Patient empowerment improves follow-up data collection after fetal surgery for spina bifida: institutional audit.

OBJECTIVES: To define and grade fetal and maternal adverse events following fetal surgery for spina bifida and to report on the impact of engaging patients in collecting follow-up data. METHODS: This prospective single-center audit included 100 consecutive patients undergoing fetal surgery for spina bifida between January 2012 and December 2021. In our setting, patients return to their referring unit for further pregnancy care and delivery. On discharge, referring hospitals were requested to return outcome data. For this audit, we prompted patients and referring hospitals to provide data in cases of missing outcomes. Outcomes were categorized as missing, returned spontaneously or returned following additional request, by the patient and/or referring center. Postoperative maternal and fetal complications until delivery were defined and graded according to Maternal and Fetal Adverse Event Terminology (MFAET) and the Clavien-Dindo classification. RESULTS: There were no maternal deaths, but severe maternal complications occurred in seven women (anemia in pregnancy, postpartum hemorrhage, pulmonary edema, lung atelectasis, urinary tract obstruction and placental abruption). No cases of uterine rupture were reported. Perinatal death occurred in 3% of fetuses and other severe fetal complications in 15% (perioperative fetal bradycardia/cardiac dysfunction, fistula-related oligohydramnios, chorioamnionitis and preterm prelabor rupture of membranes (PPROM) before 32 weeks). PPROM occurred in 42% of patients and, overall, delivery took place at a median gestational age of 35.3 weeks (interquartile range, 34.0-36.6 weeks). Information provided following additional request, from both centers and patients but mainly from the latter, reduced missing data by 21% for gestational age at delivery, 56% for uterine-scar status at birth and 67% for shunt insertion at 12 months. Compared with the generic Clavien-Dindo classification, the MFAET system ranked complications in a more clinically relevant way. CONCLUSIONS: The nature and rate of severe complications following fetal surgery for spina bifida were similar to those reported in other large series. Spontaneous return of outcome data by referring centers was low, yet patient empowerment improved data collection. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Core outcome set for perinatal interventions for congenital diaphragmatic hernia.

OBJECTIVE: To develop a core set of prenatal and neonatal outcomes for clinical studies evaluating perinatal interventions for congenital diaphragmatic hernia, using a validated consensus-building method. METHODS: An international steering group comprising 13 leading maternal-fetal medicine specialists, neonatologists, pediatric surgeons, patient representatives, researchers and methodologists guided the development of this core outcome set. Potential outcomes were collected through a systematic review of the literature and entered into a two-round online Delphi survey. A call was made for stakeholders with experience of congenital diaphragmatic hernia to review the list and score outcomes based on their perceived relevance. Outcomes that fulfilled the consensus criteria defined a priori were discussed subsequently in online breakout meetings. Results were reviewed in a consensus meeting, during which the core outcome set was defined. Finally, the definitions, measurement methods and aspirational outcomes were defined in online and in-person definition meetings by a selection of 45 stakeholders. RESULTS: Overall, 221 stakeholders participated in the Delphi survey and 198 completed both rounds. Fifty outcomes met the consensus criteria and were discussed and rescored by 78 stakeholders in the breakout meetings. During the consensus meeting, 93 stakeholders agreed eventually on eight outcomes, which constituted the core outcome set. Maternal and obstetric outcomes included maternal morbidity related to the intervention and gestational age at delivery. Fetal outcomes included intrauterine demise, interval between intervention and delivery and change in lung size in utero around the time of the intervention. Neonatal outcomes included neonatal mortality, pulmonary hypertension and use of extracorporeal membrane oxygenation. Definitions and measurement methods were formulated by 45 stakeholders, who also added three aspirational outcomes: duration of invasive ventilation, duration of oxygen supplementation and use of pulmonary vasodilators at discharge. CONCLUSIONS: We developed with relevant stakeholders a core outcome set for studies evaluating perinatal interventions in congenital diaphragmatic hernia. Its implementation should facilitate the comparison and combination of trial results, enabling future research to better guide clinical practice. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Placental gas exchange during amniotic carbon dioxide insufflation in sheep.

OBJECTIVE: Insufflation of the amniotic cavity with carbon dioxide (CO2 ) is used clinically to improve visibility during complex fetoscopic surgery. Insufflation with heated, humidified CO2 has recently been shown to reduce fetal hypercapnia and acidosis in sheep, compared with use of cold and dry CO2 , but the underlying mechanisms are unclear. The aim of this study was to investigate whether differences in placental CO2 and oxygen (O2 ) exchange during insufflation with heated and humidified vs cold and dry CO2 could explain these findings. METHODS: Thirteen fetal lambs at 105 days of gestation (term, 146 days) were exteriorized partially, via a midline laparotomy and hysterotomy, and instrumented with an umbilical artery catheter, an umbilical vein catheter and a common umbilical vein flow probe. Arterial and venous catheters and flow probes were also inserted into the maternal uterine circulation. Six ewes were insufflated with cold, dry CO2 (22°C; 0-5% humidity) and seven with heated, humidified CO2 (40°C; 95-100% humidity) at 15 mmHg for 180 min. Blood-flow recordings and paired arterial and venous blood gases were sampled from uterine and umbilical vessels. Rates of placental CO2 and O2 exchange were calculated. RESULTS: After 180 min of insufflation, fetal survival was 33% (2/6) using cold, dry CO2 and 71% (5/7) using heated, humidified CO2 . By 120 min, fetuses insufflated with heated, humidified CO2 had lower arterial CO2 levels and higher arterial pH compared to those insufflated with cold, dry gas. Insufflation decreased significantly placental gas exchange in both groups, as measured by rates of both (i) fetal CO2 clearance and O2 uptake and (ii) maternal O2 delivery and CO2 uptake from the fetal compartment. CONCLUSIONS: Lower arterial CO2 and higher pH levels in fetuses insufflated with heated and humidified, compared to cold and dry, CO2 could not be explained by differences in placental gas exchange. Instead, heated and humidified insufflation appeared to reduce fetal CO2 absorption from the uterus, supporting its use in preference to cold, dry CO2 . © 2019 International Society of Ultrasound in Obstetrics and Gynecology.

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia.

OBJECTIVES: Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, owing to lung hypoplasia that impairs fetal pulmonary vascular development. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rabbit and rodent CDH models, but whether this translates to functional improvements after birth remains unknown. We aimed to evaluate the effect of antenatal sildenafil on neonatal pulmonary hemodynamics and lung function in lambs with diaphragmatic hernia (DH). METHODS: DH was surgically induced at approximately 80 days' gestation in 16 lamb fetuses (term in lambs is approximately 147 days). From 105 days' gestation, ewes received either sildenafil (0.21 mg/kg/h intravenously) or saline infusion until delivery (n = 8 fetuses in each group). At approximately 138 days' gestation, all lambs were instrumented and then delivered via Cesarean section. The lambs were ventilated for 120 min with continuous recording of physiological (pulmonary and carotid artery blood flow and pressure; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions. Only lambs that survived until delivery and with a confirmed diaphragmatic defect at postmortem examination were included in the analysis; these comprised six DH-sildenafil lambs and six DH-saline control lambs. RESULTS: Lung-to-body-weight ratio (0.016 ± 0.001 vs 0.013 ± 0.001; P = 0.06) and dynamic lung compliance (0.8 ± 0.2 vs 0.7 ± 0.2 mL/cmH2 O; P = 0.72) were similar in DH-sildenafil lambs and controls. Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH-sildenafil lambs, and was 4-fold lower by 120 min after cord clamping than in controls (0.6 ± 0.1 vs 2.2 ± 0.6 mmHg/(mL/min); P = 0.002). Pulmonary arterial pressure was also lower (46 ± 2 vs 59 ± 2 mmHg; P = 0.048) and pulmonary blood flow higher (25 ± 3 vs 8 ± 2 mL/min/kg; P = 0.02) in DH-sildenafil than in DH-saline lambs at 120 min. Throughout the 120-min ventilation period, the partial pressure of arterial carbon dioxide tended to be lower in DH-sildenafil lambs than in controls (63 ± 8 vs 87 ± 8 mmHg; P = 0.057), and there was no significant difference in partial pressure of arterial oxygen between the two groups. CONCLUSIONS: Sustained maternal antenatal sildenafil infusion reduced pulmonary arterial pressure and increased pulmonary blood flow in DH lambs for the first 120 min after birth. These findings of improved pulmonary vascular function are consistent with improved pulmonary vascular structure seen in two previous animal models. The data support the rationale for a clinical trial investigating the effect of antenatal sildenafil in reducing the risk of neonatal pulmonary hypertension in infants with CDH. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Physiological effects of partial amniotic carbon dioxide insufflation with cold, dry vs heated, humidified gas in a sheep model.

OBJECTIVE: Partial amniotic carbon dioxide (CO2 ) insufflation (PACI) is used to improve visualization and facilitate complex fetoscopic surgery. However, there are concerns about fetal hypercapnic acidosis and postoperative fetal membrane inflammation. We assessed whether using heated and humidified, rather than cold and dry, CO2 might reduce the impact of PACI on the fetus and fetal membranes in sheep. METHODS: Twelve fetal lambs of 105 days' gestational age (term = 145 days) were exteriorized partially, via a midline laparotomy and hysterotomy, and arterial catheters and flow probes were inserted surgically. The 10 surviving fetuses were returned to the uterus, which was then closed and insufflated with cold, dry (22 °C at 0-5% humidity, n = 5) or heated, humidified (40 °C at 100% humidity, n = 5) CO2 at 15 mmHg for 180 min. Fetal membranes were collected immediately after insufflation for histological analysis. Physiological data and membrane leukocyte counts, suggestive of membrane inflammation, were compared between the two groups. RESULTS: After 180 min of insufflation, fetal survival was 0% in the group which underwent PACI with cold, dry CO2 , and 60% (n = 3) in the group which received heated, humidified gas. While all insufflated fetuses became progressively hypercapnic (PaCO2  > 68 mmHg), this was considerably less pronounced in those in which heated, humidified gas was used: after 120 min of insufflation, compared with those receiving cold, dry gas (n = 3), fetuses undergoing heated, humidified PACI (n = 5) had lower arterial partial pressure of CO2 (mean ± standard error of the mean, 82.7 ± 9.1 mmHg for heated, humidified CO2 vs 170.5 ± 28.5 for cold, dry CO2 during PACI, P < 0.01), lower lactate levels (1.4 ± 0.4 vs 8.5 ± 0.9 mmol/L, P < 0.01) and higher pH (pH, 7.10 ± 0.04 vs 6.75 ± 0.04, P < 0.01). There was also a non-significant trend for fetal carotid artery pressure to be higher following PACI with heated, humidified compared with cold, dry CO2 (30.5 ± 1.3 vs 8.7 ± 5.5 mmHg, P = 0.22). Additionally, the median (interquartile range) number of leukocytes in the chorion was significantly lower in the group undergoing PACI with heated, humidified CO2 compared with the group receiving cold, dry CO2 (0.7 × 10-5 (0.5 × 10-5 ) vs 3.2 × 10-5 (1.8 × 10-5 ) cells per square micron, P = 0.02). CONCLUSIONS: PACI with cold, dry CO2 causes hypercapnia, acidosis, hypotension and fetal membrane inflammation in fetal sheep, raising potential concerns for its use in humans. It seems that using heated, humidified CO2 for insufflation partially mitigates these effects and this may be a suitable alternative for reducing the risk of fetal acid-base disturbances during, and fetal membrane inflammation following, complex fetoscopic surgery. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Lung size and liver herniation predict need for extracorporeal membrane oxygenation but not pulmonary hypertension in isolated congenital diaphragmatic hernia: systematic review and meta-analysis.

OBJECTIVES: To identify antenatal predictors of persistent pulmonary hypertension (PPH) and the need for extracorporeal membrane oxygenation (ECMO) in fetuses with congenital diaphragmatic hernia (CDH). METHODS: We performed a systematic literature review on antenatal diagnostic tests in fetuses with isolated CDH. The primary outcomes assessed were PPH within 28 days of age and the need for ECMO. Quality of studies was assessed with the QUADAS-2 tool. Meta-analysis was performed when at least three studies reported on the same test. Sensitivity analysis was performed according to prenatal management of CDH (tracheal occlusion vs expectant management). RESULTS: Thirty-eight studies met the inclusion criteria. Fifteen reported on the incidence of PPH only, 19 on the need for ECMO only and four reported on both outcomes. The general quality of the studies was moderate; most studies were retrospective (61%) and single-center series (92%). One study included only fetuses undergoing tracheal occlusion, 22 included only fetuses managed expectantly in utero and 15 included both populations. We could not identify antenatal predictors of PPH. The need for ECMO was predicted by parameters indicative of lung size: lung-to-head ratio (LHR) (relative risk (RR) for LHR < 1, 1.65 (95% CI, 1.27-2.14)) and observed/expected LHR (standardized mean difference (SMD), -0.70 (95% CI, -0.98 to -0.42)) measured by ultrasound and observed/expected total lung volume (SMD, -1.00 (95% CI, -1.52 to -0.48)) measured by magnetic resonance imaging. Liver herniation was also associated with an increased risk of need for ECMO (RR, 3.04 (95% CI, 2.23-4.14)). These results were confirmed by a sensitivity analysis of studies that included only expectantly managed cases. Data on vascular assessment for the prediction of PPH could not be pooled as most of the parameters were evaluated in a single series or in different series by the same principal investigator. CONCLUSIONS: In fetuses with CDH, lung size and liver herniation predict the need for ECMO, however a predictor for PPH is still lacking. Further studies aimed at diagnosing impaired vascular development in utero should therefore be undertaken. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Fertility, pregnancy and gynecological outcomes after fetoscopic surgery for congenital diaphragmatic hernia.

STUDY QUESTION: What is the impact of fetoscopic surgery for isolated Congenital Diaphragmatic Hernia (CDH) on future reproductive and gynecological outcomes? SUMMARY ANSWER: We did not observe an increase of obstetric or gynecological problems after fetoscopic surgery nor was there an increased risk for subsequent infertility. WHAT IS KNOWN ALREADY: The reproductive and gynecological outcomes of patients undergoing open maternal-fetal surgery are known. The most relevant counseling items are the elevated risk for uterine dehiscence and rupture (up to 14%). STUDY DESIGN, SIZE, DURATION: Bi-centric study over a 10-year period including 371 women carrying a fetus with isolated CDH either managed expectantly (n = 167) or operated in utero (n = 204). PARTICIPANTS/MATERIALS, SETTING, METHODS: Consenting patients filled out a survey with 23 questions (2 open and 21 multiple choice). Questionnaires were custom designed to obtain information on subsequent reproductive or gynecological problems as well as psychological impact. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate was 40% (147/371). More women in the FETO group attempted a subsequent pregnancy: 70% (62/89) when compared with 47% (27/58) in controls (P = 0.009). This coincided with a longer follow-up in the FETO group (76 versus 59 months; P < 0.001) and a lower survival rate in the index pregnancy (53 versus 72%; P = 0.028). There was no difference in the number of nulliparous or parous women, neither in the conception rate. In total, there were 129 subsequent pregnancies. Nobody reported secondary fertility problems. Four women in the FETO group and one in the control reported a congenital anomaly in a subsequent pregnancy. Twenty-one pregnancies were reported with at least one complication (FETO: 23% (14/60), controls 27% (7/26)). During delivery or in the post-partum period 11 patients reported at least 1 complication (FETO 17% (10/59), controls 4% (1/24)). New onset gynecological problems occurred in 14 participants (10%). None of these events were more likely in one or the other group. Psychological and emotional impacts were frequent in both the FETO (41%) and the control groups (46%) (P = 0.691). LIMITATIONS, REASONS FOR CAUTION: The response rate was 40% (147/371), less than desired. The use of unvalidated self-reported outcomes may skew exact determination of the nature and severity of medical complications. The number of observations for uncommon events was low. The mean follow-up period to detect gynecological complications may be too short. WIDER IMPLICATIONS OF THE FINDINGS: This is the first evidence that fetoscopic surgery for CDH does not compromise future reproductive potential or obstetrical outcome when compared with expectant management. A pregnancy complicated by a serious congenital birth defect, such as CDH, frequently has a measurable psychological impact. STUDY FUNDING/COMPETING INTEREST: The authors have no conflicts to declare. J.D. receives a fundamental clinical research grant of the Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO; 18.01207). A.C.E. is supported by the Erasmus+Program of the European Union (Framework agreement number 2013-0040; contract 1011990). This was presented at the 61st meeting of the Society of Gynaecologic Investigation, in Florence, March 2014 (F-111).

Collagen plug sealing of iatrogenic fetal membrane defects after fetoscopic surgery for congenital diaphragmatic hernia.

OBJECTIVES: To investigate the efficacy of collagen plugs at reducing the risk of preterm premature rupture of membranes (PPROM) after fetoscopic surgery for congenital diaphragmatic hernia (CDH). METHODS: This was a single-center cohort study on all consecutive cases undergoing fetoscopic endoluminal tracheal occlusion (FETO) for severe or moderate CDH, between April 2002 and May 2011 (n = 141). Cases either received a collagen plug for sealing the fetal membrane defect after FETO or did not, depending on the operating surgeon. The principal outcome measure was the time from fetal surgery to PPROM, further referred to as 'latency'. A multivariable Cox regression model was used to investigate the association between collagen plug and latency while adjusting for risk factors for PPROM. RESULTS: Of the 141 cases, 54 (38%) received a collagen plug and 87 (62%) did not. Sixty cases experienced PPROM, 26 among cases with and 34 among cases without a plug (48 vs 39%). The hazard ratio of plug use was 1.29 (95% CI, 0.76-2.19), which does not exclude a potentially increased risk for PPROM when a collagen plug is used. For cases with a plug, 24% had PPROM before balloon removal and 24% had PPROM after elective balloon removal. For cases without a plug, these rates were 30 and 9%, respectively. Perinatal outcomes were similar in both groups. CONCLUSIONS: No evidence was found that collagen plugs reduce the risk of PPROM after FETO for CDH.

Cardiac assessment in fetuses with right-sided congenital diaphragmatic hernia: case-control study.

OBJECTIVE: To evaluate cardiac anatomy and function in fetuses with right-sided congenital diaphragmatic hernia (RCDH), and to compare these values with those of normal controls. METHODS: Fetal echocardiography was performed in 17 consecutive cases with isolated RCDH and 17 gestational age-matched controls. Two-dimensional measurements included ventricular and outflow tract diameters. Doppler ultrasound was used to measure the flow pattern in the ductus venosus and over the pulmonary and aortic valves, right and left ventricular myocardial performance index and the E/A wave ratio over the atrioventricular valves. Stroke volume, cardiac output and shortening fraction were calculated. RESULTS: Median gestational age at evaluation was 27.4 (interquartile range, 24.4-28.9) weeks. RCDH cases had a significantly smaller right ventricle and pulmonary valve diameter. Furthermore, stroke volume and cardiac output from the right ventricle were lower than in controls. Myocardial contractility, however, appeared normal. CONCLUSIONS: Despite significantly reduced right ventricular dimensions and cardiac output, cardiac contractility was normal in a cohort of fetuses with RCDH.

Identification of dosage-sensitive genes in fetuses referred with severe isolated congenital diaphragmatic hernia.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) is a fetal abnormality affecting diaphragm and lung development with a high mortality rate despite advances in fetal and neonatal therapy. CDH may occur either as an isolated defect or in syndromic form for which the prognosis is worse. Although conventional karyotyping and, more recently, chromosomal microarrays support a substantial role for genetic factors, causal genes responsible for isolated CDH remain elusive. We propose that chromosomal microarray analysis will identify copy number variations (CNVs) associated with isolated CDH. METHODS: We perform a prospective genome-wide screen for CNVs using chromosomal microarrays on 75 fetuses referred with apparently isolated CDH, six of which were later reclassified as non-isolated CDH. RESULTS: The results pinpoint haploinsufficiency of NR2F2 as a cause of CDH and cardiovascular malformations. In addition, the 15q25.2 and 16p11.2 recurrent microdeletions are associated with isolated CDH. By using gene prioritisation and network analysis, we provide strong evidence for several novel dosage-sensitive candidate genes associated with CDH. CONCLUSIONS: Chromosomal microarray analysis detects submicroscopic CNVs associated with isolated CDH or CDH with cardiovascular malformations.

In vitro sealing of iatrogenic fetal membrane defects by a collagen plug imbued with fibrinogen and plasma.

OBJECTIVES: We aimed to demonstrate local thrombin generation by fetal membranes, as well as its ability to generate fibrin from fibrinogen concentrate. Furthermore, we aimed to investigate the efficacy of collagen plugs, soaked with plasma and fibrinogen, to seal iatrogenic fetal membrane defects. METHODS: Thrombin generation by homogenized fetal membranes was measured by calibrated automated thrombography. To identify the coagulation caused by an iatrogenic membrane defect, we analyzed fibrin formation by optical densitometry, upon various concentrations of fibrinogen. The ability of a collagen plug soaked with fibrinogen and plasma was tested in an ex vivo model for its ability to seal an iatrogenic fetal membrane defect. RESULTS: Fetal membrane homogenates potently induced thrombin generation in amniotic fluid and diluted plasma. Upon the addition of fibrinogen concentrate, potent fibrin formation was triggered. Measured by densiometry, fibrin formation was optimal at 1250 µg/mL fibrinogen in combination with 4% plasma. A collagen plug soaked with fibrinogen and plasma sealed an iatrogenic membrane defect about 35% better than collagen plugs without these additives (P = 0.037). CONCLUSIONS: These in vitro experiments suggest that the addition of fibrinogen and plasma may enhance the sealing efficacy of collagen plugs in closing iatrogenic fetal membrane defects.

Fetal stress hormone changes during intrauterine transfusions.

OBJECTIVE: To document fetal stress hormone and Doppler changes after intrauterine transfusions (IUTs) in either the intrahepatic portion of the umbilical vein (IHV) or the placental cord insertion (PCI). METHOD: Pregnant women scheduled for IUT for fetal anemia (N = 25) were included prospectively. Cortisol, ß-endorphin and noradrenalin concentrations in fetal plasma and middle cerebral artery pulsatility index before and after transfusion were compared. Transfusions were performed through the (IHV), thus puncturing the fetus, or at the PCI. RESULTS: There were no measurable differences between the transfusion sites. CONCLUSION: In anemic fetuses undergoing transfusion, Doppler changes and fetal stress hormone changes were unrelated to the site of needle insertion.

Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study.

OBJECTIVES: To investigate the value of the observed to expected fetal lung area to head circumference ratio (o/e LHR) and liver position in the prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia (CDH). METHODS: Neonatal morbidity was recorded in 100 consecutive cases with isolated CDH diagnosed in fetal medicine units, which were expectantly managed in the prenatal period, were delivered after 30 weeks and survived until discharge from hospital. Regression analysis was used to identify the significant predictors of morbidity, including prenatal and immediate neonatal findings. RESULTS: The o/e LHR provided significant prediction of the need for prosthetic patch repair, duration of assisted ventilation, need for supplemental oxygen at 28 days, and incidence of feeding problems. An additional independent prenatal predictor of the need for patch repair was the presence of fetal liver in the chest. CONCLUSIONS: In isolated CDH the prenatally assessed size of the contralateral lung is a significant predictor of the need for prosthetic patch repair, the functional consequences of impaired lung development and occurrence of feeding problems.

Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion.

OBJECTIVES: To examine operative and perinatal aspects of fetal endoscopic tracheal occlusion (FETO) in congenital diaphragmatic hernia (CDH). METHODS: This was a multicenter study of singleton pregnancies with CDH treated by FETO. The entry criteria for FETO were severe CDH on the basis of sonographic evidence of intrathoracic herniation of the liver and low lung area to head circumference ratio (LHR) defined as the observed to the expected normal mean for gestation (o/e LHR) equivalent to an LHR of 1 or less. RESULTS: FETO was carried out in 210 cases, including 175 cases with left-sided, 34 right-sided and one with bilateral CDH. In 188 cases the CDH was isolated and in 22 there was an associated defect. FETO was performed at a median gestational age of 27.1 (range, 23.0-33.3) weeks. The first eight cases were done under general anesthesia, but subsequently either regional or local anesthesia was used. The median duration of FETO was 10 (range, 3-93) min. Successful placement of the balloon at the first procedure was achieved in 203 (96.7%) cases. Spontaneous preterm prelabor rupture of membranes (PPROM) occurred in 99 (47.1%) cases at 3-83 (median, 30) days after FETO and within 3 weeks of the procedure in 35 (16.7%) cases. Removal of the balloon was prenatal either by fetoscopy or ultrasound-guided puncture, intrapartum by ex-utero intrapartum treatment, or postnatal either by tracheoscopy or percutaneous puncture. Delivery was at 25.7-41.0 (median, 35.3) weeks and before 34 weeks in 65 (30.9%) cases. In 204 (97.1%) cases the babies were live born and 98 (48.0%) were discharged from the hospital alive. There were 10 deaths directly related to difficulties with removal of the balloon. Significant prediction of survival was provided by the o/e LHR and gestational age at delivery. On the basis of the relationship between survival and o/e LHR in expectantly managed fetuses with CDH, as reported in the antenatal CDH registry, we estimated that in fetuses with left CDH treated with FETO the survival rate increased from 24.1% to 49.1%, and in right CDH survival increased from 0% to 35.3% (P < 0.001). CONCLUSIONS: FETO in severe CDH is associated with a high incidence of PPROM and preterm delivery but a substantial improvement in survival.

IGFBP-1 levels in cervicovaginal secretions before and after amniocentesis.

BACKGROUND: To evaluate the levels of insulin-like growth factor-binding protein-1 (IGFBP-1) in cervicovaginal secretions before and after midtrimester amniocentesis and relate to clinical outcome. METHODS: 100 consecutive amniocentesis procedures were studied. We measured the IGFBP-1 concentration by radioimmunoassay in a cervicovaginal specimen before and after mid-trimester amniocentesis. The post-amniocentesis occurrence of vaginal loss of fluid or blood and abdominal pain was assessed by questionnaire. RESULTS: In 6 cases there was a 100-fold increase in IGFBP-1 levels after amniocentesis. Loss of fluid per vaginam occurred in 4 (67%) of these pregnancies, compared to 3.2% of pregnancies without significant surge (p < 0.0001). In addition, post-procedural abdominal pain was more common among women with increased IGFBP-1 levels after amniocentesis (50 vs. 14%, p = 0.05). Two (33%) of the 6 patients with increased IGFBP-1 after amniocentesis delivered prior to 37 weeks as a result of spontaneous preterm labor and/or preterm ruptured membranes, compared to 7 (7%) in the group without surge in IGFBP-1 (p = 0.09). CONCLUSION: Increased post-procedure IGFBP-1 levels are after mid-trimester amniocenteses are related to procedure-related complications like abdominal pain and subsequent amniotic fluid leakage.

Biochemical composition of fluids for amnioinfusion during fetoscopy.

OBJECTIVE: To evaluate which of the commercially available solutions is best suited for amnioinfusion during fetoscopy, based on resemblance with the biochemical properties of amniotic fluid. MATERIALS AND METHODS: Amniotic fluid samples from 10 pregnancies were studied. Specimens were obtained from 5 pathologic pregnancies (of which 3 were complicated by polyhydramnios) and 5 uncomplicated pregnancies. The concentrations of sodium, potassium, chloride, bicarbonate, calcium, glucose, osmolality, pH, total protein content and albumin were determined in each sample. A literature search (PubMed, Embase) was performed to identify commercially available fluids used for amnioinfusion in clinical practice. The composition of these infusion solutions was compared to the amniotic fluid samples mentioned above. RESULTS: We identified two different electrolyte solutions used in clinical practice for amnioinfusion. We identified four additional commercially available solutions that could potentially be used for amnioinfusion. Most of these infusion solutions differ considerably from midtrimester amniotic fluid samples both in electrolyte composition and pH, with the most striking difference in the latter. CONCLUSION: Lactated Ringer's solution approximates amniotic fluid the closest for both electrolyte composition and pH. This infusion solution seems to be the most suitable choice for amnioinfusion during fetoscopy.

Fetal membrane healing after spontaneous and iatrogenic membrane rupture: a review of current evidence.

In view of the important protective role of the fetal membranes, wound sealing, tissue regeneration, or wound healing could be life saving in cases of preterm premature rupture of the membranes. Although many investigators are studying the causes of preterm premature rupture of membranes, the emphasis has not been on the wound healing capacity of the fetal membranes. In this review, the relevant literature on the pathophysiologic condition that leads to preterm premature rupture of membranes will be summarized to emphasize a continuum of events between rupture and repair. We will present the current knowledge on fetal membrane wound healing and discuss the clinical implications of these findings. We will critically discuss recent experimental interventions in women to seal or heal the fetal membranes after preterm premature rupture of membranes.

Natural protective mechanisms against endoscopic white-light injury in the fetal lamb eye.

OBJECTIVE: To evaluate light transmission, possible light trauma, and techniques for protection of the fetal eyes during intrauterine videoendoscopic surgery in a sheep model. METHODS: In vitro studies were done at various gestational ages, including spectrometry of light output by a halogen light source and telescope and light transmission by spectrophotometry in the range of 180-3000 nm through amniotic fluid (AF) and fetal eyelids. In vivo electron-microscopic, morphologic analysis of the retinas of 65-, 95-, 108-, and 112-day-old fetal lambs with (n = 8) and without (n = 8) 30 minutes' light exposure to the open eye was also done. RESULTS: The light spectrum at the tip of the telescope was 400-750 nm, with a maximum irradiance of 3x10(-3) W/cm2 at 580 nm. In the ultraviolet spectrum (less than 300 nm), irradiance was less than 0.5x10(-3) W/cm2. Light transmission through ovine AF ranged from 30% at 300 nm to 89% at 700 nm at 84 days' gestation, decreasing to less than 0.01% (300 nm) and 70% (700 nm) at 112 days. Fetal eyelids did not transmit more than 1% of light (any wavelength). After direct in vivo light exposure, no retinal damage was found. Photoreceptors were present from 108 days onward, but chromophores were scant or absent at all ages studied. CONCLUSION: The light spectrum of a standard endoscope is limited to 400-750 nm; ultraviolet light is filtered out. The AF transmits harmful blue light poorly. Fetal eyelids seem to protect the eye by extremely low transmission and light dispersion. Even with the eye open, no morphologic retinal damage was found. The strong light sources used with fetal endoscopy did not appear to pose a threat to the fetal retina.

Fetoscopy-guided fetal endoscopy in a sheep model.

Video-endoscopic surgical treatment of the fetus may, in the future, become an alternative to open fetal operation. Six 95-day-old fetal lambs were examined through intrauterine endoscopy using amnioinfusion and specially designed balloon-tipped cannulas. The fetuses were monitored endoscopically for oxygen saturation, heart rate and temperature throughout the procedure. With a rigid 5 millimeter telescope and a flexible 3 millimeter endoscope, the respiratory and upper gastrointestinal tracts could be examined. No mucosal or other trauma was noted upon completion of the endoscopy; all lambs survived the procedure. While the applications of fetal endosurgery are likely to be similar to those of open fetal operation, fetal endoscopy (looking in the fetus) is a new entity for which clinical relevance (rather than mere feasibility) remains to be demonstrated. This technique, however, could become a valuable research tool to study fetal gastrointestinal and pulmonary physiologic factors in situ.

Matrix metalloproteinases-2 and -9 and their endogenous tissue inhibitors in tissue remodeling after sealing of the fetal membranes in a sheep model of fetoscopic surgery.

OBJECTIVES: We studied collagen plugging of the fetoscopic access site in an in vivo fetal lamb model for fetoscopic surgery and possible role for matrix metalloproteinase (MMP)-2 and -9 and tissue inhibitors (TIMPs). METHODS: Eight ewes had fetoscopic balloon occlusion of the trachea as an experimental treatment for congenital diaphragmatic hernia between days 88 and 99 of gestation (term 145 days) with sampling of amniotic, allantoic, and tracheal fluid. Nonoperated cotwins were used as controls. The fetoscopy port was closed using a collagen plug. Ten days (range 9-12) later, fluids were sampled and plug sites collected for histologic analysis. Activity of MMP-2 (72 kDa, gelatinase A) and MMP-9 (92 kDa, gelatinase B) was determined in the fluids by zymography and secretion of TIMPs (27-30 kDa; TIMP-1, glycosylated TIMP-3 and TIMP-4, 24 kDa; unglycosylated TIMP-3, 21 kDa; TIMP-2) by reverse zymography and quantified by densitometric analysis. RESULTS: No pregnancy was complicated by amniorhexis or preterm labor. At cesarean, normal volumes of amniotic and allantoic fluid were present in all cases. Histology of the plug sites revealed good integration of the collagen plug without complete restoration of membrane integrity. MMP-2, MMP-9, and TIMPs were detected in all fluids. In the operated animals, significantly (P <.05) higher activity of MMP-9 was found in amniotic fluid, with lower concentrations of TIMPs in allantoic fluid (P <.01). Tracheal occlusion was associated with a significant (P <.02) increase in both MMP-2 and -9 in tracheal fluid. CONCLUSION: Collagen plugging of the fetoscopic access port sites in sheep resulted in functionally effective sealing of the fetal membranes. Changes in MMP-2, MMP-9, and TIMPs suggest an active remodeling of both the fetal lung and the fetal membranes.