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With the increased use of invasive fetal procedures, the number of women facing post-procedure membrane rupture is increasing. Here we review the use of platelets and fresh frozen plasma for sealing iatrogenic fetal membrane defects by describing the mechanisms of action of the amniopatch procedure as well as published experience. In cases of iatrogenic preterm pre-labour rupture of the membranes, amniopatch effectively seals the fetal membranes in over two-thirds of cases. There is a risk of 16% of in utero fetal death, which may occur at varying intervals from the procedure and often for unknown reasons. Amniopatch has also been used as a treatment of chorionic membrane separation. In summary, current experience suggests that in cases of early onset but persistent amniotic fluid leakage following an invasive fetal procedure, amniopatch is an option., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: With the increased use of invasive fetal procedures, the number of patients facing postprocedure membrane rupture is increasing. We aimed to describe the use of platelets and fresh frozen plasma for sealing iatrogenic fetal membrane defects., Patients and Methods: We describe the mechanisms of action of the amniopatch procedure as well as published experience., Results: Amniopatch effectively sealed the fetal membranes in over two thirds of published cases (n=44). There is a risk of 17% of in utero fetal death, which may occur remotely from the procedure and is often unexplained., Discussion and Conclusion: In case of early onset but persistent amniotic fluid leakage following an invasive fetal procedure, amniopatch may be offered., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objective: To evaluate the incidence and clinical outcome of inadvertent septostomy after fetoscopic laser therapy for twin-twin transfusion syndrome (TTTS) and, particularly, to explore its association with the risk of developing pseudoamniotic band syndrome (PABS)., Methods: In a cohort of 414 consecutive monochorionic twin pregnancies with confirmed TTTS treated with laser, the incidence of postoperative septostomy within 1 week of the procedure was recorded prospectively. Rates of preterm delivery, preterm premature rupture of membranes (PPROM), intrauterine fetal demise (IUFD) and PABS were compared among cases with and without septostomy., Results: The mean gestational age at laser therapy was 20.4 (range, 15.3-27.6) weeks. Postoperative septostomy occurred in 30 (7.2%) cases. Pregnancies complicated with septostomy had a significantly higher proportion of preterm delivery before 32 weeks (76.7% vs. 30.2%, P < 0.001), PPROM before 32 weeks (46.7% vs. 19.0%, P < 0.001), IUFD (43.3% vs. 25.8%, P < 0.05) and PABS (13.3% vs. 1.0%, P < 0.001), compared with pregnancies without septostomy., Conclusions: Inadvertent septostomy occurred in 7% of cases after fetoscopic laser therapy and was associated with a substantially increased risk of adverse perinatal outcome and PABS., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Objectives: To predict neonatal survival and pulmonary hypertension by measurement of fetal pulmonary artery reactivity to maternal hyperoxygenation in fetuses with severe congenital diaphragmatic hernia treated by fetoscopic endoluminal tracheal occlusion (FETO)., Methods: Thirty-eight fetuses underwent FETO at around 28 weeks' gestation and the balloon was removed at 34 weeks in most cases. We performed a hyperoxygenation test and measured the lung-to-head ratio of each fetus before and after each procedure. Outcome measures were neonatal survival, occurrence of pulmonary hypertension and its response to inhaled nitric oxide (iNO)., Results: Fetuses that survived had a larger increase in lung size and decrease of resistance in the first branch of the main pulmonary artery than did those that died. Both measures were also predictive of pulmonary hypertension unresponsive to iNO. The hyperoxygenation test and lung-to-head ratio were both best predictive for neonatal survival when measured following removal of the balloon (P < 0.002). Discriminant analysis confirmed that these two parameters are independent predictors of outcome., Conclusions: In fetuses undergoing FETO, pulmonary vascular reactivity in relation to oxygen and lung size are independent predictors of neonatal survival and pulmonary hypertension. The hyperoxygenation test merits further study in expectantly managed cases., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Purpose: In fetuses with isolated congenital diaphragmatic hernia (CDH), lung development can be measured by the lung-to-head ratio (LHR) using ultrasound as well as by lung volumetry determined by fetal magnetic resonance imaging (MRI). We aimed to investigate their relationship as well as to analyze the factors that may have an impact on it., Material and Methods: In 153 consecutive fetuses with isolated CDH, both the LHR and total fetal lung volume (TFLV) were measured. The observed LHR was calculated by dividing the lung area by the head circumference. On MRI, planimetric measurements of ipsilateral, contralateral and TFLV were performed on T(2)-HASTE (half-Fourier acquisition single-shot turbo spin echo) sequences in transverse as well as coronal or sagittal planes. All values were expressed as a ratio of what was observed over what is expected in a gestational age-matched normal fetus. Secondary analyses were performed for right- versus left-sided hernia and for measurements made prior to 25 weeks' gestation. A multivariate linear regression approach was used to determine the influence of the independent variables such as observed/expected (O/E) LHR, gestational age, liver position and CDH side on the dependent variables O/E TFLV and O/E contralateral FLV, and to determine the optimal formulas for calculation of the O/E TFLV as well as contralateral FLV., Results: In total, 200 pairs of measurements were obtained between 20 and 37 weeks' gestation (median 26+6). There was a significant association between the O/E contralateral FLV and O/E LHR (R(2) = 0.44; p < 0.001) as well as between the O/E TFLV and the O/E LHR (R(2) = 0.37; p < 0.001). After adding the independent variables that were first shown to be significant on univariate analysis, the multiple regression analysis demonstrated that gestational age (p = 0.017) and side of the defect (p < 0.001) were predictive of O/E LHR (p < 0.001) and strongly improved the estimation of O/E TFLV (R(2) = 0.43 instead of 0.37 when using O/E LHR only). In terms of estimating O/E contralateral FLV, only the O/E LHR was a significant (p < 0.001) independent predictor (R(2) = 0.44). These correlations also applied when considering only left-sided CDH cases. For measurements done prior to the third trimester, the O/E LHR (p = 0.034), gestational age (p = 0.035) as well as liver herniation (p = 0.029) were significantly correlated to the O/E TFLV (R(2) = 0.33). In terms of predicting the O/E contralateral FLV (R(2) = 0.25), only O/E LHR (p = 0.008) and gestational age (p = 0.037) were useful predictors., Conclusion: Measurement of the O/E LHR on ultrasound allows a good estimation of the O/E contralateral FLV as well as TFLV as measured by MRI. Whereas the additional parameters such as gestational age, liver position and side of the defect did not improve the estimation of the contralateral FLV, they did so for estimating the TFLV., (Copyright © 2010 S. Karger AG, Basel.)

Objective: The aim of this study was to identify predictors of twin-to-twin transfusion syndrome (TTTS) and selective intrauterine growth restriction (sIUGR) in monochorionic diamniotic (MCDA) twin pregnancies with moderate amniotic fluid discordance (mAFD)., Methods: Monochorionic twins with mAFD (n = 45; gestational age, 15-29 weeks) were assessed for extent of fluid discordance, fetal growth discordance and fetal cardiac dysfunction, and were followed longitudinally. A prediction algorithm was constructed for TTTS and sIUGR and validated in an unrelated cohort (n = 52)., Results: Cardiac dysfunction could not predict TTTS or sIUGR. Twins below 20 weeks of gestation with a fluid discordance of ≥ 3.1 cm had a risk of TTTS of 85.7%. Sensitivity for TTTS was nevertheless only 55%. An intertwin weight discordance of ≥ 25% had 63% sensitivity and 76% specificity for sIUGR without TTTS., Conclusion: The outcome of MCDA twins with mAFD remains unpredictable, yet high-risk and low-risk subgroups for TTTS can be identified based on severity of fluid discordance and gestational age.

The pregnant patient is a vulnerable subject, and even more so when a serious fetal condition is diagnosed. (Invasive) fetal therapy should only be offered when there is a good chance that the life of the fetus will be saved, or irreversible damage by the disease or disability is prevented. Following diagnosis of a potentially treatable condition, the patient needs to be referred to a center with sufficient expertise in diagnosis and all therapeutic options. Preferences of the physician towards one or another antenatal intervention is not at stake prior to that moment. When fetal therapy is justified--, it should be offered with full respect for maternal choice and individual assessment and perception of potential-- risks, and should be at the location where there is sufficient expertise. For therapies of unproven benefit, the absence of evidence must be disclosed, and therapy should only be undertaken with full voluntary consent of the mother. These ought to be undertaken within well designed and approved trials and only by experts in the treatment modality. Potential risks and eventual morbidities in case of therapeutic failure should be part of the counselling, neither-- should fetal therapy be presented as an alternative to termination of pregnancy.

The role of prenatal ultrasound and magnetic resonance imaging in the diagnosis and management of congenital diaphragmatic hernia (CDH) is reviewed. Topics include morphologic imaging and vascular assessment of the developing lung, the value of imaging parameters as prognostic predictors in CDH and the role of imaging following percutaneous fetoscopic endoluminal tracheal occlusion., (Copyright © 2010 S. Karger AG, Basel.)

The fetal and the maternal cardiovascular compartment undergo dramatic functional changes during pregnancy. In this thesis we examined the heart of fetuses with twin-to-twin transfusion syndrome (TTTS) and congenital diaphragmatic hernia (CDH) using two new ultrasound parameters of ventricular function : the myocardial performance index and speckle tracking derived myocardial strain. Fetal cardiac function was grossly abnormal in recipient fetus of TTTS, yet normalized within 6 weeks after therapy. Ultrasound based cardiac function assessment could not predict short term fetal survival after therapy, nor could it predict eventual further progression to full-blown TTTS in a pre-disease stage. Fetuses with CDH on the other hand, have normal myocardial function, yet smaller left ventricles leading to decreased left ventricular output. We showed that the lower output leads to decreased cerebral perfusion, yet without apparent impact on brain and cranial growth. On the maternal side, plasma volume strongly increases in pregnancy, in parallel with an increase in insulin-like-growth factor(IGF) II which is secreted at the level of the placenta. Experimental administration of IGF-II by continuous infusion leads to increases in plasma volume whereas decreasing IGF-II by reduction of the feto-placental mass leads to decreased plasma volumes. In contrast to IGF-II, the highly vasoactive peptide apelin decreases near term due to a faster elimination as a consequence of an increase in placental angiotensin-converting-enzyme 2. Our experiments with IGF-II and apelin substantiate an important role for the feto-placental unit in regulating maternal plasma volume expansion and (auto)regulating uterine perfusion and fetal growth.

Objectives: Left ventricular cardiac output is decreased in fetuses with congenital diaphragmatic hernia (CDH). Our aim was to assess whether this alters cerebral perfusion or growth in utero., Methods: Fetal head circumference, biparietal diameter, lung-to-head ratio and middle cerebral artery (MCA) Doppler flow patterns were assessed by ultrasonography in 103 fetuses with prenatally diagnosed CDH. Total fetal lung volume and cerebral volume were measured using magnetic resonance imaging. Values were transformed to gestational age-independent scores (multiples of the median (MoM)) and compared with controls. Subanalyses were made according to whether the CDH was left- (n = 86) or right-sided (n = 17) and to whether it was isolated (n = 86) or associated with other anomalies (n = 17)., Results: MCA flow velocity was significantly lower in fetuses with CDH than in healthy fetuses (0.79 ± 0.19 MoM; P < 0.0001) but MCA pulsatility index was unchanged (0.99 ± 0.25 MoM; P = 0.79). Cranial biometry and cerebral volume in CDH fetuses fell in the normal range. Gestational age-adjusted lung area was correlated with MCA peak systolic velocity, which was in turn correlated with brain volume., Conclusions: Fetal cerebral blood flow velocities are decreased in CDH yet cranial and cerebral growth are conserved. Further work will be needed to address whether part of the neurologic impairment observed in long-term survivors of CDH finds its origin in the prenatal period., (Copyright © 2010 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: Apelin is a multifunctional peptide which is catabolized by the angiotensin-converting enzyme-related carboxypeptidase-2 (ACE2). The peptide is well known for its hemodynamic effects and its role in energy and fluid homeostasis. Pregnancy is a state of dramatically altered maternal hemodynamics and metabolism, but the role of apelin is unknown. To gain further insight in apelin physiology, we investigated relative tissue expression, plasma clearance and metabolic pathways of apelin in pregnant rats., Methods: We measured maternal plasma apelin levels throughout normal rat gestation and examined relative apelin gene expression in several tissues, including the placenta. We documented apelin clearance using radiolabeled apelin and assessed maternal plasma levels in rats that underwent surgical reduction of the fetoplacental mass, thereby further examining the role of the placenta in apelin clearance. Finally, we localized apelin and ACE2 in the placenta and mesometrial triangle using immunohistochemistry., Results: Maternal apelin plasma concentrations dropped by 50% between mid- and late gestation. Apelin expression was comparable between non-pregnant and late-pregnant rats in non-reproductive tissues. The placenta showed low apelin gene expression compared to brain tissue. Apelin clearance was enhanced in term gestation as evidenced by a steeper decline of the slow phase of the elimination curve of radiolabeled apelin. Compared to sham-operated dams, maternal plasma apelin was raised by 23% in late-pregnant rats in which half of the fetoplacental units were removed at day 16 of gestation. ACE2 mRNA expression was detectable in late- but not mid-pregnancy placental tissue; immunohistochemically, ACE2 was primarily localized in the smooth muscle layer of fetal arterioles in the labyrinth., Conclusion: Maternal circulating apelin drops considerably between mid- and late- pregnancy owing to faster clearance. The current data suggest a role for placental ACE2 in the accelerated apelin metabolism.

Objectives: To describe the prevalence, management and outcome of spontaneous twin anemia polycythemia sequence (TAPS) diagnosed in the prenatal period., Method: Retrospective analysis of 142 consecutive monochorionic twin pregnancies not diagnosed with twin to twin transfusion syndrome. TAPS cases were identified based on the presence of discordant middle cerebral artery peak systolic velocity (MCA-PSV) measurements and signs suggestive of a chronic intertwin transfusion imbalance: either an elevated reticulocyte count in the anemic twin or the presence of few small unidirectional anastomoses during fetoscopy or at postnatal placental examination., Results: Three cases were identified, giving an estimated prevalence of 2%. Prenatal interventions were tailored to the characteristics of each case and consisted of intrauterine transfusion and interruption of the shared circulation by cord coagulation or laser separation., Conclusion: In monochorionic twin pregnancies, TAPS is an uncommon prenatal finding. Nonetheless, its incidence seems high enough to recommend screening for this disease by MCA-PSV measurements.

Background: The aim of this study was to assess speckle tracking-derived fetal cardiac function in a normal population and in recipient fetuses of twin-to-twin transfusion syndrome (TTTS)., Methods: A case-control study was conducted of 59 uncomplicated singleton pregnancies and 17 recipient fetuses of TTTS. Peak systolic strain, strain rate, velocity, and displacement were calculated, corrected for gestational age, and compared between patients with TTTS and controls., Results: The feasibility of speckle tracking was 83% in controls but only 61% in patients with TTTS. Myocardial velocity and displacement increased over gestation, and regional differences were present within each wall and between walls. Strain and strain rate were stable within each wall but were higher in the right ventricle than in the left ventricle and septum. Right ventricular strain was decreased in patients with TTTS compared with controls (0.75+/-0.34 vs 1.00+/-0.37 multiples of the median, P=.04)., Conclusion: The feasibility of speckle tracking is low when imaging conditions are challenging, but it can identify right ventricular failure in selected patients with TTTS., (Copyright (c) 2010 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

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., (2010 Mosby, Inc.)

Twin-to-twin transfusion syndrome is a severe complication occurring in 10% of monochorionic twin pregnancies. The disease is usually explained as due to an intrauterine imbalance in intertwin blood exchange, which leads to a volume depleted-donor twin and an overfilled recipient twin. The recipient has signs of cardiac dysfunction, which can be measured using echocardiography or blood and amniotic fluid derived biomarkers. Whereas cardiac dysfunction typically progresses in pregnancies treated with amniodrainage, it usually disappears within a few weeks after fetoscopic laser coagulation of the connecting intertwin anastomoses. Nevertheless, recipients remain at a increased risk of pulmonary stenosis. In this paper, we summarize the cardiac alterations in twin-to-twin transfusion syndrome, describe the changes seen after fetal therapy, list the newly proposed staging systems based on fetal cardiac function, and make recommendations about the use of fetal echocardiography in the evaluation and followup of pregnancies complicated by twin-to-twin transfusion syndrome.

About 30% of monochorionic twin pregnancies are complicated by twin-to-twin transfusion syndrome (TTTS), isolated discordant growth, twin anemia-polycythemia sequence, congenital defects or intrauterine demise. About 15% will be eligible for invasive fetal therapy, either fetoscopic laser treatment for TTTS or fetoscopic or ultrasound-guided umbilical cord coagulation for a severe congenital defect in one twin or severe discordant growth with imminent demise of the growth-restricted twin. Ultrasound examination in the first and early second trimester can differentiate the monochorionic twins at high risk for adverse outcome from those likely to be uneventful, which may be useful for patient counselling and planning of care., (Copyright 2010 S. Karger AG, Basel.)

Fetal cardiac function is increasingly recognized as a marker of disease severity and prognosis in selected fetal conditions. Magnetic resonance imaging (MRI) has been used in experimental (animal) fetal cardiology but the lack of a noninvasive fetal electrocardiogram (ECG) to trigger image acquisition remains a major limiting factor precluding its application in humans. Fetal medicine specialists are therefore limited to ultrasound to evaluate human fetal cardiac function. In this review, we aim to provide a complete overview of the different ultrasound techniques that can be used for fetal cardiac function assessment and we discuss their (theoretical) strengths and shortcomings. Conventional methods include M-mode assessment of ventricular contractility and Doppler assessment of the precordial veins and cardiac output (CO). More recent techniques such as the measurement of the myocardial performance index (MPI), myocardial motion analysis with tissue Doppler, speckle tracking and three-dimensional (3D) ultrasound techniques are also discussed., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

The relationship between maternal plasma volume (PV) expansion and fetal growth is well established, but the underlying mechanisms remain unclear. Here, we examined the influence of maternal body weight and fetoplacental mass on gestational PV increment in the rat. Because IGF-I and IGF-II have growth-promoting and vasoactive properties, their relationship to PV expansion and fetoplacental growth was also studied. In normal rats, the gradual expansion of PV (+35% at day 22, i.e., term) was accompanied by a rise in circulating IGF-II (+45%) and a considerable drop in IGF-I (-73%). Increased maternal body weight induced by an obesogenic diet did not influence PV and circulating IGFs compared with rats on the standard diet. Combining the results from both diets, circulating IGF-II was the principal correlate of PV. A second experiment examined the effect of fetoplacental mass reduction by surgically removing half of the gestational sacs at day 16. This procedure reduced maternal PV and circulating IGF-II at term by 14% and 20%, respectively. We then investigated the effect of a constant infusion of IGF-II (1 mgxkg(-1)xday(-1)) from day 16, which raised circulating IGF-II by 38% and found increased PV (+19%) and a larger placental trophospongial area (+29%) at term. Our results indicate that the placenta, the primary source of IGF-II synthesis in pregnancy, drives PV expansion, and that IGF-II is among the regulatory factors of the gestational PV increment. Further studies should clarify whether IGF-II directly affects vascular function and/or indirectly promotes the secretion of placenta-derived vasoactive substances.

Objectives: The pre-existing compression of the left ventricle in congenital diaphragmatic hernia (CDH) could be aggravated by the amplified lung growth after fetoscopic endoluminal tracheal occlusion (FETO). Our aim was to document left ventricular (LV) size and function in fetuses with isolated left-sided CDH and to document the effect of FETO on the fetal heart., Methods: We determined cardiac axis, LV diameters, ejection fraction, shortening fraction, mitral E/A index and myocardial performance index (MPI) in 27 fetuses with isolated left-sided CDH, and compared these with values in a reference population (n = 117). In fetuses with severe CDH that subsequently underwent FETO and/or reversal of occlusion, additional measurements were obtained 24 h before and after each fetal intervention. We recorded fetal electrocardiograms non-invasively in six CDH fetuses and compared the duration of the QRS complex with data obtained from 12 controls., Results: LV end-diastolic diameter was 32% smaller in CDH fetuses than in controls (P < 0.0001) but LV function was comparable. QRS duration was no different between CDH and control fetuses. FETO did not affect cardiac size but reduced the MPI (P = 0.004). Reversal of FETO had no significant effect on cardiac size and function., Conclusions: CDH fetuses have a smaller left ventricle than do healthy fetuses. There is no overall adverse impact of CDH and FETO on LV cardiac function.

Objectives: The role of middle cerebral artery (MCA) peak systolic velocity (PSV) has become established in the management of fetal anemia. To date, singleton reference ranges have also been used in twin pregnancies. However, in monochorionic twin pregnancies, normal ranges for cerebral blood flow may differ from those in singletons owing to intertwin blood exchange. We aimed to establish gestational age-specific reference ranges for MCA-PSV in monochorionic diamniotic (MCDA) twin pregnancies, to compare them with previously reported singleton reference ranges, and to establish terms for calculating conditional reference intervals appropriate for individual serial measurements., Methods: In a prospective longitudinal study we examined 50 uncomplicated MCDA pregnancies that were recruited between 11 and 14 weeks of gestation. Fetal MCA Doppler waveforms were assessed biweekly from 15 weeks of gestation onwards. Multilevel modeling was used to estimate gestational age-specific reference ranges for MCA-PSV and terms for conditional reference intervals were established., Results: Based on 824 observations in 100 fetuses, normative ranges from 15 to 37 weeks of gestation were constructed. Median MCA-PSV increased with advancing gestational age. Measurements between 18 and 37 weeks were comparable to those in singletons. However, before 18 weeks MCA-PSV values were higher in MCDA twin pregnancies compared with singleton references., Conclusions: Between 18 and 37 weeks of gestation, reference ranges of singletons can be used to assess fetal anemia in MCDA twin pregnancies. Prior to 18 weeks the application of singleton references may lead to an increased number of false-positive diagnoses of presumed fetal anemia in MCDA twin pregnancies.

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: 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.

Objectives: To estimate the accuracy of ultrasound to predict birth weight (BW) and BW discordance in monochorionic diamniotic (MCDA) twin pregnancies., Methods: A prospective series of MCDA twin pregnancies was subjected to ultrasound fetal weight estimations (EFW) at 16, 20, and 26 weeks of gestation and within 2 weeks of birth. Intertwin weight discordance (DeltaEFW and DeltaBW) was calculated. The correlation between DeltaEFW, DeltaBW, EFW, and BW was assessed (Pearson) and least square regression analysis was performed. Positive and negative predictive values of ultrasound to detect severe DeltaBW were calculated. Receiver-operating characteristics (ROC) curves were constructed to predict DeltaBW >25% at different time points of gestation., Results: Sixty pregnancies were included. Median DeltaBW was 9.98%. Ten(16,7%), 8(13,3%) and 5(8,3%) twin pairs had a DeltaBW >20%, >25% and >30%, respectively. BW and EFW (r = 0.96; p < 0.001) as well as DeltaBW and DeltaEFW were well correlated with each other (r = 0.75; p < 0.001). Bland-Altman analysis showed that ultrasound evaluation overestimated DeltaBW if >20%. Negative predictive value of ultrasound for DeltaBW >25% was 98%. The area under the curve (AUC) to predict a DeltaBW >25% at 16, 20, and 26 weeks and <2 weeks before birth was 0.79, 0.87, 0.93, and 0.95, respectively., Conclusions: Ultrasound estimations of BW and DeltaBW are highly correlated with actual BW and DeltaBW in MCDA twin pregnancies.

Objective: To study cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy., Study Design: Newly collected time-concentrations profiles and reported studies investigating cefazolin disposition (plasma, amniotic fluid) were pooled. Nonlinear mixed effect modeling was applied. A 2-compartment linear disposition model was used to fit cefazolin plasma observations. A third compartment was used to model amniotic fluid concentration., Results: One hundred eighty-seven plasma and 96 amniotic fluid samples were collected in 82 pregnancies (17-40 weeks gestational age). Cefazolin clearance and distribution estimates were 7.44 L/h and 12.04 L without gestational age-dependent trends in maternal plasma. The equilibration half-life (T(eq)) between plasma and amniotic fluid at term gestational age was 4.4 hours, increased with decreasing gestational age, and was 9.09 times longer in patients with polyhydramnios., Conclusion: Cefazolin clearance and distribution volume are increased during pregnancy. The cefazolin T(eq) depends on gestational age and polyhydramnios. On the basis of these observations, dosing regimes to attain higher amniotic fluid concentrations were formulated.

Minimal invasive intrauterine interventions have gained their place in fetal medicine. Interventions on the placenta, umbilical cord, fetal membranes or on the fetus require special endoscopes with their respective sheaths, cannulas and additional instruments. Instruments for fetal therapy are purpose designed for the procedure of interest and most gynaecologists are therefore not familiar with them. We review the currently available instrumentation used during operations for complicated monochorionic multiple pregnancies, congenital diaphragmatic hernia, amniotic band syndrome, urinary tract obstruction and hydrothorax.

Objectives: To test the validity of the myocardial performance index (MPI) and its components against the more conventional methods of fetal cardiac function assessment: the ejection fraction (EF) for systolic function and the E/A index (ratio of transmitral flow during early (E) ventricular filling to flow during atrial (A) contraction) for diastolic function, both in a normal population and in a population at risk for cardiac failure because of volume overload (recipient fetuses in cases of twin-twin transfusion syndrome (TTTS))., Methods: The MPI was measured prospectively in addition to more commonly used indices of systolic (EF) and diastolic (E/A index) cardiac function in 117 healthy fetuses (gestational age range, 20-36 weeks) and in 14 fetuses suspected of cardiac failure because of the presence of TTTS. Nomograms were constructed for all variables, and correlations between the MPI, EF and E/A index were assessed. The time taken to obtain the measurements as well as the interobserver and intraobserver variability were determined for the MPI and EF., Results: In healthy fetuses, the MPI and EF were independent of gestational age, whereas the E/A index and isovolumetric relaxation time (IRT) increased with gestational age. The MPI correlated inversely with the EF (P<0.001). The IRT showed a trend towards an inverse correlation with the E/A index (P=0.10). The mean+/-SD time needed to measure the MPI and EF was 140+/-65 s and 185+/-187 s, respectively (P=0.43). Interobserver and intraobserver intraclass correlation coefficients for the MPI were 0.98 (95% CI, 0.85-0.99) and 0.82 (95% CI, 0.14-0.95), respectively; those for the EF were 0.58 (95% CI, -0.16 to 0.85) and 0.51 (95% CI, -0.46 to 0.83), respectively; and those for the E/A index were 0.97 (95% CI, 0.88-0.99) and 0.91 (95% CI, 0.66-0.98), respectively. All variables, except ejection time, were significantly different between normal fetuses and those with TTTS., Conclusions: The MPI is an indicator of the systolic component of fetal left ventricular function that can be easily acquired and reproduced. The MPI is strongly correlated with the EF but shows less interobserver and intraobserver variability., (Copyright (c) 2008 ISUOG.)

Congenital diaphragmatic hernia (CDH) affects one in 2500 to 5000 births and can be detected in utero by means of ultrasound screening Associated structural problems aggravate the prognosis. The survival rate is 70% or more for cases managed in tertiary care centers. The commonest causes of neonatal death in this setting are pulmonary hypoplasia and pulmonary hypertension. Prenatal imaging findings can now accurately predict postnatal outcome, based mainly on ultrasound determination of the lung-to-head ratio and liver position. This information can be used to counsel patients. In severe cases, prenatal intervention can reverse pulmonary hypoplasia. We review current data on prenatal prediction of neonatal survival. We also discuss experimental and clinical data on the benefits of fetal tracheal occlusion. The TOTAL trial (Tracheal Occlusion To Accelerate Lung growth) is currently ongoing in Europe.

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, 0.3-4.6)., 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.

Objective: The purpose of this study was to determine the value of ultrasound examination in the first trimester and at 16 weeks to predict fetal complications in monochorionic diamniotic (MCDA) twin pregnancies, defined as the occurrence of either twin-to-twin transfusion syndrome, severe discordant growth, or intrauterine death., Study Design: We identified risk factors to predict a complicated fetal outcome in the first trimester and at 16 weeks in a prospective cohort of 202 twin pregnancies recruited during the first trimester in 2 centers of the EuroTwin2Twin project., Results: Significant predictors in the first trimester were the difference in crown-rump length (odds ratio [OR], 11) and discordant amniotic fluid (OR, 10). At 16 weeks, significant predictors were the difference in abdominal circumference (OR, 29), discordant amniotic fluid (OR, 7), and discordant cord insertions (OR, 3). Risk assessment in the first trimester and at 16 weeks detected 29% and 48% of cases with a complicated fetal outcome, respectively, with a false-positive rate of 3% and 6%, respectively. Combined first-trimester and 16 week assessment identified 58% of fetal complications, with a false-positive rate of 8%., Conclusion: Of the MCDA twin pregnancies classified as high risk on the combined first trimester and 16 weeks assessment (n = 41), 73% had a complicated fetal outcome with a survival rate of only 69%. In contrast, of the pregnancies classified as low risk (n = 154), 86% had an uneventful fetal outcome with a survival rate of 95%.

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.

Background: Restrictive bariatric surgery decreases obesity-related morbidity and mortality. With the widespread use of these interventions, an increasing number of women who have undergone bariatric surgery become pregnant., Case: A women, pregnant 2 years after laparoscopic gastric banding, presented with prolonged vomiting due to slippage of the gastic band resulting in gastric outlet obstruction. Parenteral feeding was initiated for 3 weeks until the patient was delivered because of a nonreassuring fetal heart rate pattern. A postnatal diagnosis of an extensive intracranial fetal hemorrhage due to maternal vitamin K deficiency was made., Conclusion: Although restrictive bariatric surgery is generally considered safe, we want to warn of possible severely adverse outcomes related to the intervention. In case of food intolerance, early vitamin substitution is indicated.

Congenital diaphragmatic hernia (CDH) can be associated with genetic or structural anomalies with poor prognosis. In isolated cases, survival is dependent on the degree of lung hypoplasia and liver position. Cases should be referred in utero to tertiary care centers familiar with this condition both for prediction of outcome as well as timed delivery. The best validated prognostic indicator is the lung area to head circumference ratio. Ultrasound is used to measure the lung area of the index case, which is then expressed as a proportion of what is expected normally (observed/expected LHR). When O/E LHR is < 25% survival chances are < 15%. Prenatal intervention, aiming to stimulate lung growth, can be achieved by temporary fetal endoscopic tracheal occlusion (FETO). A balloon is percutaneously inserted into the trachea at 26-28 weeks, and reversal of occlusion is planned at 34 weeks. Growing experience has demonstrated the feasibility and safety of the technique with a survival rate of about 50%. The lung response to, and outcome after FETO, is dependent on pre-existing lung size as well gestational age at birth. Early data show that FETO does not increase morbidity in survivors, when compared to historical controls. Several trials are currently under design.

Purpose of Review: We aimed to review the current clinical status and advances in endoscopic and open surgical interventions on the fetus in terms of indications, technical aspects and reported outcomes., Recent Findings: In numbers, there has been a move away from open toward fetoscopic surgery. The indications for each access modality are, however, different, and hence cannot substitute each other. Complications of monochorionic twinning are the leading indication today. Other increasingly frequent indications are severe congenital diaphragmatic hernia and myelomeningocele, and to a certain extent valvuloplasty by needle puncture. Although maternal safety is not at stake, rupture of the membranes and preterm delivery remain a problem. Today, there is level I evidence that fetoscopic laser surgery for twin-to-twin-transfusion syndrome is the preferred therapy. This has triggered the interest of several units to embark on fetoscopic surgery, although the complexity and the overall rare indications act as a limitation to sufficient turnover., Summary: Fetal surgery seems safe and has therefore become a clinical reality. With the current state of technology, open and endoscopic interventions do not compete, each having their indications. Although the stage of technical experimentation is over, most interventions remain investigational. Inclusion of patients into trials whenever possible should be encouraged rather than building up casuistic experience. Healthcare providers and individual centers should be encouraged to consider viability and efficacy of new treatment programs.

Purpose: In breast cancer, in vitro as well as in vivo experiments have shown an inverse relationship between HER-2 and steroid hormone receptors. It is unknown whether circulating estrogens affect HER-2 expression. We hypothesize that the postmenopausal body mass index (BMI) as a surrogate marker for bio-available estrogens, is inversely associated with HER-2 over-expression., Patients and Methods: A total of 535 women over age 50 or with known postmenopausal status, with a unilateral, not previously treated, operable breast cancer were evaluated the evening prior to surgery for body weight, height, abdominal and hip circumference over a 3 years period. Waist-to-hip ratio (WHR) and BMI were calculated. HER-2, estrogen receptor and progesterone receptor staining was done by immunohistochemistry. All tumours with DAKO 2+ staining were submitted for HER-2 detection by FISH analysis. HER-2 was defined as positive if DAKO 3+ or FISH positive. We assessed the frequency of HER-2 positivity in each of 6 quantiles for all parameters of body composition and tested for a trend in HER-2 expression across the 6 quantiles. Furthermore, we investigated whether BMI contributed, together with other known predictors for HER-2, in a standard multivariate logistic regression model that predicts HER-2 over-expression., Results: There is a decrease in HER-2 over-expression per increasing quantile of BMI. In a multivariate model-including both steroid receptors-BMI remains an independent predictor for HER-2 over-expression., Conclusion: In women over age 50 or with known postmenopausal status with an operable breast cancer, there is an inverse association between BMI and HER-2 over-expression.

Objectives: To prospectively examine the relationship between contralateral lung area measured by two-dimensional (2D) ultrasound examination and contralateral and total fetal lung volume (FLV) estimated by magnetic resonance imaging (MRI) in the assessment of fetuses with congenital diaphragmatic hernia (CDH)., Methods: Sixty-six fetuses with isolated CDH were entered in this prospective study. Contralateral fetal lung area was measured by 2D ultrasonography using the longest axis method. Ipsilateral, contralateral and total FLV were measured using multiplanar axial T2-weighted MRI. Regression analysis was used to determine the significance of associations between contralateral lung area and contralateral and total FLV, and the predicted total FLV was subsequently calculated using the regression equation. Univariate regression analysis was used to investigate the effect on the proportionate difference between the predicted and the observed total FLV of gestational age, proportionate volume of ipsilateral vs. total FLV, side of CDH, intrathoracic herniation of the liver and intratracheal presence of a balloon., Results: The 66 fetuses underwent a total of 191 paired 2D ultrasound and MRI examinations at a median gestational age of 30 (range, 18-38) weeks. It was possible to visualize and measure the contralateral lung area by 2D ultrasound, as well as both the ipsilateral and contralateral lung volumes by MRI, in all instances. There was a significant association between contralateral lung area and contralateral lung volume (r = 0.86; P < 0.001) and with total FLV (r = 0.84; P < 0.001). Univariate regression analysis showed that the proportionate difference between the predicted and the observed total FLV was significantly associated with the proportionate volume of ipsilateral vs. total FLV but not with gestational age, side of CDH, intrathoracic herniation of the liver or intratracheal presence of the balloon., Conclusions: In CDH, contralateral lung area measurement by 2D ultrasound correlates well with the total FLV estimated by MRI, irrespective of gestational age, liver herniation or side of herniation. Inconsistencies between the two measurements are attributable to the contribution of the ipsilateral lung to the total lung volume.

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.

Background: : The low incidence of ovarian adenosarcomas explains the paucity of available data regarding their biologic markers. Our aim was to investigate the presence of CD10, estrogen and progesterone receptors (ER and PR) in these tumors., Case: : Four cases of primary ovarian adenosarcoma were retrieved in our pathology databases. We assessed the immunohistochemical stainings for ER, PR and CD10 in 3 ovarian adenosarcomas without sarcomatous overgrowth (OAS), and 1 ovarian adenosarcoma with sarcomatous overgrowth (OAS-S). When considering the malignant stromal component, 2 OAS showed the presence of ER and PR, whereas the OAS-S was only ER positive. CD10 positivity was observed in the sarcomatous cells of all 3 OAS but was absent in the OAS-S., Conclusion: : The identification of a hormone sensitive disease is the main clinical implication of this study. Moreover, the current results add OAS to the list of CD10 positive ovarian tumors.