Dissemination of Best Practices in Preterm Care Through a Novel Mobile Phone-Based Interactive e-Learning Platform.

OBJECTIVE: To describe an innovative interactive e-learning method to disseminate knowledge to larger group of participants over a wide geographical area. METHODS: The course material included standard training tool "Best Practices in Preterm Care," hosted on Telegram, a cloud-based instant messaging platform. The participants were enrolled in the group created on Telegram by the facilitators and included in-service nurses from India, Bhutan, Bangladesh, and UAE. They were mentored by 62 facilitators over 10 wk. Content of each module was loaded every week on two specific days. Mentors specified for that week facilitated learning through discussions. There was a live session every week to address any additional queries and to summarize the key messages of the week. Each week ended with weekly assessments through quiz. RESULTS: In this course, 4623 nursing professionals from India and Southeast Asian Region involved in providing neonatal care, participated. There were 9939 posts with an average of 126 posts per day. Majority of the participants felt that the topics were relevant (~95%) and they were comfortable in asking questions and could clarify their doubts (~90%). Majority rated their overall experience as very good to excellent (~98%). CONCLUSIONS: Interactive e-learning using the current approach if channelized optimally seems to be acceptable and feasible method to reach wide geographical area. This, however, needs local champions ready to mentor their own health professionals with context-specific guidance.

Pharmacokinetics-Based Optimization of Phototherapy in Neonates Undergoing Treatment for Hyperbilirubinemia.

Introduction: Neonatal jaundice results from combined effects of both increased production of bilirubin and decreased hepatic excretory capacity in neonates. Since its discovery, phototherapy is the most widespread treatment used in neonatal jaundice. In this work, we try to search for a relationship between exposure to phototherapy and decrease in serum bilirubin (linearity vs proportionality). Methods:The present research was non-randomized prospective study conducted in the Neonatal Intensive Care Unit (NICU), Department of Paediatrics, AIIMS, New Delhi, and the Department of Pharmacology, AIIMS, New Delhi, India. Subjects were recruited from neonates admitted in NICU AIIMS, which meets our selection criteria. Infants were given a low dose of either phototherapy continuously or phototherapy for the first six hours and a double dose of phototherapy for the next six hours. Samples were collected before the beginning of the study (0 hours) and then at six and 12 hours. Bilirubin concentration was measured using HPLC and (LC-MS/MS). Results and conclusion:The percentage of reduction during the 6-12-hour interval was compared with that during the 0-6-hour interval if all experimental conditions were kept unchanged. A relationship curve between percentage of reduction and irradiance was created based on the percentage of reduction in serum bilirubin during the 0-6-hour and 0-12-hour intervals. The present study suggests that the relationship between efficacy, as measured by percentage of reduction in serum bilirubin, and irradiance is unlikely to be linear. Collected data are insufficient to clearly distinguish between proportionality and saturation point, considering that the results may be possible with both of these hypotheses.

Stepwise interventions for improving hand hygiene compliance in a level 3 academic neonatal intensive care unit in north India.

OBJECTIVE: We evaluated effect of sequentially introducing four WHO-recommended interventions to promote hand-hygiene compliance in tertiary-care NICU. STUDY DESIGN: Four dedicated research nurses directly observed doctors and nurses to record success in hand-hygiene opportunities at randomly selected NICU beds and randomly sampled time-slots in four phases (of 4-weeks each): I-Baseline, II-Self-directed learning; III-Participatory learning; IV-Closed-Circuit Television (CCTV); and V-CCTV-plus (with feedback). FINDINGS: Hand-hygiene compliance changed from 61.8% (baseline) to 77% (end) with overall relative change: 24.6% (95% CI 18, 32; p value= 0.003); compared with preceding phase, relative changes of 21% (15, 28; <0.001), 4% (0, 8; 0.008), -10% (-13, -6; <0.001), and 10% (5, 15; <0.001) during phases II, III, IV, and V, respectively were observed. Rise in hand-hygiene compliance was higher for after-WHO-moments (12.7%; upto 2.5-folds for moment 5, <0.001) compared to before-WHO-moments (5.2%). Educational interventions, feedback and monitoring WHO moments can improve hand-hygiene compliance significantly among health-care providers in NICU.

Aqueous chlorhexidine 1% versus 2% for neonatal skin antisepsis: a randomised non-inferiority trial.

OBJECTIVE: To evaluate whether 1% aqueous chlorhexidine gluconate (CHG) when compared with 2% aqueous chlorhexidine gluconate is non-inferior for neonatal skin antisepsis. DESIGN: Parallel, blinded, non-inferiority randomised trial. SETTING: Level III, academic, neonatal intensive care unit. PATIENTS: Infants born at 260/7 to 426/7 weeks of gestation from June 2019 to December 2019. INTERVENTIONS: Participants were randomised to skin antisepsis by either 1% aqueous CHG or 2% aqueous CHG. MAIN OUTCOME MEASURES: The primary outcome was the proportion of negative skin swab cultures after skin antisepsis. Secondary outcomes were local skin reactions at 0, 6, 12 and 24 hours and plasma chlorhexidine levels in a subset of the study population. RESULTS: A total of 308 neonates with a median gestation age of 34 (31-37) weeks and mean birth weight of 2029 g were randomised on 685 occasions (1% CHG: n=341; 2% CHG: n=344). 93.0% of the post-antisepsis skin swabs were sterile in 1% CHG group compared with 95.6% of the swabs in the 2% CHG group (risk difference -2.7%, 95% CI -6.2% to +0.8%). The lower bound of 95% CI crossed the pre-specified absolute non-inferiority limit of 5%. Neonates developed mild dermatitis on 16 (2.3%) occasions. There was no significant difference in median plasma CHG levels in the two groups, 19.6 (12.5-36.4) and 12.6 (8.7-26.6) ng/mL, respectively. CONCLUSIONS: Application of 1% aqueous CHG was not shown to be non-inferior to 2% chlorhexidine aqueous for skin antisepsis in neonates. There were no severe skin-related adverse events in either of the two groups. TRIAL REGISTRATION NUMBER: CTRI/2019/06/019822; (http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=33453&EncHid=&userName=CTRI/2019/06/019822).

Validation of visual estimation of neonatal jaundice in low-income and middle-income countries: a multicentre observational cohort study.

OBJECTIVE: Determine the sensitivity and specificity of neonatal jaundice visual estimation by primary healthcare workers (PHWs) and physicians as predictors of hyperbilirubinaemia. DESIGN: Multicentre observational cohort study. SETTING: Hospitals in Chandigarh and Delhi, India; Dhaka, Bangladesh; Durban, South Africa; Kumasi, Ghana; La Paz, Bolivia. PARTICIPANTS: Neonates aged 1-20 days (n=2642) who presented to hospitals for evaluation of acute illness. Infants referred for any reason from another health facility or those needing immediate cardiopulmonary resuscitation were excluded. OUTCOME MEASURES: Infants were evaluated for distribution (head, trunk, distal extremities) and degree (mild, moderate, severe) of jaundice by PHWs and physicians. Serum bilirubin level was determined for infants with jaundice, and analyses of sensitivity and specificity of visual estimations of jaundice used bilirubin thresholds of >260 µmol/L (need for phototherapy) and >340 µmol/L (need for emergency intervention in at-risk and preterm babies). RESULTS: 1241 (47.0%) neonates had jaundice. High sensitivity for detecting neonates with serum bilirubin >340 µmol/L was found for 'any jaundice of the distal extremities (palms or soles) OR deep jaundice of the trunk or head' for both PHWs (89%-100%) and physicians (81%-100%) across study sites; specificity was more variable. 'Any jaundice of the distal extremities' identified by PHWs and physicians had sensitivity of 71%-100% and specificity of 55%-95%, excluding La Paz. For the bilirubin threshold >260 µmol/L, 'any jaundice of the distal extremities OR deep jaundice of the trunk or head' had the highest sensitivity across sites (PHWs: 58%-93%, physicians: 55%-98%). CONCLUSIONS: In settings where serum bilirubin cannot be measured, neonates with any jaundice on the distal extremities should be referred to a hospital for evaluation and management, where delays in serum bilirubin measurement and appropriate treatment are anticipated following referral, the higher sensitivity sign, any jaundice on the distal extremities or deep jaundice of the trunk or head, may be preferred.

Transcutaneous bilirubinometry reduces the need for blood sampling in neonates with visible jaundice.

OBJECTIVES: We determined usefulness of transcutaneous bilirubinometry to decrease the need for blood sampling to assay serum total bilirubin (STB) in the management of jaundiced healthy Indian neonates. METHODS: Newborns, > or =35 weeks' gestation, with clinical evidence of jaundice were enrolled in an institutional approved randomized clinical trial. The severity of hyperbilirubinaemia was determined by two non-invasive methods: i) protocol-based visual assessment of bilirubin (VaB) and ii) transcutaneous bilirubin (TcB) determination (BiliCheck). By a random allocation, either method was used to decide the need for blood sampling, which was defined to be present if assessed STB by allocated method exceeded 80% of hour-specific threshold values for phototherapy (2004 AAP Guidelines). RESULTS: A total of 617 neonates were randomized to either TcB (n = 314) or VaB (n = 303) groups with comparable gestation, birth weight and postnatal age. Need for blood sampling to assay STB was 34% lower (95% CI: 10% to 51%) in the TcB group compared with VaB group (17.5% vs 26.4% assessments; risk difference: -8.9%, 95% CI: -2.4% to -15.4%; p = 0.008). CONCLUSION: Routine use of transcutaneous bilirubinometry compared with systematic visual assessment of bilirubin significantly reduced the need for blood sampling to assay STB in jaundiced term and late-preterm neonates. (ClinicalTrials.gov number, NCT00653874).

Efficacy of two dose regimes of intravenous immunoglobulin in Rh hemolytic disease of newborn--a randomized controlled trial.

OBJECTIVE: To compare the effect of two dose regimes of IVIg (0.5 g/kg vs. 1g/kg given soon after birth) on duration of phototherapy in Rh-isoimmunized neonates 32 week and above gestation. DESIGN: Randomized controlled trial. SETTING: Tertiary care hospital. SUBJECTS: Rh positive blood group neonates of gestation 32 weeks and above born to Rh negative mothers having positive Direct Coombs test and without any major malformation. INTERVENTION: Intravenous immunoglobulin (IVIg) infusion over 2 h either 0.5 g/kg (low dose group, n=19) or 1.0 g/kg (high dose group, n=19). PRIMARY OUTCOME VARIABLE: Duration of phototherapy. RESULTS: The mean duration of phototherapy was 77.3+/-57.2 h in low dose group versus 55.4+/-49 h in high dose group (mean difference=21.9; 95% CI-13.1 to 56.9). There was no difference in need for exchange transfusion (21% in both the groups) and requirement of packed red blood cells transfusion (12 transfusions in both groups). The duration of hospital stay was similar [8.4+/-6.9 and 13.6+/-14.8 days, respectively (mean difference=-5.1; 95% CI-12.8 to 2.5)]. No adverse effects of IVIg administration were noted. CONCLUSION: Two regimens of IVIg (0.5 g/Kg or 1 g/Kg) had comparable effect on duration of phototherapy, duration of hospital stay and exchange transfusion requirement, in Rh isoimmunized neonates of gestation 32 weeks and above.

Clinical significance of airways colonization with Ureaplasma urealyticum in premature (<34 wk) neonates.

BACKGROUND & OBJECTIVE: Ureaplasma urealyticum has been implicated in various neonatal morbidities in preterm infants. Its association with chronic lung disease (CLD) remains controversial. The aim of this prospective study was to investigate colonization of U. urealyticum in preterm infants (with gestational age <34 wk) and to evaluate the relationship between U. urealyticum colonization and neonatal morbidity including CLD. METHODS: U. urealyticum was cultured from nasopharyngeal or endotracheal aspirates collected within 24 h of birth from infant

Clinicoepidemiological profile and predictors of severe illness in young infants (< 60 days) reporting to a hospital in North India.

OBJECTIVES: To describe the clinical and epidemiological profile of young infants reporting to a hospital and assess previously proposed simple clinical signs for their value in enabling health workers to detect young infants with severe illness warranting hospital admission. METHODS: Observational study of infants less than 2 months of age presenting consecutively to a large public hospital in South Delhi who were evaluated by a health worker (nurse), on a standardized list of signs and symptoms, and the ability of these were evaluated against the need for hospital admission which was assessed by an independent pediatrician. RESULTS: Of the 1624 young infants triaged, 878 were enrolled into the study. Of these 100 (11%) were below 7 days of age, for whom the common reasons for seeking care were jaundice (52%), not feeding well (6%) and fever (5%). The remaining 778 (89%) were 7-59 days of age with respiratory symptoms as the main presenting complaints (29.1%). The primary clinical diagnoses in infants with serious illness needing admission to hospital in the age group <7 days (n = 66) were hyperbilirubinemia (56%) and sepsis (21%). In those between 7-27 days of age (n = 60), primary diagnoses were sepsis (27%), pneumonia (13%), diarrhea, dysentery or dehydration (10%), while in the age group 28-59 days of age (n = 47) pneumonia (40%), sepsis (19%) and diarrhea or dehydration (13%) were the common primary diagnoses. Signs that had at least a prevalence of 5% and were strong predictors for all the age categories studied were history of difficult feeding (OR 6.8 for 0-6 days, 15.1 for 2-27 days and 6.2 for 28-59 days age groups), not feeding well on observation (OR 13.7, 27.6 and 20.9 respectively for the 3 age groups), temperature > 37.5C (OR 21.8, 14.6 and 30.0 respectively for the 3 age groups) and respiratory rate > 60 per minute (OR 6.8, 15.1 and 21.0 respectively for the 3 age groups). Additional strong predictors with > 5% prevalence were history of convulsions (OR 7.9, only in 0-6 day age group), lethargy (OR 26.1, only in 7-27 day age group), and history of diarrhea (OR 3.0 for 2-27 days and 2.2 for 28-59 days age groups). CONCLUSIONS: Simple clinical signs are useful in hands of health worker for identifying neonates with serious illness warranting hospital admission. These will be of use in the further development of clinical algorithms for the national integrated management of childhood illnesses.

Reliability of transcutaneous bilirubinometry from shielded skin in neonates receiving phototherapy: a prospective cohort study.

OBJECTIVE: To determine the agreement between transcutaneous bilirubin (TcB) measured from shielded skin and serum total bilirubin (STB) in infants (34 to 41 weeks of gestation) with hyperbilirubinemia receiving phototherapy (PT). STUDY DESIGN: In this prospective cohort study, we shielded a small area of skin on sternum using a commercial photo-opaque patch (BilEclipseTM, Philips Respironics, Murrysville, PA, USA). The TcB from the shielded skin (TcBs) and STB were measured at four time points-before initiation, 12 and 24 h during and once after (12 h) cessation of PT. TcB was measured using multiwavelength transcutaneous bilirubinometer (BiliChek, Philips Children's Medical Ventures, Monroeville, PA, USA). The STB was measured in triplicate by spectrophotometry (Apel BR 5100, APEL, Japan). Bland and Altman plots were drawn to determine agreement between the TcBs and STB. RESULTS: The gestation and birth weight of enrolled neonates were 37.0 (1.0) weeks and 2750 (458) g, respectively. The age at initiation and duration of PT were 75 (27 to 312) and 25.3 (4.4) h, respectively. Bland and Altman plot showed poor agreement between TcBs and STB at all time points. The gradient (median, range) between TcBs and STB at 0, 12, 24 h and 12 h after cessation of PT were -0.2 (-4.9 to 3.5), 1.4 (-4.7 to 4.0), 1.5 (-3.8 to 9.4) and 2 (-2.9 to 5.8) mg dl-1. The proportions of TcBs values outside ±1.5 mg dl-1 of STB ranged from 47 to 64% at four time points. CONCLUSION: TcBs does not appear to be reliable for estimating serum bilirubin in late preterm and term neonates receiving PT.

Incidence of periventricular leucomalacia among a cohort of very low birth weight neonates(< 1500 g).

BACKGROUND: Periventricular leucomalacia (PVL) is the most important neuropathologic lesion underlying major neuro-motor deficits of pre-term very low birth weight (VLBW) infants. Published data regarding PVL is not available from our country. OBJECTIVES: A study was planned with main objectives to estimate incidence and describe natural history of PVL among a very low birth weight cohort. STUDY DESIGN: A cohort study was performed on inborn VLBW babies over one year period at a tertiary neonatal intensive care unit. Serial weekly cranial ultrasounds were performed on 97 enrolled subjects until discharge, to diagnose and describe natural history of PVL. RESULTS: 31 out of 97 enrolled subjects developed PVL. No case of PVL developed beyond 19 days of postnatal life. Serial ultrasounds for each baby were tracked until discharge or death. Majority of lesions at onset were flares. Cysts tended to develop in over one third of cases during course of hospital stay. About 50% of ultrasound had normalized at discharge and sequelae such as cerebral atrophy and ventriculomegaly had appeared in few, the rest of lesions being either flares or cysts of PVL. CONCLUSIONS: PVL is fairly common among very low birth weight neonates. Ultrasonographic lesions of PVL undergo dynamic evolution from time of first detection to either progress, regress or leave sequelae before discharge. Ultrasound remains an important bedside diagnostic tool for PVL.

Comparison of conventional, immunological and molecular techniques for the diagnosis of symptomatic congenital human cytomegalovirus infection in neonates and infants.

PURPOSE: Human cytomegalovirus (HCMV) is the commonest pathogen causing congenital infection globally. The diagnosis of congenital infection is based either on viral isolation (in cell culture) or demonstration of HCMV DNA from the urine. Saliva is also being used as an alternative sample to urine for the same. The objective of this study was to compare the following assays-polymerase chain reaction (PCR) from urine, saliva and blood, serology (anti-HCMV IgM) and antigen detection (HCMV pp65 antigenaemia) for the diagnosis of congenital HCMV infection. MATERIALS AND METHODS: Urine and blood samples were collected from 31 infants (median age: 13 weeks) with suspected HCMV infection. For 18 infants, additional saliva samples were collected and all the above assays were compared. RESULTS: PCR for HCMV DNA from urine and anti-HCMV IgM were performed for all 31 infants. Of these, 22 (70.9%) were positive for both assays. In 18 (of the 22) infants positive by both assays, PCR for HCMV DNA from saliva was positive in all 18 (100%), PCR from blood in 7/18 (38.8%) and HCMV pp65 antigenaemia only in 1/18 (5.5%) of the infants. CONCLUSION: Detection of HCMV DNA in urine combined with anti-HCMV IgM are suitable assays to diagnose HCMV infection in infants. Both PCR from the blood and HCMV pp65 antigenaemia lack sensitivity in infants. Salivary PCR combines convenience with high sensitivity and can substitute PCR from urine, especially in the outpatient and field settings. To the best of our knowledge, this is the first study from India to evaluate salivary PCR for the diagnosis of congenital HCMV infection.

Safety and effectiveness of BCG vaccination in preterm babies.

AIM: To assess the cell mediated immune response to BCG vaccine in preterm babies. METHODS: Sixty two consecutive preterm babies born at < 35 weeks of gestation were randomly allocated into two groups. Babies in group A were vaccinated early at 34-35 weeks and group B were vaccinated late at 38-40 weeks of postconceptional age. The two groups were similar in terms of: gestational age (mean (SD) 33.1 (1. 1) and 33 (1.2) weeks, respectively); birthweight 1583 (204) and 1546 (218) g; neonatal problems; socioeconomic status; and postnatal weight gain. The cell mediated immune response to BCG was assessed using the Mantoux test and the lymphocyte migration inhibition test (LMIT) 6-8 weeks after BCG vaccination. Induration of >5 mm after the Mantoux test was taken as a positive response. RESULTS: There was no significant difference in the tuberculin conversion rates (80% and 80.7%, respectively), positive LMIT (86.6% and 90.3%, respectively), or BCG scar (90.0% and 87.1%, respectively) among the two groups. CONCLUSIONS: Prematurity seems to be an unlikely cause for poor vaccine uptake. Preterm babies can be effectively vaccinated with BCG at 34-35 weeks of postconceptional age, the normal time of discharge in a developing country.

A four year study on neonatal morbidity in a New Delhi hospital.

The neonatal morbidity was studied in 7015 neonates born at the All India Institute of Medical Sciences Hospital, New Delhi. The incidence of low birth weight babies was 26.7 per cent; one seventh (13.5%) of the series were preterm (less than 37 wk), while 6.6 per cent were 'small-for-dates'. Birth asphyxia of varying severity developed in 5.9 per cent infants. Respiratory distress syndrome was diagnosed in 5.7 per 100 live-births; most being due to hyaline membrane disease (33.5%), which affected 14.1 per cent of preterm babies. Neonatal hyperbilirubinemia occurred in 5.9 per cent, most of whom were premature. In nearly one-fifth, the cause of jaundice could not be identified after detailed investigations. Minor bacterial infections (conjunctivitis, pyoderma, oral thrush, umbilical sepsis) were observed in 1.8 per cent while major infections (septicemia, meningitis, diarrhoea) in 3.0 per cent. The overall incidence of major malformations was 2.3 per cent. Reasons for low incidence of bacterial infections and common occurrence of hyaline membrane disease in premature infants, are highlighted.

Perinatal & neonatal mortality in a hospital.

A total of 7109 consecutive births were studied over four years to assess perinatal and neonatal mortality. The extended perinatal mortality rate was 57 while conventional perinatal mortality rate (PNMR) was 41 per 1000 total births. Perinatal hypoxia (28.7%), immaturity (24.8%), congenital malformations (14.6%) and infections (5.6%) accounted for most perinatal deaths. The ranking of causes of neonatal deaths was immaturity, birth asphyxia, bacterial infections and congenital malformations. Neonatal mortality rate was 31 per 1000 live births and nearly 90 per cent mortality occurred in low birth weight (LBW) neonates. Hyaline membrane disease accounted for 13.4 per cent of early neonatal deaths. The case fatality rate among LBW babies and preterm babies was 10 per cent and 20 per cent respectively. There is a need to identify strategies to reduce the incidence of prematurity and LBW babies. Comprehensive antenatal coverage and adequate care followed by optimal management of infants at birth is likely to reduce PNMR and improve quality of life among the survivors.

Safety of oral rehydration solutions in non-cholera diarrhoea.

PIP: The safety of 2 oral rehydration solutions (ORS) containing 60 and 90 mEq/1 of sodium respectively was evaluated in 50 children with mild to moderate dehydration secondary to noncholera diarrhea. Hypernatremia developed in 1 patient (3.7%) on high sodium formula. The risk of hypernatremia and hyponatremia in the 2 groups did not differ significantly. 3 patients (6.1%) showed hypokalemia 24 hours after oral rehydration was initiated. While these data confirm that ORS containing 90 mEq/1 of sodium is safe, an increase in potassium content should be considered.^ieng

Preparation & standardization of the goat lung surfactant extract.

Exogenous goat lung surfactant extract (GLSE) was obtained by chloroform-methanol extraction of the centrifuged lung lavage. Four lungs provided around 250 mg of surfactant. GLSE has a phospholipid content of 50 percent, cholesterol of 1.5 percent and protein content under 1 percent. The preparation was bacteriologically sterile and had a shelf life of at least one month at 4 degrees C. Endotracheal administration of surfactant (50 mg/kg) in a rat lung model rendered surfactant deficient by saline lavage, restored the compliance characteristics to normal, thus documenting biological activity of the preparation. The cost of a course of 2 doses of surfactant replacement therapy was estimated to be as low as Rs 500/-. The study opens up the possibility of surfactant replacement therapy for the management of neonatal respiratory distress syndrome in India by an indigenous product at an affordable cost.

Histologic chorioamnionitis & its association with prematurity in a hospital-based study.

This prospective study was undertaken to study the occurrence of histologic chorioamnionitis and determine its association with prematurity; and to assess whether colonization of the genital tract of pregnant women by genital mycoplasmas or Chlamydia trachomatis is a risk factor for histologic chorioamnionitis. A total of 268 women with singleton pregnancies of over 26 weeks gestation were subjected to high vaginal cultures of genital mycoplasmas and endocervical specimens for chlamydia antigen. Placental histopathology was performed on multiple sections. Histologic chorioamnionitis was documented in 22.4 per cent (60/208) placentae. Genital tract colonization with Ureaplasma urealyticum or C. trachomatis was not a risk factor for histologic chorioamnionitis. Neonates born in association with histologic chorioamnionitis had a mean birth weight 111 g lower than those born without this lesion (2626.9 +/- 702 g vs 2737.8 +/- 500 g, NS). The relative risk (95% confidence interval) of prematurity in the presence of histologic chorioamnionitis was 1.49 (0.87-2.53). Analysis of linear trend in proportions for prevalence of histologic chorioamnionitis with decreasing gestation showed a significant association (P = 0.047, 1-tail). These results taken together suggest that histologic chorioamnionitis may be a risk factor of prematurity, but of only a modest magnitude.