Introduction Ibuprofen exposure results in acute transient renal dysfunction in preterm neonates, but we are unaware of data on long-term renal safety.
Methods In a previously studied cohort of extreme low birth weight (ELBW, <1000 g) cases, the PREMATurity as predictor of children’s Cardiovascular-renal Health study generated data on renal function (renal length, estimated glomerular filtration rate based on cystatin C (eGFRcysC) at the age of 11 years. This data set in 93 ELBW cases may also generate data on long-term drug safety on ibuprofen. In this post hoc analysis, we linked markers of renal function in young adolescence in ELBW cases with their perinatal (prenatal maternal, setting at birth, treatment modalities including drug prescription during neonatal stay, neonatal creatinine values, postdischarge growth) characteristics, including but not limited to ibuprofen exposure during neonatal stay.
Results Ibuprofen exposure was not associated with significant differences in renal length or eGFRcysC. Moreover, we were unable to identify any other risk factor (perinatal characteristics, postnatal creatinine trends, postdischarge growth) on renal outcome in this cohort.
Conclusions Neonatal exposure to ibuprofen did not affect renal function. Larger studies are needed to explore the confounders of variability in renal function in former ELBW cases. This matters since ELBW relates to risk for hypertension, cardiovascular events and renal disease in later life and identification of risk factors holds the promise of secondary prevention.
Trial registration number NCT02147457.
- Cystatin C
- drug safety
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What is already known on this topic?
Former extreme low birth weight (ELBW, <1000 g) infants have a mean estimated glomerular filtration rate for cystatin C (eGFRcysC) that is about 1 SD lower compared with term-born controls at young adolescence, and a relevant portion (20%–25%) has an eGFRcysC <90 mL/min/1.73 m2.
Ibuprofen exposure in preterm neonates results in a transient reduction in urine output, a significant increase in creatinine up to 6 weeks afterwards and a transient decrease GFR.
What this study adds?
Ibuprofen exposure is not associated with differences in renal length or eGFRcysC in this cohort of ELBW neonates at young adolescent age.
We were unable to identify any specific association of eGFRCysC with any of the perinatal characteristics, postdischarge growth patterns or postnatal creatinine trends.
As a result of improved survival following extreme preterm birth and the shift towards proactive safety surveillance after (conditional) market authorisation as part of a contemporary drug product cycle, long-term safety assessment following drug exposure in neonates becomes even more relevant.1 Safety signals on ibuprofen are available for short-term renal outcome in human neonates and juvenile animals and also for long-term outcome in these animals. In contrast, data on long-term renal outcome following ibuprofen exposure in former preterm neonates are not yet available.
Ibuprofen (on label intravenous dose 10–5–5 mg/kg/day, closure of the patent ductus arteriosus) exposure in preterm neonates results in transient reduction of urine output, a significant increase in creatinine up to 6 weeks after exposure and a decrease in drug clearance (–20%) for drugs cleared by glomerular filtration.2–4 Besides these short-term outcome observations in human neonates, there are animal experimental observations on the reduction (–7% to –12%) of the glomerular number count in adult rodents5 and a reduction (–27%) of the renal cortex in adult primates6 following exposure to ibuprofen at a maturational age equivalent to the human extreme preterm neonate.
The recently finalised PREMATurity as predictor of children’s Cardiovascular-renal Health (PREMATCH) study cohort generated data on microvascular and macrovascular outcome in a cohort of former extreme low birth weight (ELBW, ie, <1000 g) infants, including data on biomarkers of renal function, and term-born age-matched controls in young adolescence (~11 years). The mean renal length was 0.28 cm shorter (8.73 (0.65) vs 9.01 (0.59) cm) in cases while cystatin C (0.96 (0.12) vs 0.87 (0.11) mg/dL) and estimated glomerular filtration rate (eGFRcysC) (97.2 (13.6) vs 108.7 (15.3) mL/min/1.73 m2) were shifted by about 1 SD in ELBW cases compared with controls (all p≤0.01).7 We aimed to link these biomarkers of renal function in ELBW cases during young adolescence with their perinatal confounders—including ibuprofen—and postnatal growth characteristics in a post hoc analysis to explore associations to retrieve potential safety signals.3 7 8 This matters since this relates to the risk for hypertension, cardiovascular events and renal disease in later life and holds the promise of secondary prevention.5–7
Ethics and study registration
The study was conducted in accordance with the Helsinki declaration for investigations in human subjects. The Ethics Committee of the University Hospitals Leuven (Belgium) approved the study. Based on good clinical practice guidelines and national legislation, parents or custodians provided written informed consent and the children provided informed assent. The study was registered at ClinicalTrials.gov (NCT02147457).
Clinical cohort and characteristics
We recruited cases for enrolment in PREMATCH from a cohort of 140 neonates born between 2000 and 2005, who survived after having been born with a birth weight of <1000 g and after a gestation ranging from 23 to 33 weeks.3
The perinatal characteristics of this initial cohort have been reported previously and cover prenatal maternal (pre-labour preterm rupture of the membranes (PPROM), tocolysis, pre-eclampsia, chorioamnionitis, betamethasone) characteristics, characteristics at birth (birth weight, gestational age, Apgar, intubation, small for gestational age, height) and postnatal variables (duration of ventilation, duration of supplemental oxygen, postnatal steroids, ibuprofen (dose as labelled, 10–5–5 mg/kg/day), days until full enteral, retinopathy of prematurity, any intraventricular haemorrhage, creatinine trends).3 We divided the cohort into those exposed and those not exposed to ibuprofen. In addition and as part of the PREMATCH study, weight and height characteristics at birth, but also at 9 months, 24 months and 11 years were available as postdischarge characteristics. These data were converted to Z–scores using population growth charts.8 9
Assessment of renal function
Renal function was assessed based on renal ultrasound and eGFRcysC.7 The renal ultrasound was performed with participants in supine, left or right decubitus, using a Vivid7 Pro (GE 125 Vingmed, Horten, Norway) interfaced with a 1.5–4.5 MHz convex transducer according to standardised procedures. The digitally stored images were postprocessed using a workstation running EchoPac software (V.4.0.4; GE 125 Vingmed). Renal length was the largest longitudinal distance in the sagittal plane. Parenchymal thickness was the distance between the outer margin and the renal sinus. Each participant was characterised by the average of two measurements obtained from optimal images. For renal length, the average absolute and relative differences between pairwise readings by the same observer were 0.07±0.56 cm and 0.51%±5.0%, respectively. The corresponding estimates for interobserver variability were –0.03±0.54 cm and –0.29%±5.0%.7
After application of a Rapydan patch (70 mg lidocaine/70 mg tetracaine, Eurocept, Ankeveen, The Netherlands) to minimise discomfort, a study nurse collected a venous blood sample, which was immediately spun. Aliquots were stored at –20°C until analysis. As part of a more extensive analysis, serum cystatin C by the particle-enhanced immuno-turbidimetric Tina-quant cysC Generation 2 assay on a COBAS Integra 400 system (Roche Diagnostics, Basel, Switzerland) was measured. Measurements of cystatin C were calibrated to the ERM-DA471/IFCC international standard. GFR was estimated from cystatin C (eGFRcysC) by the Caucasian–Asian–Pediatric–Adult equation, eGFR=130 × Cys C–1.069 × age –0.117 – 7.7 10
Clinical characteristics of recruited and non-recruited former ELBW cases were compared with explore potential recruitment bias.3 Perinatal characteristics, postdischarge growth patterns and markers of renal function (renal ultrasound measurements, cystatin C, eGFRcysC) in young adolescence were described by median and range, mean and SD or incidence. Bivariate analysis (Mann-Whitney U, χ2, rank correlation) was used to search for perinatal factors of these biomarkers of renal function. Statistical analysis was performed using Medcalc program (Medcalc Software V.16.2.1 Ostend, Belgium). Significance was a two–sided p value of<0.05.
Clinical cohort and characteristics
In total, 93 former ELBW cases from the initial cohort were included in this analysis. There were no statistically significant differences in the perinatal characteristics between included (n=93) and non-included (n=47) cases. In total, 45 cases were exposed to ibuprofen, 48 cases were not exposed to ibuprofen. Due to suboptimal quality of the ultrasound pictures, 9 cases were excluded from the ultrasound analysis, resulting in 84 renal measurements. Similarly, blood collection and subsequent analysis for cystatin C was only successful in 59/93 (refusal n=8; too small sample volume n=10; failed collection after one or two attempts n=16) cases. In 55 cases, both renal measurements and cystatin C values were available (figure 1). The perinatal characteristics and postdischarge growth patterns in included ELBW cases are provided in tables 1 and 2, respectively.
Assessment of renal function
The observations on renal ultrasound findings and CysC observations are provided in table 3.
For the ultrasound data, 41/84 of former ELBW cases were exposed to ibuprofen in early neonatal life, but there was no difference in renal length for the left kidney (ibuprofen=8.44 (7.50–10.32) vs 8.76 (7.3–10.72) cm, p=0.38). This was neither the case for the right kidney (ibuprofen=8.57 (7.58–10.39) vs 8.82 (7.49–11.01) cm, p=0.28). None of the perinatal (maternal, at birth, postnatal) characteristics and none of the postdischarge growth patterns (tables 1 and 2) were associated with differences in renal length in young adolescence.
When we focus on the data on eGFRcysC, 36/59 of the former ELBW cases were exposed to ibuprofen in early neonatal life (figure 1). There was no difference in eGFRcysC values between cases exposed or not exposed to ibuprofen (95 (73–130) vs 96.8 (70.2–120.6) mL/min/1.73 m2, p=0.92). Also, 17 (28%) of cases had an eGFRcysC <90 mL/min/1.73 m2, equal to stage 2 of chronic kidney disease (CKD), but none had CKD stage 3. Of these 17 CKD stage 2 cases, 10/36 (28 %) were exposed to ibuprofen, compared with 7/23 (30 %) cases not exposed to ibuprofen. Moreover, none of the perinatal (maternal, at birth, postnatal) characteristics and none of the postdischarge growth characteristics (cf. tables 1 and 2) were associated with differences in eGFRcysC in young adolescence, nor with CKD stage 2. Since there were no significant confounders in the bivariate analysis, additional analysis like multivariable regression was not performed.
The primary aim of this post hoc analysis was to assess the impact of ibuprofen exposure on long-term renal function in former ELBW cases. Although renal function (smaller kidney length, higher cystatin C, lower eGFRcysC) was significantly different in ELBW cases compared with term-born age-matched controls in young adolescence,7 we were unable to unveil any impact of perinatal risk factors—including ibuprofen exposure—or postdischarge growth patterns on these markers of altered renal function within this ELBW cohort.
Although the absence of a difference in renal function after ibuprofen exposure is reassuring, these data should be interpreted cautiously. Renal ultrasound and eGFRCysC were only based on 84 and 59 observations, respectively, be it with a reasonable distribution between ibuprofen-exposed and non-exposed cases and high p values. This was a planned, but post hoc analysis of a data set initially intended to compare biomarkers of renal function in former ELBW cases to term-born controls at young adolescent age.11 Taking this limitation into account, a major impact of ibuprofen on renal function in early adolescence is unlikely. These observations on the renal tolerance of ibuprofen are in line with the data of Frankfurt et al following indomethacin exposure.10 Their cohort included cases (n=107) that had at birth weight up to 1500 g. Assessment was done at 1–3 years of age and data were limited to cystatin C. They showed that eGFRcysC at 3 years was not associated with neonatal indomethacin exposure.10
We were neither able to unveil any other confounder to explain some of the variability in biomarkers of renal function in this former ELBW cohort despite the fact that an extensive list of perinatal characteristics (prenatal, at birth, postnatal), growth patterns and creatinine trends was evaluated (tables 1 and 2). This does not mean that all these perinatal characteristics are excluded as potential contributors to the smaller renal length and lower eGFRcysC in ELBW neonates. Based on animal experiments, accelerated renal maturation after prenatal lung maturation may result in earlier cessation of nephrogenesis,12 but observations in the human former preterm neonates are very limited. In a cross–sectional study of three groups of 30 infants (preterm with antenatal steroids, preterm without antenatal steroids or term), differences in cystatin C were explained by preterm birth and not the use of antenatal steroids.13 The overall very high use of prenatal steroids in our cohort (table 1, 90%) made any exploration on their impact impossible. The same holds true for the growth patterns. Based on the inclusion criterion (ie, ELBW), there was already a relevant portion of growth-restricted newborns at birth (39%). This was further aggravated to an almost uniform postnatal growth restriction at 9 and 24 months, with only partial catch up at 11 years. Both extrauterine and intrauterine growth restriction impair renal function in former preterm neonates.14 15
One of the strengths is the link with a rich data set on creatinine values up to 6 weeks of postnatal life in these cases, but again no associations were found.3 While gestation age-specific creatinine threshold values (1.6, 1.1 and 1 mg/dL at 24–27, 28–29 and 30–32 weeks, respectively) to document acute kidney injury (AKI) were associated with mortality before discharge and non-optimal neurodevelopmental outcome16 (as also in our cohort17), the group of Bruel et al was neither able to document any association between these AKI threshold values and subsequent renal function at 6.6 years.18 A large proportion (23%) of very preterm infants (<33 weeks) presented with signs of nephron reduction, especially those with very low birth weight.18 This is similar to our cohort (<1000 g) where 17/57 (28%) of cases had an eGFRcysC <90 mL/min/1.73 m2, equal to stage 2 of CKD, but none had CKD stage 3, but we were unable to identify any risk factor to predict this outcome.
Despites the fact that we were not able to identify risk factors for reduced eGFRcysC in the current single-unit cohort, additional data-rich, pooled analyses are urgently needed to explore the potential impact of nutritional strategies and pharmacotherapy. The clinical relevance of such studies relates to the link between a lower nephron number and an individual’s risk for hypertension, cardiovascular events and renal disease in later life. This fits into the recently described strategies to improve the understanding of long-term renal consequences after neonatal AKI or perinatal events as part of the shifting focus towards reducing long-term morbidities.19–21
In conclusion, the absence of a decrease in renal function in young adolescence following ibuprofen administration in ELBW neonates in early neonatal life is somewhat reassuring. Larger studies are needed to explore the confounders of variability in renal function.
JAS and KA contributed equally.
Contributors AR developed the study protocol, contributed to data collection, data analysis, interpreting and writing, ZYZ, NC and LJ contributed to data collection, data analysis, interpreting and writing, EL, SS and LPH contributed to writing and interpreting of the study. JAS and KA were the coordinators of the study, including advices on study protocol, data collection, data analysis, interpreting and writing. All authors agreed on the final version of the paper.
Funding This research is supported by the Agency for Innovation, Science and Technology in Flanders (IWT) through the SAFEPEDRUG project (IWT/SBO 120033).
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Ethics approval The study was conducted in accordance with the Helsinki declaration for investigations in human subjects. The Ethics Committee of the University Hospitals Leuven (Belgium) approved the study.
Provenance and peer review Not commissioned; externally peer reviewed.
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