OBJECTIVE: To characterize tracheal fluid flow during fetal breathing movements by Doppler ultrasound. STUDY DESIGN: To use pulsed Doppler to measure flow velocity during inspiration and expiration in a cross-sectional study of 15 normal fetuses and determine the correlation, if any, between flow velocity and gestational age. RESULTS: Cyclic respiratory profiles - both regular and irregular - were observed. Intratracheal flow velocity was very elevated during inspiration, ranging from 10 to 80cm/s and from 5 to 20cm/s during expiration. CONCLUSION: This technique enables the noninvasive semiquantitative evaluation of fetal breathing movements. This Doppler application opens the field for future studies to characterize the extent of pulmonary hypoplasia.

BACKGROUND: Fetal endoscopic tracheal occlusion (FETO) is a promising treatment for severe congenital diaphragmatic hernia, a condition that carries significant morbidity and mortality. It is hypothesised that balloon occlusion of the fetal trachea leads to an improvement in lung growth and development. The major documented complications of FETO to date are related to preterm delivery. OBJECTIVE: To report a series of five infants who developed tracheomegaly following FETO. MATERIALS AND METHODS: Review of all children referred with tracheomegaly to the paediatric intensive care and tracheal service at two referral centres. RESULTS: Five neonates presented with features of respiratory distress shortly after birth and were subsequently found to have marked tracheomegaly. Two neonates had tracheomalacia in addition. CONCLUSION: There are no previous reports in the literature describing tracheomalacia, or more specifically, tracheomegaly, as a consequence of FETO. We propose that the particularly compliant fetal airway is at risk of mechanical damage from in utero balloon occlusion. This observation of a new problem in this cohort suggests a thorough evaluation of the trachea should be performed in children who have had FETO in utero. It may be that balloon occlusion of the trachea earlier in utero (before 26 weeks' gestation) predisposes to this condition.

OBJECTIVES: To investigate developmental changes in the apparently unaffected contralateral lung by using signal intensity ratios (SIR) and lung volumes (LV), and to search for correlation with clinical outcome. METHODS: Twenty-five fetuses (22-37 weeks' gestation) were examined. Lung/liver signal intensity ratios (LLSIR) were assessed on T1-weighted and T2-weighted sequences for both lungs, then together with LV compared with age-matched controls of 91 fetuses by using the U test. Differences in LLSIRs and lung volumes were correlated with neonatal outcomes. RESULTS: LLSIRs in fetuses with congenital diaphragmatic hernia (CDH) were significantly higher in both lungs on T1-weighted images and significantly lower on T2-weighted images, compared with normals (p < 0.05), increasing on T2-weighted imaging and decreasing on T1-weighted imaging during gestation. Total LV were significantly smaller in the CDH group than in controls (p < 0.05). No significant differences in LLSIR of the two lungs were found. Outcomes correlated significantly with total LV, but not with LLSIR. CONCLUSION: Changes in LLSIR seem to reflect developmental impairment in CDH; however, they provide no additional information in predicting outcome. LV remains the best indicator on fetal MR imaging of neonatal survival in isolated, left-sided CDH.

Congenital diaphragmatic hernia (CDH) occurs in 1 in 3,000 newborns. Mortality and morbidity are due to the amount of pulmonary hypoplasia (PH), the response on artificial ventilation and the presence of therapy-resistant pulmonary hypertension. The pathogenesis and etiology of CDH and its associated anomalies are still largely unknown despite all research efforts over the past years. Several animal models have been proposed to study CDH. In this review we compare surgical, pharmacological and transgenic models, and discuss their strengths and limitations to study PH.

Pulmonary hypoplasia and persistent pulmonary hypertension are the most important reasons for the high morbidity and mortality of congenital diaphragmatic hernia(CDH). Despite surgical advances and advances in neonatal intensive care, the mortality still remains high. Then the research on how to improve prenatal fetal lung growth has become a focus. Some researches involved in fetal surgery, tracheal occlusion, prenatal use of corticosteroidson etc., have been carried out in CDH animal models and humans. But the results either showed no benefit for the outcome of CDH or were unproved. Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the root of Stephania tetrandra. It has been used in traditional Chinese medicine for several decades to treat patients with silicosis, asthma and pulmonary hypertension etc. Some researches showed that prenatal tetrandrine administration can improve the lung development in CDH rat models. We hypothesize that prenatal treatment with tetrandrine can reverse the abnormal condition in the lung of newborn with CDH, and thus decrease the mortality.

PURPOSE: Fetal tracheal occlusion (TO) is offered to fetuses with severe pulmonary hypoplasia due to congenital diaphragmatic hernia (CDH). TO induces lung growth, but even when performed minimally invasive, there is a risk for iatrogenic preterm delivery. Whenever this is anticipated, maternal glucocorticoids (GC) may be given to enhance lung maturation. The pulmonary effects of GC in fetuses with CDH that underwent TO are yet poorly defined. Therefore, we conducted a placebo-controlled study in the nitrofen (NF) rat model for CDH. METHODS: Pregnant rats were gavage fed NF or olive oil (OO) on ED9.5. At ED19.0, fetuses were either assigned to TO or left untouched. Maternal betamethasone (BM) or saline (PLAC) was administered on ED20. Necropsy was done on ED21.5 to obtain lung-to-body-weight ratio (LBWR), and perform quantitative RT-PCR and fluorescent immunostaining for Ki-67 and proliferating cell nuclear antigen (PCNA) in fetal lungs. RESULTS: CDH fetuses had a lower LBWR than normal fetuses, but comparable pulmonary PCNA and Ki-67 expression levels. TO increased LBWR, irrespective of maternal BM or PLAC. However, BM but not PLAC inhibited proliferation in TO and unoperated fetuses. CONCLUSION: Rats with NF-induced CDH have hypoplastic lungs with normal proliferation indices. TO triggers proliferation, an effect countered by BM.

With increasing use of fetal ultrasound comes an increase in the detection of clinically silent 'abnormalities' which pose diagnostic and management dilemmas for perinatologists and paediatricians. Congenital thoracic malformations (CTMs)(excluding congenital diaphragmatic hernia) are one such example, where a few cases are symptomatic in early life and management options are clear, but the majority are clinically asymptomatic, giving rise to difficulties in defining postnatal management of the well child with a sonographic or radiological lesion. Here, we will outline the prenatal presentation and natural history of CTMs that are not congenital diaphragmatic herniae and briefly discuss the approach to postnatal management, which is covered in more detail in the review by Laje and Liechty in this issue. Copyright (c) 2008 John Wiley & Sons, Ltd.

Today, modern ultrasound equipment and the wide implementation of screening programmes allow the timely diagnosis of many congenital anomalies. For some of these, fetal surgery may be a life-saving option. In Europe, open fetal surgery became poorly accepted because of its invasiveness and the high incidence of postoperative premature labour and rupture of the fetal membranes. In the 1990s, the merger of fetoscopy and advanced video-endoscopic surgery formed the basis for endoscopic fetal surgery. We review the current applications of fetal surgery via both methods of access. The first clinical fetoscopic surgeries were interventions on the umbilical cord and the placenta, often referred to as obstetrical endoscopy. The outcome of a randomized clinical trial demonstrating that fetoscopic laser coagulation of chorionic plate vessels is the most effective treatment for twin-twin transfusion syndrome (TTTS) has revived interest in endoscopic fetal therapy. Operating on the fetus is another more challenging enterprise. Clinical fetal surgery programmes were virtually non-existent in Europe until minimally invasive fetoscopic surgery made such operations clinically possible as well as maternally acceptable. At present, most experience has been gathered with fetal tracheal occlusion as a therapy for severe congenital diaphragmatic hernia. As in other fields, minimally invasive surgery has pushed back boundaries and now allows safe operations to be performed on the fetal patient. Whereas minimal access seems to solve the problem of preterm labour, all procedures remain invasive, and carry a risk to the mother and a substantial risk of preterm prelabour rupture of the membranes (PPROM). The latter problem may prove to be a bottleneck for further developments, although treatment modalities are currently being evaluated.

OBJECTIVE: The purpose of this study was to examine the clinical and placental characteristics of monochorionic diamniotic twin pregnancies with early-onset discordant growth diagnosed at 20 weeks, late-onset discordant growth diagnosed at 26 weeks or later, and concordant growth. STUDY DESIGN: We studied a prospective cohort that underwent an ultrasound scan in the first trimester, at 16, 20, and 26 weeks. We excluded pregnancies complicated by twin-to-twin transfusion syndrome, miscarriage, fetal death less than 16 weeks, or severe congenital anomalies. Placental sharing and angioarchitecture were assessed by injection of each cord vessel with dyed barium sulphate. The 2 territories were delineated on an X-ray angiogram. The diameter of each intertwin anastomosis was measured on a digital photograph. RESULTS: We included 178 twin pairs. Early onset discordant growth, late-onset discordant growth, and concordant growth occurred in 15, 13, and 150 pregnancies, respectively. Twin pairs with early-onset discordant growth had lower survival rates and were delivered at an earlier gestational age than pairs with late-onset discordant and concordant growth. The degree of birthweight discordance was similar in early- and late-onset discordant growth. Severe intertwin hemoglobin differences at the time of birth occurred in 0%, 38%, and 3% of pairs with early-onset discordant growth, late-onset discordant growth, and concordant growth, respectively. The placentas of pairs with early-onset discordant growth were more unequally shared and had larger arterioarterial anastomoses and a larger total anastomotic diameter as compared with placentas of pairs with late onset-discordant or concordant growth. CONCLUSION: Unequal placental sharing appears to be involved in the etiology of early-onset discordant growth, whereas a late intertwin transfusion imbalance may be involved in some cases with late-onset discordant growth.

Congenital diaphragmatic hernia (CDH) can be diagnosed in the prenatal period either as part of other anomalies or as an isolated birth defect. The clinical impact of this surgically correctable anatomical defect lies in its impairment of lung development. Currently, up to 30% of babies with isolated CDH die from the consequences of lung hypoplasia and/or pulmonary hypertension. Antenatal prediction of outcome essentially relies on the measurement of lung development by the so-called lung area to head circumference ratio (LHR). By expressing observed LHR as a proportion of what is normally expected (O/E LHR) at a certain time point in gestation, a prediction of outcome can be made. When O/E LHR is less than 25% of the normal, postnatal death is very likely. In these cases, an antenatal intervention that can improve lung development is currently offered. Currently, this is done by percutaneous fetal endoscopic tracheal occlusion (FETO) with a balloon at 26-28 weeks, and reversal of occlusion at 34 weeks. The feasibility and safety of percutaneous FETO have been established and the procedure seems to improve outcome in severe CDH. The lung response to, and outcome after, FETO depend on pre-existing lung size respectively gestational age at birth. Prenatal decision making can therefore be stratified according to measured lung size.

BACKGROUND: Today, the diagnosis of congenital diaphragmatic hernia (CDH) can readily be made in the prenatal period during screening ultrasound examination. Patients ought to be referred to rule out associated anomalies, and in isolated cases, prognosis is poor when the liver is intrathoracic and the lung-to-head ratio (LHR) is less than 1. In these patients, prenatal intervention aiming to reverse pulmonary hypoplasia can be considered. METHODS: We present our current algorithm for counselling patients presenting with CDH. Patients with a poor prognosis are offered percutaneous fetal endoluminal tracheal occlusion (FETO) with a balloon, inserted at 26 to 28 weeks. We report on the evolution of technique and results in a consecutive homogeneous case series and compare outcome in cases with similar severity managed in the postnatal period. RESULTS: Within a period of 28 months, FETO was performed between 26 and 28 weeks in 24 fetuses with severe left-sided CDH. Under general (n = 5), epidural (n = 17) or local (n = 2) anesthesia, the balloon was successfully positioned at first surgery (23/24) with a mean operation time of 20 minutes (range, 3-60 minutes). There were no serious maternal complications or direct fetal adverse effects. In the first 2 weeks after FETO, LHR increased from 0.7 to 1.7. Premature prelabour rupture of the membrane (PPROM) occurred in 16.7% and 33.3% at 28 and 32 weeks or earlier, respectively. Gestational age at delivery was 33.5 weeks. Patency of airways was restored either in the prenatal (n = 12) or perinatal period (n = 12). Early (7 days) and late (28 days) survival, and survival at discharge were 75%(18/24), 58.3%(14/24) and 50%(12/24), respectively. Half of nonsurvivors (n = 6) died of pulmonary hypoplasia and hypertension, in combination with PPROM and preterm delivery (n = 4) and balloon dislodgement (n = 2), which coincided with a short tracheal occlusion (TO) period (12 days). In the other 6, TO period was comparable to that in the 12 survivors (47 vs 42 days, respectively). In that group of 6 babies, only 2 died of pulmonary problems. Late neonatal survival (28 days) was higher with prenatal vs perinatal balloon retrieval 83.3% vs 33.3%(P =.013). In a multicentre study validating the criteria, survival till discharge in 37 comparable cases was 9%(3/32) and 13%(5/37) of parents opted for termination. CONCLUSION: Fetuses with isolated left-sided CDH, liver herniation, and LHR of less than 1 have a poor prognosis. Percutaneous FETO is minimally invasive and may improve the outcome in these highly selected cases. Airways can be restored before birth, allowing vaginal delivery and return to the referring tertiary unit and may improve survival rate. The procedure carries a risk for PPROM, although that may decrease with experience.

Congenital diaphragmatic hernia (CDH) should be diagnosed in the prenatal period and prompt referral to a tertiary referral center for imaging, genetic testing, and multidisciplinary counseling. Individual prediction of prognosis is based on the absence of additional anomalies, lung size, and liver herniation. In severe cases, a prenatal endotracheal balloon procedure is currently being offered at specialized centers. Fetal intervention is now also offered to milder cases within a trial, hypothesizing that this may reduce the occurrence of bronchopulmonary dysplasia in survivors. Postnatal management has been standardized by European high-volume centers for the purpose of this and other trials.

OBJECTIVE: The purpose of this study was to document pregnancy and neonatal outcome of monochorionic diamniotic twin pregnancies. STUDY DESIGN: This observational study describes a prospective series included in the first trimester in 2 centers of the Eurotwin2twin project. RESULTS: Of the 202 included twin pairs, 172 (85%) resulted in 2 survivors, 15 (7.5%) in 1 survivor, and 15 (7.5%) in no survivors. The mortality was 45 of 404 (11%), and 36 of 45 (80%) were fetal losses of 24 weeks or less, 5 of 45 (11%) between 24 weeks and birth, and 4 of 45 (9%) were neonatal deaths. Twin-to-twin transfusion syndrome (TTTS) occurred in 18 of 202 (9%). The mortality of TTTS was 20 of 36 (55%), which accounted for 20 of 45 (44%) of all losses. Severe discordant growth without TTTS occurred in 29 of 202 (14%). Its mortality was 5 of 58 (9%), which accounted for 5 of 45 (11%) of all losses. Major discordant congenital anomalies occurred in 12 of 202 (6%). Of the 178 pairs that continued after 24 weeks, 10 (6%) had severe hemoglobin differences at birth. After 32 weeks, the prospective risk of intrauterine demise was 2 in 161 pregnancies (1.2%; 95% confidence interval, 0.3 to 4.6). CONCLUSION: Of the monochorionic twins recruited in the first trimester, 85% resulted in the survival of both twins, and 92.5% resulted in the survival of at least 1 twin. Most losses were at 24 weeks or less, and TTTS was the most important cause of death. After 32 weeks, the risk of intrauterine demise appears to be small.

PURPOSE OF REVIEW: We aim to review the recent literature regarding early prenatal prediction of outcome in babies diagnosed with isolated congenital diaphragmatic hernia, as well as results of fetal therapy for this condition. RECENT FINDINGS: Current survival rates in population-based studies are around 55-70%. Highly specialized centers report 80% and more, but discount the hidden mortality, mainly in the antenatal period. Fetuses presenting with liver herniation and a lung-to-head ratio of less than 1.0 measured in midgestation have a poor prognosis. Other volumetric techniques are being evaluated for use in midtrimester. Recently, a randomized trial failed to show benefit from prenatal therapy, but lacked power to document the potential advantage of prenatal therapy in severe cases. We proposed percutaneous fetal endoluminal tracheal occlusion with a balloon at 26-28 weeks through a 3.3 mm incision. In severe cases, fetal endoluminal tracheal occlusion increased lung size as well as survival, with an early (7 day) survival, late neonatal (28 day) survival and survival at discharge of 75, 58 and 50%, respectively, comparing favorably with 9% in contemporary controls. Airways can be restored prior to birth improving neonatal survival (83.3% compared with 33.3%). The procedure carries a risk for preterm prelabour rupture of the fetal membranes, although that may decrease with experience. SUMMARY: Fetuses with severe congenital diaphragmatic hernia can be identified in the second trimester. Fetal endoluminal tracheal occlusion can be considered as a minimally invasive fetal therapy, improving outcome in such highly selected cases.

PURPOSE OF REVIEW: We aim to review the recent literature regarding early prenatal prediction of outcome in babies diagnosed with isolated congenital diaphragmatic hernia, as well as results of fetal therapy for this condition. RECENT FINDINGS: Current survival rates in population-based studies are around 55-70%. Highly specialized centers report 80% and more, but discount the hidden mortality, mainly in the antenatal period. Fetuses presenting with liver herniation and a lung-to-head ratio of less than 1.0 measured in midgestation have a poor prognosis. Other volumetric techniques are being evaluated for use in midtrimester. Recently, a randomized trial failed to show benefit from prenatal therapy, but lacked power to document the potential advantage of prenatal therapy in severe cases. We proposed percutaneous fetal endoluminal tracheal occlusion with a balloon at 26-28 weeks through a 3.3 mm incision. In severe cases, fetal endoluminal tracheal occlusion increased lung size as well as survival, with an early (7 day) survival, late neonatal (28 day) survival and survival at discharge of 75, 58 and 50%, respectively, comparing favorably with 9% in contemporary controls. Airways can be restored prior to birth improving neonatal survival (83.3% compared with 33.3%). The procedure carries a risk for preterm prelabour rupture of the fetal membranes, although that may decrease with experience. SUMMARY: Fetuses with severe congenital diaphragmatic hernia can be identified in the second trimester. Fetal endoluminal tracheal occlusion can be considered as a minimally invasive fetal therapy, improving outcome in such highly selected cases.

OBJECTIVE: The objective of the study was to determine whether cardiac troponin T (cTnT) and natriuretic peptides can be isolated from the amniotic fluid (AF) of pregnancies complicated by twin-to-twin transfusion syndrome (TTTS) and whether they correlate with fetal echocardiographic findings and recipient survival. STUDY DESIGN: AF samples from the recipient sac were obtained in 52 TTTS cases and 16 controls. Samples were assayed for cTnT and natriuretic peptides. Prior to fetoscopic laser therapy, 34 recipient twins underwent assessment of atrioventricular flow patterns, myocardial performance index (MPI), and precordial venous Dopplers. Fetal survival was assessed 48 hours postoperatively. RESULTS: AF B-type natriuretic peptide and cTnT levels were elevated in TTTS and correlated with functional echocardiographic findings. Postoperative recipient survival was 72% when both AF-cTnT and left ventricular MPI were increased. If 1 of both markers was normal, survival was 100%(P =.046). CONCLUSION: Combining ultrasound and AF-cTnT measurements allows the identification of fetuses at risk of postoperative demise.

OBJECTIVE: We sought to assess fetal cardiac function in monochorionic twins before and after therapy for twin-to-twin transfusion syndrome (TTTS) and compare it with control subjects. STUDY DESIGN: We conducted prospective longitudinal assessment of fetal cardiac function in cases undergoing curative fetal therapy for TTTS (n = 39) until 4 weeks postoperatively and in uncomplicated monochorionic twins (n = 23). Fetal cardiac function was assessed by the left and right ventricular myocardial performance index, atrioventricular valve flow pattern, ductus venosus a-wave, and umbilical vein pulsations. RESULTS: Nomograms for the myocardial performance index were constructed. Fetal cardiac function was grossly abnormal in recipient twins of TTTS when compared with control subjects (P <.001 for all indices) but normalized by 4 weeks postoperatively. The donor developed abnormal ductus venosus flow and tricuspid regurgitation postoperatively that regressed within 4 weeks. CONCLUSION: The cardiac dysfunction in the recipient twin of TTTS normalizes within 1 month after laser. The donor develops a transient impairment of cardiac function postoperatively.