Modification of erythrocyte membrane phospholipid composition in preterm newborns with retinopathy of prematurity: The omegaROP study.

N-3 polyunsaturated fatty acids (PUFAs) may prevent retinal vascular abnormalities observed in oxygen-induced retinopathy, a model of retinopathy of prematurity (ROP). In the OmegaROP prospective cohort study, we showed that preterm infants who will develop ROP accumulate the n-6 PUFA arachidonic acid (ARA) at the expense of the n-3 PUFA docosahexaenoic acid (DHA) in erythrocytes with advancing gestational age (GA). As mice lacking plasmalogens -That are specific phospholipids considered as reservoirs of n-6 and n-3 PUFAs- Display a ROP-like phenotype, the aim of this study was to determine whether plasmalogens are responsible for the changes observed in subjects from the OmegaROP study. Accordingly, preterm infants aged less than 29 weeks GA were recruited at birth in the Neonatal Intensive Care Unit of University Hospital Dijon, France. Blood was sampled very early after birth to avoid any nutritional influence on its lipid composition. The lipid composition of erythrocytes and the structure of phospholipids including plasmalogens were determined by global lipidomics using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). LC-HRMS data confirmed our previous observations by showing a negative association between the erythrocyte content in phospholipid esterified to n-6 PUFAs and GA in infants without ROP (rho = -0.485, p = 0.013 and rho = -0.477, p = 0.015 for ethanolamine and choline total phospholipids, respectively). Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) species with ARA, namely PtdCho16:0/20:4 (rho = -0.511, p < 0.01) and PtdEtn18:1/20:4 (rho = -0.479, p = 0.015), were the major contributors to the relationship observed. On the contrary, preterm infants developing ROP displayed negative association between PtdEtn species with n-3 PUFAs and GA (rho = -0.380, p = 0.034). They were also characterized by a positive association between GA and the ratio of ethanolamine plasmalogens (PlsEtn) with n-6 PUFA to PlsEtn with n-3 PUFAs (rho = 0.420, p = 0.029), as well as the ratio of PlsEtn with ARA to PlsEtn with DHA (rho = 0.843, p = 0.011). Altogether, these data confirm the potential accumulation of n-6 PUFAs with advancing GA in erythrocytes of infants developing ROP. These changes may be partly due to plasmalogens.

Mediolateral episiotomy and risk of obstetric anal sphincter injuries and adverse neonatal outcomes during operative vaginal delivery in nulliparous women: a propensity-score analysis.

BACKGROUND: The potential protective effect of mediolateral episiotomy for obstetrical anal sphincter injuries (OASIs) remains controversial during operative vaginal delivery because of the difficulties to take into account the risk factors and clinical conditions at delivery; in addition, little is known about the potential benefits of mediolateral episiotomy on neonatal outcomes. The objectives were to investigate the associations between mediolateral episiotomy and both OASIs and neonatal outcomes, using propensity scores. METHODS: We performed a retrospective population-based observational study from a perinatal registry that includes all births in a French region between 2010 and 2017. All nulliparous women with singleton pregnancy delivering by operative vaginal deliveries at 37 weeks gestational age or later were included. Inverse-probability-of-treatment weighting with propensity scores was used to minimize indication bias. OASIs was defined as third and fourth-degree tears according to Royal College of Obstetricians and Gynecologists. Two neonatal outcomes were studied: condition at birth (5-min Apgar score less than 7 and/or umbilical artery pH less than 7.10), and admission to neonatal intensive care unit. RESULTS: The study population consisted of 7589 women; 2880 (38.0%) received mediolateral episiotomy. After applying propensity scores, episiotomy was associated with a lower rate of OASIs in forceps/spatula delivery (2.3 vs 6.8%, Risk Ratio (RR) 0.38, 95% Confidence Interval (CI) 0.28-0.52) and in vacuum delivery (1.3 vs 3.4%, RR 0.27, 95% CI 0.20-0.38) as compared with no episiotomy. Mediolateral episiotomy was associated with better condition at birth in case of forceps/spatula delivery (4.5 vs 8.8%, RR 0.56, 95% CI 0.39-0.81). In cases of fetal distress (40.7%), mediolateral episiotomy was associated with better condition of infant at birth in women who delivered by forceps/spatula (4.2 vs 13.5%, RR 0.52, 95% CI 0.31-0.89). No association was found with neonatal unit admission (RR 0.93, 95% CI 0.50-1.74). CONCLUSIONS: Use of mediolateral episiotomy was associated with a lower rate of OASIs during operative vaginal delivery, and in infants it was associated with better condition at birth following forceps/spatula delivery.

A novel classification for evaluating episiotomy practices: application to the Burgundy perinatal network.

BACKGROUND: Though the rate of episiotomy has decreased in France, the overall episiotomy rate was 20% in the 2016 national perinatal survey. We aimed to develop a classification to facilitate the analysis of episiotomy practices and to evaluate whether episiotomy is associated with a reduction in the rate of obstetric anal sphincter injuries (OASIS) for each subgroup. METHODS: This population-based study included all the deliveries that occurred in the Burgundy Perinatal Network from 2011 to 2016. The main outcome was episiotomy, which was identified thanks to the French Common Classification of Medical Procedures. An ascending hierarchical cluster analysis was performed to build the classification. A clinical audit using the classification was conducted yearly in all obstetric units. The episiotomy rates were described throughout the study period for each subgroup of the classification. The OASIS rates were evaluated by subgroup and the association between mediolateral episiotomy and OASIS was investigated for each subgroup. RESULTS: Our analyses included 81,290 pregnant women. The classification comprised 7 subgroups: (1) nulliparous single cephalic at term, (2) nulliparous single cephalic at term with instrumental delivery, (3) multiparous single cephalic at term, (4) multiparous single cephalic at term with instrumental delivery, (5) all preterm deliveries (< 37 weeks gestation), (6) all breech deliveries, (7) all multiple deliveries. Episiotomy rates ranged from 6.2% in Group 3 to 40.9% in Group 2. From 2011 to 2016, every group except breech deliveries experienced a significant decrease in episiotomy rates, ranging from - 28.1 to - 61.0%. The prevalence of OASIS was the highest in Groups 2 (3.0%) and 4 (2.2%). Overall OASIS rates did not significantly differ with episiotomy use (P = 0.25). However, we found that the use of episiotomy was associated with a reduction in OASIS rates in Groups 1 and 2 (odds ratio 0.6 [95% CI 0.4-0.9] and 0.4 [0.3-0.5], respectively). This reduction was only observed in Group 4 with forceps delivery (odds ratio 0.4 [0.1-0.9]). CONCLUSION: We developed the first classification for the evaluation of episiotomy practices based on 7 clinically relevant subgroups. This easy-to-use tool can help obstetricians and midwives improve their practices through self-assessment.

Alteration of erythrocyte membrane polyunsaturated fatty acids in preterm newborns with retinopathy of prematurity.

Extremely preterm infants are at high risk for retinopathy of prematurity (ROP), a potentially blinding disease characterized by abnormalities in retinal vascularization. Whereas animal studies revealed that n-3 polyunsaturated fatty acids (PUFAs) may be of benefit in preventing ROP, human studies conducted on preterm infants during the 1st weeks of life showed no association between blood n-3 PUFA bioavailability and ROP incidence and/or severity, probably because of the influence of nutrition on the lipid status of infants. In the OmegaROP prospective cohort study, we characterized the erythrocyte concentrations of PUFAs in preterm infants aged less than 29 weeks gestational age (GA) without any nutritional influence. We show that GA is positively associated with the erythrocyte n-6 to n-3 PUFA ratio, and particularly with the ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA), in infants with ROP. A time-dependent accumulation of AA at the expense of DHA seems to occur in utero in erythrocytes of preterm infants who will develop ROP, thus reinforcing previous data on the beneficial properties of DHA on this disease. In addition, preliminary data on maternal erythrocyte membrane lipid concentrations suggest modifications in placental transfer of fatty acids. Documenting the erythrocyte AA to DHA ratio at birth in larger cohorts might be useful to set up new prognostic factors for ROP.

Correction: Maternal Haemoglobin and Short-Term Neonatal Outcome in Preterm Neonates.

[This corrects the article DOI: 10.1371/journal.pone.0089530.].

Maternal haemoglobin and short-term neonatal outcome in preterm neonates.

OBJECTIVE: To determine whether there is a significant association between maternal haemoglobin measured before delivery and short-term neonatal outcome in very preterm neonates. STUDY DESIGN: We included prospectively all live births occurring from 25 to 32+6 weeks of gestation in a tertiary care centre between January 1(st) 2009 and December 31(st) 2011. Outborn infants and infants presenting with lethal malformations were excluded. Three hundred and thirty-nine mothers and 409 infants met the inclusion criteria. For each mother-infant pair a prospective record of epidemiologic data was performed and maternal haemoglobin concentration recorded within 24 hours before delivery was retrospectively researched. Maternal haemoglobin was divided into quartiles with the second and the third one regarded as reference as they were composed of normal haemoglobin values. Short-term outcome was defined as poor in case of death during hospital stay and/or grades III/IV intraventricular haemorrhage and/or periventricular leukomalacia and/or necessity of ventriculoperitoneal shunt. RESULTS: The global rate of poor short-term neonatal outcome was 11.4% and was significantly associated with low maternal haemoglobin values. This association remained significant after adjustment for antenatal corticosteroids therapy, gestational age, parity, mechanism of preterm birth, mode of delivery and birth weight (aOR = 2.97 CI 95% [1.36-6.47]). There was no relation between short-term neonatal outcome and high maternal haemoglobin concentration values. CONCLUSION: We show that low maternal haemoglobin concentration at delivery is an independent risk factor for poor short-term neonatal outcome in very preterm neonates. This study is one of the first to show such an association within the preterm population.

Doxapram and hypokalaemia in very preterm infants.

BACKGROUND: We observed two preterm infants who developed severe hypokalaemia following doxapram. We therefore wished to review the possible association between doxapram and severe hypokalaemia. STUDY DESIGN: A retrospective study of preterm infants born before 32 weeks of gestation and hospitalised in our intensive care unit in 2004. For each infant, treatment with doxapram or with any drug known to interfere with potassium metabolism, potassium intakes and episodes of hypokalaemia have been recorded. RESULTS: Out of 105 infants, 54 received doxapram. Doxapram-treated infants were significantly younger and had a lower birth weight. Doxapram treated infants were more likely to receive caffeine, furosemide, insulin and mechanical ventilation. There was no difference between the two groups for the other parameters. Hypokalaemia was frequently encountered in our population since it occurred in 76% of enrolled patients and severe hypokalaemia (potassium plasma level below 3 mmol/l) was found in 41%. Bivariate analysis underlined several risk factors for severe hypokalaemia: use of doxapram, gestational age below 28 weeks, use of mechanical ventilation, furosemide, ibuprofen, insulin and postnatal corticosteroids. Cox model's multivariate analysis showed that administration of furosemide and doxapram significantly increased the occurrence of severe hypokalaemia with relative risks of 4.9 (95% CI 1.9 to 12.5) and 8.2 (95% CI 3.1 to 21.7), respectively. CONCLUSIONS: This retrospective study underlines the high incidence of severe hypokalaemia in very preterm infants and an increased risk of severe hypokalaemia during doxapram treatment. We recommend potassium monitoring during any use of doxapram.

Echocardiography as a guide for patent ductus arteriosus ibuprofen treatment and efficacy prediction.

OBJECTIVE: To evaluate echocardiography criteria in predicting the response to ibuprofen treatment. DESIGN: A prospective cohort study of preterm infants untreated or treated with ibuprofen for patent ductus arteriosus. SETTING: Three academic neonatal intensive care units. PATIENTS: Two hundred fifty-two preterm infants of 27-31 wks gestation. INTERVENTIONS: Ibuprofen treatment within the first 5 days of life was indicated when at least two out of four conventional echocardiography criteria were observed: ductal diameter >2 mm, left-right ductal shunt maximum velocity <2 m/sec, mean flow velocity in left pulmonary artery >0.4 m/sec, and end-diastolic flow velocity in left pulmonary artery >0.2 m/sec. MEASUREMENTS AND MAIN RESULTS: Of the infants analyzed, 135 had a closed ductus at an average age of 1.9 ± 0.9 days, and 43 had an open ductus but <2 predefined criteria. Seventy-four infants (29%) received ibuprofen on day 2.2 ± 1.1. Sixteen infants failed ibuprofen and nine had to undergo surgical ligation. The left-right ductal shunt maximum velocity criterion had the best negative predictive value for treatment response, while the ductal diameter criterion had the best positive predictive value. CONCLUSIONS: Echocardiography may be a useful tool to help patent ductus arteriosus management. A combined use of ductal diameter and left-right ductal shunt maximum velocity criteria allows a more accurate prediction of the response of infants with patent ductus arteriosus to ibuprofen treatment.

Ibuprofen in very preterm infants impairs renal function for the first month of life.

We carried out a study aiming to determine the renal effect of ibuprofen treatment for patent ductus arteriosus (PDA) in very preterm infants during the first month of life. Infants aged 27-31 weeks gestation were enrolled from October 2004 to August 2006. They were assigned to two different groups according to ibuprofen exposure during care of their PDA status assessed by echocardiography. Infants of both groups were matched based on gestational age, Clinical Risk Index for Babies score, birth weight and inclusion center. Renal function was evaluated at baseline and weekly for 1 month. One hundred and forty-eight infants were enrolled. Glomerular filtration rate (GFR) was significantly decreased in the ibuprofen group after treatment withdrawal (GFR on day 7, ibuprofen versus no ibuprofen: 12.8 +/- 6.2 vs. 18.1 +/- 12.1 ml/min/1.73 m(2); P < 0.001). Adjusted analysis proved this decrease to be sustained during the first month of life. Tubular function was also impaired during the first month in ibuprofen-treated infants. Ibuprofen administered for PDA is associated with a decreased GFR during the first month of life. Renal function of infants receiving ibuprofen should be carefully monitored and drugs that are eliminated by glomerular filtration handled cautiously during this period.

Long-term effects of in utero exposure to cyclosporin A on renal function in the rabbit.

The number of pregnant women who receive cyclosporin A (CsA) after transplantation or for autoimmune disease has increased. CsA and its metabolites can cross the placental barrier and thus interfere with fetal development. It was shown previously that rabbits that were exposed in utero to 10 mg/kg per d CsA from the 14th to the 18th day of gestation presented a 25% nephron reduction. Thus, this study was conducted to assess the long-term systemic and renal effects of a CsA-induced nephron reduction. Twenty-two pregnant New Zealand white rabbits were randomly divided into two groups: Twelve received 10 mg/kg per d CsA from day 14 to day 18 of gestation, and 10 were used as controls. Rabbits that were born to these animals were evaluated at 4, 11, 18, and 35 wk of life. Pups that were exposed antenatally to CsA presented first a permanent nephron deficit; second, glomerular, tubular, and intrarenal hemodynamics dysfunction; third, enlarged kidneys with numerous tubular and glomerular lesions; and, fourth, an endothelin-dependent systemic hypertension that worsened with age. In utero exposure to CsA induced a nephron reduction that led to systemic hypertension and progressive chronic renal insufficiency in adulthood. A long-term clinical survey is mandatory in infants who are born to mothers who were treated with cyclosporin during pregnancy.

Calcium, sodium and potassium urinary excretion during the first five days of life in very preterm infants.

BACKGROUND: Hypercalciuria has been associated with the risk of nephrocalcinosis and renal stones in both adults and children. Renal calcifications are frequently encountered in preterm infants because this particular population presents most of the risk factors of increased urinary calcium excretion. Urinary calcium excretion has been shown to correlate with sodium and potassium excretions in adult patients, but these correlations have not been demonstrated in the early neonatal period yet. OBJECTIVE: To define the relationship between calcium urinary excretion and sodium or potassium excretions in the first 5 days of life in preterm babies. METHODS: A prospective study was conducted in 16 preterm infants born before 32 weeks of gestation (body weight 1,373 +/- 310 g; gestational age 29.1 +/- 1.6 weeks). Fifteen consecutive 8-hour urine collections were performed for each infant from the 8th hour of life. A plasma sample was obtained at the end of each urine collection. Sodium, potassium, calcium and creatinine were measured in urine and blood samples as often as possible. RESULTS: (1) Urine sodium excretion was 6.56 +/- 4.35 mmol/kg per day. (2) Urinary calcium excretion was 5.9 +/- 5.4 mg/kg per day and the urinary calcium/creatinine ratio was 0.48 +/- 0.39 mg/mg. (3) Urinary calcium and sodium excretion were positively correlated (r = 0.65, p = 0.0001), while an inverse correlation was found between calcium and potassium excretion (r = 0.31, p = 0.004). CONCLUSION: The mean values of urinary calcium excretion and calcium/creatinine ratio observed in our population were higher than 4 mg/kg per day and 0.4 mg/mg, respectively, i.e. boundary values previously associated with an increased risk of nephrocalcinosis. We hypothesize that an increase in urinary sodium excretion in this population may facilitate calcium excretion.

Cyclosporin A administration during pregnancy induces a permanent nephron deficit in young rabbits.

Cyclosporin A (CsA) is an immunosuppressive agent used to prevent graft rejection and to treat autoimmune disorders. Successful pregnancies can be achieved among CsA-treated women, although it is known that CsA is nephrotoxic and crosses the human placenta. The aim of this study was to evaluate the harmlessness of CsA toward the embryonic kidney. Twenty-one pregnant rabbits were divided into four groups. Groups of six and four female animals were subjected to daily injections of 10 mg/kg per d CsA (administered subcutaneously) for 5 d, from day 14 to day 18 of gestation or from day 20 to day 24 of gestation, respectively. In the third group, five female animals received the CsA diluent (Cremophor) from day 14 to day 18 of gestation. The fourth group consisted of six untreated female animals. Pregnancy outcomes among CsA-treated does demonstrated a reduced number of living pups, which were also growth-retarded, with exposure to CsA from day 20 to day 24 of gestation. However, pups exposed to CsA from day 14 to day 18 of gestation exhibited normal fetal growth, and blood concentrations of CsA matched human data. Examinations of kidneys at birth demonstrated vacuolation of proximal and collecting tubules and ureteric bud ends. Increased glomerular volumes and decreased nephron densities suggested nephron mass reduction, which was quantitatively evaluated in 1-mo-old animals. The nephron numbers were reduced by 25 and 33% in day 14 to 18 CsA-treated and day 20 to 24 CsA-treated animals, respectively, which displayed compensatory adaptation of the existing nephrons. However, foci of segmental glomerular sclerosis were already present, which would possibly jeopardize renal function later in life.

Disparate effects of chronic and acute theophylline on cyclosporine A nephrotoxicity.

We previously developed a model of acute cyclosporine A (CsA)-induced vasomotor nephrotoxicity in rabbits. As exogenous adenosine infusion mimics the haemodynamic changes that characterize acute renal failure (ARF), we wanted to know whether adenosine was a mediator in this model and whether an adenosine receptor blocker could prevent the CsA-induced ARF. Group 1 were untreated controls. Group 2 received CsA (25 mg/kg per day) for 5 days. Renal function parameters were measured, showing ARF in all animals compared to controls. Theophylline (1 mg/kg i.v. bolus) was then administered and renal function was reassessed. Theophylline significantly reduced renal vascular resistance (-8%) and increased renal blood flow (RBF) (+20%), glomerular filtration rate (GFR) (+50%), filtration fraction (+24%) and diuresis (+73%), suggesting that adenosine was involved in the CsA-induced ARF. In group 3, theophylline (30 mg/kg per day) was given concomitantly with CsA for 5 days. GFR was normalized, but theophylline did not hinder the drop in RBF seen with CsA alone in group 2. Microscopy observation of the kidneys showed that chronic theophylline administration aggravated the morphological changes induced by CsA alone. We conclude that CsA administration for 5 days induced a vasomotor nephropathy with an adenosine-mediated afferent arteriolar constriction which cannot be prevented by concomitant theophylline administration.

Complementary effects of adenosine and angiotensin II in hypoxemia-induced renal dysfunction in the rabbit.

The acute renal effects of hypoxemia and the ability of the co-administration of an angiotensin converting enzyme inhibitor (perindoprilat) and an adenosine receptor antagonist (theophylline) to prevent these effects were assessed in anesthetized and mechanically-ventilated rabbits. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (-12 +/- 2%), GFR (-16 +/- 3%) and RBF (-12 +/- 3%) with a concomitant increase in renal vascular resistance (RVR) (+ 18 +/- 5%), without changes in filtration fraction (FF) (-4 +/- 2%). These results suggest the occurrence of both pre- and postglomerular vasoconstriction during the hypoxemic stress. In 7 rabbits pretreated with intravenous perindoprilat (20 microg/kg), the hypoxemia-induced changes in RBF and RVR were prevented. FF decreased significantly (-18 +/- 2%), while the drop in GFR was partially blunted. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction by perindoprilat. In 7 additional rabbits, co-administration of perindoprilat and theophylline (1 mg/kg) completely prevented the hypoxemia-induced changes in RBF (+ 11 +/- 3%) and GFR (+ 2 +/- 3%), while RVR decreased significantly (-14 +/- 3%). Since adenosine and angiotensin II were both shown to participate, at least in part, in the renal changes induced by hypoxemia, the beneficial effects of perindoprilat and theophylline in this model could be mediated by complementary actions of angiotensin II and adenosine on the renal vasculature.