Fetal Pain

Recent studies have suggested that the fetus is capable of exhibiting a stress response to intrauterine needling, resulting in alterations in fetal stress hormone levels. Intrauterine transfusions are performed by inserting a needle either in the umbilical cord root at the placental surface (PCI), or in the intrahepatic portion of the umbilical vein (IHV). Aim of our study was to test the hypothesis that fetal hormonal changes during intrauterine transfusion are more pronounced when the needle is inserted in the fetal abdomen. Furthermore we aimed to evaluate the effect of fetal analgesia with remifentanil on the fetal stress hormone changes. Exploring the hemodynamic changes following a noxious stimulus, we saw no differences in transfusions through the IHV or the PCI. Remifentanil did not influence the stress hormone changes. We concluded that the stress hormone changes are independent of both site of transfusion and the use of remifentanil. Our results do not confirm nor deny that the fetus is capable to react to a potential painful stimulus, or to show signs of stress or even pain. However, previous research has suggested that presumably painful fetal conditions can lead to alterations in stress reactions after birth. This phenomenon is called ‘fetal programming’. Fetal programming could possibly lead to life-long changes in stress responses and even to increased susceptibility for certain diseases. With the current understanding of fetal pain and fetal analgesia we would advocate the following: 1. Fetal analgesia for invasive procedures should be provided from at least 20 weeks gestation onwards 2. All invasive fetal procedures warrant fetal analgesia, but in procedures involving more than just a single puncture with a thin needle it is obligatory. 3. Analgesics should be given intravenously to the mother. The drug of choice should be ultra-short working (like remifentanil) therefore minimising possible undesirable side-effects to both fetus and mother.LUMC / Geneeskund

The ANTENATAL multicentre study to predict postnatal renal outcome in fetuses with posterior urethral valves: objectives and design

Abstract Background Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted in utero with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature. Methods Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming α = 0.05, 1–β = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature. Results In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment. Conclusions Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV

Vesicoamniotic shunting versus conservative management in fetal lower urinary tract obstruction: a 10-year registry : a 10-year registry

ObjectivesTo assess the perinatal mortality and the postnatal outcome in fetal lower urinary tract obstructions (LUTO) according to the prenatal management.MethodsThis was a retrospective study of all cases with suspected LUTO encountered in a ten-year period (2005 – 2014) in all 8 academic centres in the Netherlands and eventually treated at the Leiden University Medical Center. Antenatal management, sonographic findings and postnatal outcome were documented. The postnatal renal function (estimated Glomerular Filtration Rate or eGFR) was calculated using the Schwartz formula, considering the length of the infants and the nadir creatinine within one year of postnatal surgical intervention.Results341 fetuses were included: 275 cases with conservative management, 29 cases with vesico-amniotic shunting and 37 LUTO managed with vesicocentesis. The survival rate was respectively 76.7%, 82.6% and 60%. Oligohydramnios, abnormal karyotype and severe associated anomalies were significantly different comparing shunting to conservative management (respectively 100% vs 55%; 0% vs 15%; 24% vs 3%). Subgroup analysis was unable to show a significant difference in survival rate and postnatal renal function in vesico-amniotic shunt placement versus conservative management (survival rate: 68% vs 79%, p > 0.05; eGFR: 52 ml/min/1.73 m2 vs 61 ml/min/1.73 m2, p > 0.05).ConclusionsLUTO cases treated over the past ten years with vesico-amniotic shunt did not show any significant improvement in perinatal survival and postnatal renal function. The study suggests that prenatal selection of cases eligible for the treatment needs further refinement

Antenatal staging of congenital lower urinary tract obstruction

Objective: To propose a staging system for congenital lower urinary tract obstruction (LUTO) capable of predicting the severity of the condition and its prognosis. Methods: This was a national retrospective study carried out at the eight Academic Hospitals in The Netherlands. We collected prenatal and postnatal data of fetuses at high risk of isolated LUTO that were managed conservatively. Postnatal renal function was assessed by the estimated glomerular filtration rate (eGFR), calculated using the Schwartz formula, considering the length of the infant and the creatinine nadir in the first year after birth. Receiver–operating characteristics (ROC) curve analysis, univariate analysis and multivariate logistic regression analysis with stepwise backward elimination were performed in order to identify the best antenatal predictors of perinatal mortality and postnatal renal function. Results: In total, 261 fetuses suspected of having LUTO and managed conservatively were included in the study. The pregnancy was terminated in 110 cases and perinatal death occurred in 35 cases. Gestational age at appearance of oligohydramnios showed excellent accuracy in predicting the risk of perinatal mortality with an area under the ROC curve of 0.95 (P < 0.001) and an optimal cut-off at 26 weeks' gestation. Fetuses with normal amniotic fluid (AF) volume at 26 weeks' gestation presented with low risk of poor outcome and were therefore defined as cases with mild LUTO. In fetuses referred before the 26 th week of gestation, the urinary bladder volume (BV) was the best unique predictor of perinatal mortality. ROC curve analysis identified a BV of 5.4 cm 3 and appearance of oligohydramnios at 20 weeks as the best threshold for predicting an adverse outcome. LUTO cases with a BV ≥ 5.4 cm 3 or abnormal AF volume before 20 weeks' gestation were defined as severe and those with BV < 5.4 cm 3 and normal AF volume at the 20 weeks' scan were defined as moderate. Risk of perinatal mortality significantly increased according to the stage of severity, from mild to moderate to severe stage, from 9% to 26% to 55%, respectively. Similarly, risk of severely impaired renal function increased from 11% to 31% to 44%, for mild, moderate and severe LUTO, respectively. Conclusions: Gestational age at appearance of oligo- or anhydramnios and BV at diagnosis can accurately predict mortality and morbidity in fetuses with LUTO. Our proposed staging system can triage reliably fetuses with LUTO and predict the severity of the condition and its prognosis

Fetal megacystis : prediction of spontaneous resolution and outcome

Objectives: To investigate the natural history of fetal megacystis from diagnosis in utero to postnatal outcome, and to identify prognostic indicators of spontaneous resolution and postnatal outcome after resolution. Methods: This was a national retrospective cohort study. Fetal megacystis was defined in the first trimester as a longitudinal bladder diameter (LBD) ≥ 7 mm, and in the second and third trimesters as an enlarged bladder failing to empty during the entire extended ultrasound examination. LBD and gestational age (GA) at resolution were investigated with respect to likelihood of resolution and postnatal outcome, respectively. Sensitivity, specificity and area under the receiver–operating characteristics curve (AUC) were calculated. Results: In total, 284 cases of fetal megacystis (93 early megacystis, identified before the 18th week, and 191 late megacystis, identified at or after the 18th week) were available for analysis. Spontaneous resolution occurred before birth in 58 (20%) cases. In cases with early megacystis, LBD was predictive of the likelihood of spontaneous resolution (sensitivity, 80%; specificity, 79%; AUC, 0.84), and, in the whole population, GA at regression was predictive of postnatal outcome, with an optimal cut-off at 23 weeks (sensitivity, 100%; specificity, 82%; AUC, 0.91). In the group with early megacystis, the outcome was invariably good when resolution occurred before the 23rd week of gestation, whereas urological sequelae requiring postnatal surgery were diagnosed in 3/8 (38%) cases with resolution after 23 weeks. In the group with late megacystis, spontaneous resolution was associated with urological complications after birth, ranging from mild postnatal hydronephrosis in infants with resolution before 23 weeks, to more severe urological anomalies requiring postnatal surgery in those with resolution later in pregnancy. This supports the hypothesis that an early resolution of megacystis is often related to a paraphysiological bladder enlargement that resolves early in pregnancy without consequences, while antenatal resolution occurring later in pregnancy (after the 23rd week of gestation) should suggest a pathological condition with urological sequelae. Conclusions: In fetal megacystis, LBD and GA at regression can be used as predictors of resolution and outcome, respectively. These parameters could help in fine-tuning the prognosis and optimizing the frequency of follow-up scans

Abstracts of the 26th World Congress on Ultrasound in Obstetrics and Gynecology, Rome, Italy, 24-28 September 2016

ObjectivesTo assess the perinatal mortality and the postnatal outcome in fetal lower urinary tract obstructions (LUTO) according to the prenatal management.MethodsThis was a retrospective study of all cases with suspected LUTO encountered in a ten-year period (2005 – 2014) in all 8 academic centres in the Netherlands and eventually treated at the Leiden University Medical Center. Antenatal management, sonographic findings and postnatal outcome were documented. The postnatal renal function (estimated Glomerular Filtration Rate or eGFR) was calculated using the Schwartz formula, considering the length of the infants and the nadir creatinine within one year of postnatal surgical intervention.Results341 fetuses were included: 275 cases with conservative management, 29 cases with vesico-amniotic shunting and 37 LUTO managed with vesicocentesis. The survival rate was respectively 76.7%, 82.6% and 60%. Oligohydramnios, abnormal karyotype and severe associated anomalies were significantly different comparing shunting to conservative management (respectively 100% vs 55%; 0% vs 15%; 24% vs 3%). Subgroup analysis was unable to show a significant difference in survival rate and postnatal renal function in vesico-amniotic shunt placement versus conservative management (survival rate: 68% vs 79%, p > 0.05; eGFR: 52 ml/min/1.73 m2 vs 61 ml/min/1.73 m2, p > 0.05).ConclusionsLUTO cases treated over the past ten years with vesico-amniotic shunt did not show any significant improvement in perinatal survival and postnatal renal function. The study suggests that prenatal selection of cases eligible for the treatment needs further refinement

Persistent fetal sinus bradycardia associated with maternal anti-SSA/Ro and anti-SSB/La antibodies

To study the clinical course and outcome of fetal sinus bradycardia (SB) due to maternal antibody-induced sinus node dysfunction. We reviewed the maternal, prenatal, and postnatal findings of fetuses with SB associated with elevated maternal anti-SSA/Ro and anti-SSB/La antibodies. Of the 6 cases diagnosed prenatally, 3 had isolated SB persisting after birth and had a good prognosis. Three fetuses with SB and severe myocardial involvement (congenital complete heart block and/or endocardial fibroelastosis) succumbed in utero in spite of treatment. Postmortem histopathology in 1 fetus showed inflammatory destruction of the sinus and atrioventricular nodes. SB was detected incidentally in a 7-year-old girl. She had intermittent heart block with progressive sinus arrest requiring permanent pacemaker. Fetal SB associated with maternal autoantibodies may persist in childhood, with a good prognosis in the absence of widespread cardiac involvemen