vulnerable newborns.
Prior work has shown that CHWs can accurately detect severe illness in newborns after birth and reduce mortality through postnatal visits which include screening for neonatal danger signs via physical assessment [19][20][21][22][23][24][25][26] .CHW home visits in the first days after birth in rural Bangladesh reduced newborn mortality by 34% 9,35,36 .The performance of CHW physical examination to detect clinical danger signs in newborns was validated and the examinations had 81% sensitivity and 96% specificity to detect clinical danger signs 21 .This research has influenced the WHO guidelines to integrate seven newborn danger signs as a part of the Integrated Management of Childhood Illness guidelines and we used these danger signs as a part of our algorithm to manage neonatal hyperbilirubinemia 7,19,37 .We will use this validated screening method to identify newborns add with hyperbilirubinemia without danger signs and are otherwise healthy and can safely be treated with home phototherapy.We also screen for maternal danger signs to assess the ability of the mother to successfully provide care at home 20 .
The home screening and treatment protocol was developed by applying evidence on neonatal hyperbilirubinemia screening to reduce the incidence of severe hyperbilirubinemia in rural Bangladesh.In South Africa, a study estimated that for newborns born in the hospital, universal newborn TcB screening prior to discharge from the hospital reduced the risk of severe hyperbilirubinemia by 73% in comparison to physical examination screening 8 .Newborns were screened only one time with a TcB at the time of discharge and vaginal births were discharged after six hours and caesarean section births were discharged after 48 hours 8 .With more TcB screenings and beginning at 24-48 hours of age, we believe this program will ultimately reduce hyperbilirubinemia-related disability and death.Universal hospital-based bilirubin screening in the US has reduced the incidence of hyperbilirubinemia above the exchange transfusion threshold 11 .
The home screening and treatment arm will rely on mobile health to extend the capabilities of CHWs to manage hyperbilirubinemia at home.Mobile health applications have been used by CHWs in LMICs to improve newborn care 38 .mHealth has been shown to improve the accuracy of CHW newborn clinical assessments, improve the completion of assessments, their speed, and the adherence to clinical management guidelines with high satisfaction 38 .In particular, mHealth has been used by CHWs to improve the classification and management of hypothermia and infant feeding problems 38 .We will use mHealth to improve the management of newborns after birth and extend the capabilities of CHWs to improve management of neonatal hyperbilirubinemia.
The home screening and treatment arm leverages evidencebased strategies to reduce the risk of rebound hyperbilirubinemia after treatment and increase the likelihood of resolution of hyperbilirubinemia with CHW-led home treatment.Chang et al. found that diagnosing the need for phototherapy early and treating early reduces the risk of rebound hyperbilirubinemia by about 50% per day 39 .In addition, stopping treatment after longer phototherapy durations when the difference between the bilirubin on stopping treatment and the bilirubin treatment threshold is larger reduces the risk of rebound hyperbilirubinemia by about 50% for each mg/dL decrease in bilirubin 39 .We will begin TcB screening early, by day two after birth and screen daily for 3 days.We will diagnose and treat cases of hyperbilirubinemia early reducing the risk of rebound hyperbilirubinemia.CHWs will treat with high intensity phototherapy (>50 μW/cm 2 /nm) for 36-hour total treatment duration (Figure 2b).The 36-hour treatment duration will decrease the bilirubin below the treatment threshold and reduce the risk of rebound hyperbilirubinemia and hospital referral after phototherapy.Treatment with high intensity phototherapy with irradiances >30 μW/cm 2 /nm cause a faster and larger declines in bilirubin than phototherapy of lower intensity and cause a 50% reduction in the first 24 hours of treatment 16 .
In a past study of a population of newborns that needed phototherapy, 82% completed treatment within a single hospitalization with a typical duration phototherapy of 22-27 h using 22-25 μW/cm 2 /nm phototherapy 40 .LED phototherapy has minimal side effects and uses light of blue wavelength (455-470nm) to help lower the concentration of bilirubin in the body 16 .We propose a 6-hour break overnight so that the mother does not have to monitor at night.Intermittent phototherapy is successful in reducing hyperbilirubinemia 16 .
We chose to use the 2004 AAP management of hyperbilirubinemia guideline for phototherapy thresholds because we wanted to use an internationally recognized guideline that had a clear phototherapy treatment threshold based on age in hours that was tied to risk of developing hyperbilirubinemia related morbidity 16 .Since the study protocol was designed, an updated AAP management of hyperbilirubinemia guideline was released in 2022 which increased the bilirubin thresholds for phototherapy treatment by 0-2 mg/dL compared to the 2004 guidelines 16,41 .For home phototherapy in the 2022 guideline, the phototherapy treatment thresholds could be considered at a bilirubin level 2 mg/dL less than the hospital level treatment thresholds 41 .The home phototherapy thresholds in the 2022 are similar to the 2004 AAP phototherapy thresholds that were used in this protocol 16,41 .LMICs often use bilirubin thresholds for phototherapy treatment that are less than the 2004 and 2022 guidelines and the WHO recommends using a bilirubin treatment threshold for phototherapy of 10-15 mg/dL which is in general lower than the levels in the 2004 and 2022 guidelines [42][43][44] .The 2022 guideline also recommends considering the local healthcare resources when determining treatment thresholds for low-resource settings 41 .We were concerned that adopting the WHO guideline would result in a high percentage of all newborns being recommended to be treated with phototherapy that would be difficult to adopt in Bangladesh and other LMIC settings with potentially unclear benefit.
Accessing neonatal hospital-based care can be a barrier for families in LMICs and home-based care has been used to increase the percentage of newborns receiving the recommended treatment.In a prior study, only one-third of newborns in rural Bangladesh that were referred to the hospital from home for physical examination findings concerning for sepsis completed the referral 9 .The costs of traveling to the hospital and obtaining care were found to be a major barrier 9,10 .However, families were willing to have their newborns treated at home.Approximately 65% of parents who refused referral for neonatal sepsis evaluation in hospitals, consented to home care by CHWs with intramuscular injection with antibiotics, increasing access to care and reducing neonatal mortality by 34% 9 .Because we are increasing access to hyperbilirubinemia treatment by treating newborns at home, we believe that the home screening and treatment arm will treat more newborns than the existing system in Bangladesh and has the potential to prevent morbidity and mortality from neonatal hyperbilirubinemia.

Role of protocol contributor
EF and FJ developed the protocol.MR, VKB, SMP contributed to developing the protocol.RH, FY, SEA, SMB, MMH, MS, MSI, TA were substantial contributors in reviewing and editing the protocol.MR was the Principal Investigator and overall implementer of the study.GLD was a major contributor in developing and reviewing the protocol.All authors have read and approved the final protocol.
It is surprising that there is no discussion of G6PD.G6PD is a major risk for bilirubin encephalopathy (Olusanya et al, 2014)(Ref-2).There are several point of care G6PD tests that could be easily added to this protocol at a minor cost.
The proximity cluster design is ingenious and well thought out, but it introduces a small risk of sample bias (for example, the cluster proximity could result in women influencing each other's behaviors or low heterozygosity within the cluster that could result in an unusually high rate of G6PD within a cluster).It would be good if the authors addressed this issue as a potential limitation.
It would help to have a better description of how the authors plan on blinding the outcome assessors.As it stands, the only method for binding the outcome assessors is to have "minimal contact" with the CHWs.How will the assessors be blinded to knowledge of the intervention?Will they have any contact with the mothers?Will they see only medical records?If so, what medical records will the assessors see?
The protocol for home interventions is solid and well thought through.The authors readily acknowledge the limitations of TcB measurements and address these limitations effectively.However, it is surprising that no mention is made anywhere of the Bilirubin Induced Neurologic Dysfunction (BIND) scale (Radmacher, et al., 2015)(Ref-3).The modified BIND scale is a proven and effective way to assess the risk for acute bilirubin encephalopathy in newborns .It was also shown recently to be highly sensitive in predicting of kernicterus (Gelineau-Morel et al.,2023)(ref-3).

Minor issues:
In the abstract, the authors state that "Newborns without danger signs but with a TcB above the treatment threshold, but >15 mg/dL will be treated with light-emitting diode (LED) phototherapy at home".I believe they meant "Newborns without danger signs but with a TcB above the treatment threshold, but <15 mg/dL will be treated with light-emitting diode (LED) phototherapy at home.

1.
The abbreviation for clinical health worker (CHW) is never defined.

Are sufficient details of the methods provided to allow replication by others? Yes
Are the datasets clearly presented in a useable and accessible format?Yes Please clarify that the distance from the neonate to the PT will be fixed and not adjustable by the mother/family.
Thank you for this very important work.If shown to be safe and effective it will likely be an important tool in preventing severe neonatal hyperbilirubinemia and the tragic sequelae including ABE and KSD.
Is the rationale for, and objectives of, the study clearly described?Yes

Are sufficient details of the methods provided to allow replication by others? Yes
Are the datasets clearly presented in a useable and accessible format?Yes inform mothers how to seek help when their offspring is sick, to prevent NHB by transcutaneous bilirubin (TcB) screening at home, and to start early phototherapy (PT).PT is started at home whenever TcB < 15 mg/dL (257 µmol/L) is higher than the treatment threshold, and in-hospital when TcB ≥ 15 mg/dL or in case of danger signs.
Considering the important aim on prevention I suggest to adapt the title, and incorporate prevention in the title as well!And please incorporate this in the intervention arm as well.For example in the abstract the intervention arm reads as home screening and treatment, which is in fact not completely true.
I agree with the other reviewers that this study does have potential to change the future of many infants with NHB.Yet, apart from the scientific issues, economic and financial factors are as well important and need some clarification.An important question that arises is how resources are guaranteed after this study with a clear but relatively small sample size.And what about future costs for regular calibration of TcB and PT devices?
I have also a question on the effectiveness of home PT to increase treatment rates (as can be read in the abstract).The authors have defined treatment rate as primary outcome.But this is not the same as PT effectiveness, usually defined as reduction of bilirubin below the treatment threshold that is considered appropriate.Especially when treatment is TcB based < 15 mg/dL, and not TSBbased, overtreatment may occur.And this unnecessarily started PT will contribute to the primary outcome.Therefore I suggest to measure TSB also in newborns with TcB above treatment threshold < 15 mg/dL.In this way, resources will be reserved for newborn infants with clinically relevant hyperbilirubinemia, i.e., TSB > treatment threshold.
I have provided my suggestions and questions in the linked PDF.This PDF also contains the comments from Tina M. Slusher and Zubaida L. Farouk as part of their review of version 1 of this article 1 .
Is the rationale for, and objectives of, the study clearly described?Yes

Are sufficient details of the methods provided to allow replication by others? Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable
This study does have the potential to improve outcome in neonates with significant hyperbilirubinemia in Bangladesh and other LMICs if shown to be safe and effective.Obviously, it should be possible to provide more timely access to phototherapy and to treat neonates who are having difficulty getting to their referral center and to do it less expensively-all very important in LMICs.It is well designed as a cluster randomized trial.The most recent 2022 AAP guidelines do allow for careful and limited home phototherapy but as these authors clearly realize a protocol for home phototherapy in other countries including LMICs needs to be carefully studied for safety and efficacy before widespread implementation.We congratulate these authors for this idea.The study team is strong and quite experienced.We do have questions to which we feel answers will improve the study substantially.Thank you for allowing us to review this protocol.We suggest attaching survey questionnaires and other tools including checklists for the study.These materials would likely fill in many of the gaps we mention below. 1.
The focus of the study is timely identification and treatment of hyperbilirubinemia, why should aim 1 be about exclusive breastfeeding?We would suggest reversing the aims or simply including encouraging and supporting breastfeeding as a means to decrease hyperbilirubinemia.

2.
You do not mention training for the mothers on preventative practices like avoiding triggers for hemolysis in G6PD deficient neonates such as avoiding henna and mentholated products or jaundiced preventative measures beyond adequate breastfeeding.G6PD screening should be included in the baseline labs as Bangladesh has a G6PD deficiency rate greater than 5% in males.Without knowing G6PD status determining risk of significant or 3.
severe jaundice will be more difficult.
We also wonder about neonates with set up for Rhesus or ABO incompatibility?Will these neonates be enrolled in the study and not transferred to the referral center until after 36-48 hours or will they be excluded and referred sooner?We would be okay with starting home phototherapy in these neonates while transport was arranged but would be uncomfortable keeping these neonates on home phototherapy for a prolonged time because of their risk of rapidly developing severe hyperbilirubinemia which might be missed with only daily bilirubin checks.

4.
It would be important to know the outcomes of the comparative group i.e., the number in both the treatment arm and control arms that need hospital referral, EBT and have ABE or die from complication of the treatment or jaundice-related death.

5.
Are you looking at the proportion of newborns receiving treatment in both groups?Will the comparative or control group ever get home phototherapy?Will both groups be receiving intensive phototherapy? 6.
Agree with need to specifically look for ABE and would suggest either the BIND or modified BIND score in any neonate with possible ABE on exam in both groups.Suggest looking for signs of ABE at the time of starting phototherapy and each time the neonate is examined.You should also assess for ABE at timepoint of referral to the hospital for exchange.We also would strongly suggest surveying/examining for signs of ABE at the endpoint.

7.
What is the definition of geographical proximity for the purpose of this study?Suggest minimum distance or some other objective criteria, can individual villages or wards serve as clusters? 8.
What is this written test that the CHW will take?Is an aptitude test?Do CHW have any prior medical training?Are they certified health workers?Please clarify in more detail what assessment the CHW's will carry out and specify how it will be done.

9.
Please clarify tool that will be used to assess CHWs.What is the qualification of the field staff that will review performance of the CHW, what is the qualification of the training team?What will be used to assess the knowledge, skill, and attitude?Exactly what type of training and specific skill sets of CHW's varies from country to country therefore needs to be specified.

10.
Is the distance between the neonate and the phototherapy lights/lamps fixed in a way that parents cannot adjust the distance otherwise I would be concerned that they might change the distance which of course affect the PT intensity.What does the training on phototherapy device entails?Does it cover how to provide effective phototherapy to an infant, where to place the infant, eye cover, indications for phototherapy, safety issues regarding phototherapy, exposure?Who is responsible for checking the irradiance of the photo units?CHW? Are the CHWs measuring it and if so, will they be trained how to do it accurately?How will the phototherapy be powered at home?Is there constant and availability of electricity at all homes in the study area? 11.
Also please explain why you chose to use the AAP guidelines and if they were adapted for use in Bangladesh as strongly suggested by the AAP themselves. 12.
Please state range of values rather than TcB above phototherapy threshold or simply include the graph showing used to determine when phototherapy will be begun.If using the AAP guidelines, then should almost certainly use the more conservative 2004 guidelines not the new 2022 guidelines but it would be much better would be to adapt guidelines specifically for your locale as stated above. 13.
Comprehensive guidelines already include jaundice as a danger sign therefore you are already going against these guidelines by keeping the neonate at home therefore you will need to explain this in your protocol.Is visual jaundice on the palm and sole despite TcB a requirement for referral to a hospital in this study?Please clarify. 14.
Who will be responsible for checking of the ambient temperature?The parents or CHW? 15.
State whether all parents have access to a phone?16.
Please provide a checklist stating the potentials issues that the CHW will be checking.17.
Who is going to do the blood groups CHWs?Are they certified to do heel pricks and run these tests in Bangladesh or is that certification required or is training CHWs to do these test all that is required for them to be able to do them?With training are the CHWs or other study staff able to do these tests in this setting?18.
We are not statisticians, but we do not believe t-test is the appropriate test because t-test is used to compare between means and Chi Square test is used to compare proportions.This would also be true in secondary outcomes.

Are sufficient details of the methods provided to allow replication by others? Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable
Competing Interests: No competing interests were disclosed.
We confirm that we have read this submission and believe that we have an appropriate level

Figure 2b .
Figure 2b.Home Phototherapy Transcutaneous Bilirubin Thresholds.Newborns that were at least 35 weeks gestation, had a birthweight of at least 2 kilograms and had no danger signs were eligible for home phototherapy if the transcutaneous bilirubin < 15mg/dL (below solid black) but above the appropriate dotted line based on the 2004 AAP neonatal hyperbilirubinemia management guidelines, or if the transcutaneous bilirubin was < 15 mg/dL, but rising >= 0.2 mg/dL/hour during home visits.
. b) TcB rising ≥ 0.2 mg/dL/hour The following are the exclusion criteria for newborn home phototherapy: a) Birthweight <2000g b) Gestational age < 35 weeks c) Newborn danger signs present d) Maternal danger signs present e) TcB ≥ 15 mg/dL

Figure 1. Randomization scheme: CONSORT flow diagram.
27 the newborn temperature is between 95.9°F and 97.5°F Kangaroo Mother Care at home will be advised27.CHWs will also assess for the following maternal danger signs and refer the mother to an appropriate medical facility if any danger sign is present27.
identify which study arm the participant is in and follow the protocols for that arm.The program will guide CHWs on data collection including newborn gestational age calculation, newborn age in hours calculation, newborn and mother danger sign assessment, and TcB measurement and management.The application will calculate an estimated delivery date based on the first day of the last menstrual period collected at the baseline survey and add 280 days.The gestational age will be calculated by subtracting the birth date from the first day of the last menstrual period.The age in hours of TcB measurement will be based on the mother informing the CHW of the time of birth and by reviewing any childbirth records.CommCare will then calculate the age in hours based on the current time and subtracting the time of birth.The age in hours, TcB, gestational age, blood group or rhesus incompatibility between the mother and the newborn will determine the phototherapy threshold for each newborn based on the 2004 AAP guidelines and hours of age for the newborn (Figure

Table 2 . Safety outcomes assessed after home phototherapy was started.
% newborns with resolved hyperbilirubinemia after starting home phototherapy % newborns referred to the hospital for treatment for phototherapy at the first visit after completing home phototherapy