Dick Oepkes

Placental characteristics in monochorionic twins with and without twin anemia-polycythemia sequence.

OBJECTIVE: To study the placental angioarchitecture of monochorionic placentas with and without twin anemia–polycythemia sequence. METHODS: Eligible were all placentas from monochorionic twin gestations, not complicated by twin-to-twin transfusion syndrome and resulting in double survival. The study was conducted at two European Fetal Therapy Centers between 2002 and 2008. Placental angioarchitecture was evaluated using colored dye injection. Diagnosis of twin anemia–polycythemia sequence was based on the presence of large intertwin hemoglobin difference without the degree of amniotic fluid discordance that is required for the diagnosis of twin transfusion syndrome. RESULTS: Three-hundred thirteen monochorionic twin pregnancies were eligible for the study but placental data could not be completed for 62 placentas (20%). This left 251 monochorionic twin pregnancies of which 11 (4%) fulfilled the criteria for twin anemia–polycythemia sequence. The median number of anastomoses in monochorionic placentas with and without twin anemia–polycythemia sequence was 3 (range: 2–5) and 7 (range: 0–25), respectively (P<.001). Small anastomoses were present in 91% (10/11) of twin anemia–polycythemia sequence-placentas compared with 5% (12/240) of cases without twin anemia–polycythemia sequence (P<.001). Arterioarterial anastomoses were absent in twin anemia–polycythemia sequence-placentas and present in 89% (213/240) of placentas without twin anemia–polycythemia sequence (P<.001). CONCLUSION: Monochorionic twin placentas with twin anemia–polycythemia sequence are characterized by a paucity of anastomoses and the absence of arterioarterial anastomoses. The few anastomoses that are present in twin anemia–polycythemia sequence placentas are mostly small arteriovenous anastomoses. LEVEL OF EVIDENCE: II

Benefits and risks of fetal red-cell transfusion after 32 weeks gestation

OBJECTIVE To compare the outcome after intrauterine transfusion (IUT) between fetuses treated before and those treated after 32 weeks gestation. SETTING National referral center for intrauterine treatment of red-cell alloimmunization in The Netherlands. STUDY DESIGN Retrospective evaluation of an 11 year period, during which 209 fetuses were treated for alloimmune hemolytic disease with 609 red-cell IUTs. We compared fetal and neonatal outcome in three groups: fetuses only treated before 32 weeks gestation (group A, n=46), those treated both before and after 32 weeks (group B, n=117), and those where IUT was started at or after 32 weeks (group C, n=46). RESULTS Survival rate was 48% in group A, 100% in group B, and 91% in group C. Moreover, fetuses in group A were hydropic significantly more often. Short-term perinatal loss rate after IUT was 3.4% in the 409 procedures performed before 32 weeks and 1.0% in the 200 procedures performed after 32 weeks gestation. CONCLUSION Perinatal losses were much more common in fetuses only treated before 32 weeks gestation. Two procedure-related perinatal losses in 200 IUT after 32 weeks remain a matter of concern because of the good prospects of alternative extrauterine treatment.

Management of Twin Anemia-Polycythemia Sequence Using Intrauterine Blood Transfusion for the Donor and Partial Exchange Transfusion for the Recipient

Twin anemia-polycythemia sequence (TAPS) is a rare condition which may occur either spontaneously in uncomplicated monochorionic twin pregnancies or may develop after laser treatment in twin-twin transfusion syndrome. TAPS is characterized by a large intertwin discordance in hemoglobin levels without discordance in amniotic fluid levels, and may lead to severe complications including fetal hydrops, hematological morbidity and perinatal mortality. Several treatments have been proposed including intrauterine transfusion, laser surgery, elective delivery and expectant management. The optimal treatment remains unclear. In this case series we report 3 TAPS cases managed recently at our center with a combination of intrauterine blood transfusion for the anemic twin and intrauterine partial exchange transfusion for the polycythemic twin. In 1 case, the donor was found to have severe cerebral injury on neuroimaging examination. We propose etiologic mechanisms for cerebral injury in TAPS, discuss the rationale behind this treatment alternative, and evaluate the pros and cons of the various management options.

Obstetric history and antibody titer in estimating severity of Kell alloimmunization in pregnancy.

OBJECTIVE: To evaluate the usefulness of the obstetric history and the maternal serum Kell antibody titer in the management of pregnancies with Kell alloimmunization. METHODS: In a retrospective cohort study of 41 pregnancies complicated by Kell alloimmunization, the obstetric history, divided into presence or absence of a previous Kell-positive child, and Kell antibody titers in the index pregnancy were correlated with the gestational age at the onset of fetal anemia. RESULTS: Women with a previous Kell-positive child had a lower gestational age at the first intrauterine transfusion compared with those without a previous Kell-positive child (P=.01). However, in two of 29 pregnancies in the latter group, severe fetal anemia requiring transfusion was detected before 20 weeks of gestation. In neither group were maternal Kell antibody titers significantly correlated with gestational age at first intrauterine transfusion (P=.62 and P=.72, respectively). In all but two pregnancies (1:2 and 1:4, respectively), antibody titers were at least 1:32 before the first intrauterine transfusion. CONCLUSION: For timely detection of all cases of severe fetal anemia, Kell-alloimmunized pregnancies with a Kell-positive fetus and titers greater than or equal to 1:2 should be closely monitored from 16 to 17 weeks of gestation onward. LEVEL OF EVIDENCE: II

Invasive versus non-invasive testing in red-cell alloimmunized pregnancies

Amniocentesis for amniotic fluid bilirubin levels is the most widely used test to predict the severity of fetal disease in red-cell alloimmunization. Many textbooks and guidelines recommend serial amniocentesis to monitor these pregnancies. However, the reliability of amniotic fluid bilirubin measurements has been questioned. Two strategies have been proposed by investigators. Some advocate liberal or primary use of fetal blood sampling, while others promote the use of non-invasive ultrasonography and Doppler. The purpose of this literature review is to examine the usefulness of amniocentesis, ultrasonography and Doppler to predict the degree of fetal hemolytic anemia. The evidence suggests that amniotic fluid bilirubin measurements are of limited value in the second trimester. Furthermore, critical appraisal of the very few prospective studies is hampered by limitations in design or insufficient data given by the authors. Many ultrasound and Doppler parameters have been proposed as useful indicators of fetal anemia. The most promising of these methods are Doppler assessment of umbilical venous and middle cerebral artery flow velocities. We speculate that the accuracy of these non-invasive tests may be good enough to incorporate them in management protocols, possibly replacing amniocentesis. Well-designed prospective studies are needed to prove this hypothesis.

Quality Control for Intravascular Intrauterine Transfusion Using Cumulative Sum (CUSUM) Analysis for the Monitoring of Individual Performance

Introduction: Intravascular intrauterine transfusion (IUT) is an effective and relatively safe method for the treatment of fetal anemia. Although implemented in centers all over the world in the 1980s, the length and strength of the learning curve for this procedure has never been studied. Cumulative sum (CUSUM) analysis has been increasingly used as a graphical and statistical tool for quality control and learning curve assessment in clinical medicine. We aimed to test the feasibility of CUSUM analysis for quality control in fetal therapy by using this method to monitor individual performance of IUT in the learning phase and over the long term. Methods: IUTs performed in the Dutch referral center for fetal therapy from 1987 to 2009 were retrospectively classified as successful or failed. Failed was defined as no net transfusion or the occurrence of life-threatening procedure-related complications. The CUSUM statistical method was used to estimate individual learning curves and to monitor long-term performance. Four operators who each performed at least 200 procedures were included. Results: Individual CUSUM graphs were easily assessed. Both operators pioneering IUT in the late 1980s had long learning phases. The 2 operators learning IUT in later years in an experienced team performed acceptably from the start and reached a level of competence after 34 and 49 procedures. Discussion: CUSUM analysis is a feasible method for quality control in fetal therapy. In an experienced setting, individual competence may be reached after 30 to 50 IUTs. Our data suggest that operators need at least 10 procedures per year to keep a level of competence.

Neonatal Morbidity after Exchange Transfusion for Red Cell Alloimmune Hemolytic Disease

Background: Exchange transfusion (ET) is a high-risk procedure. The type and rate of complications in neonatal red cell alloimmune hemolytic disease exclusively are not clear. Objectives: Our aim was to study the type and rate of complications associated with ET in a large series of neonates with hemolytic disease of the fetus and newborn (HDFN) due to red cell alloimmunization. Methods: All neonates with HDFN due to red cell alloimmunization admitted to our center between January 2001 and June 2011 were eligible for this study. We recorded the number and rate of complications during admission in the group of neonates treated with ET (ET group) and not treated with ET (no-ET group). Multivariate logistic regression analysis was performed to measure the independent risk of complications of ET treatment. Results: A total of 347 infants with red cell alloimmune hemolytic disease were included; 39% (134/347) were treated with at least one ET (ET group), and 61% (213/347) did not require ET (no-ET group). Comparison between the ET group and no-ET group showed that ET treatment was independently associated with proven sepsis [8 vs. 1%, respectively; odds ratio (OR) 8.3, 95% confidence interval (CI) 1.7–40.3; p = 0.009], leukocytopenia (88 vs. 23%, respectively; OR 36.0, 95% CI 17.5–73.8; p < 0.001), severe thrombocytopenia (platelet count <50 × 109/l; 63 vs. 8%, respectively; OR 31.4, 95% CI 14.0–70.4; p < 0.001), hypocalcemia (22 vs. 1%, respectively; OR 27.4, 95% CI 5.9–126.8; p < 0.001) and hypernatremia (8 vs. 0%, respectively; p < 0.001). There were no neonatal deaths in the ET group. Conclusion: ET in neonates with HDFN is associated with an increased risk of sepsis, leukocytopenia, thrombocytopenia, hypocalcemia and hypernatremia.

Incidence of and Risk Factors for Residual Anastomoses in Twin-Twin Transfusion Syndrome Treated with Laser Surgery: A 15-Year Single-Center Experience

Objectives: To evaluate the incidence of residual anastomoses (RA) after laser therapy for twin-twin transfusion syndrome (TTS) and investigate risk factors for incomplete laser surgery. Material and Methods: All available TTS placentas treated with laser at our center between 2002 and 2016 were injected with color dye to assess the presence of RA. We evaluated the incidence of RA over the past 15 years by dividing the cohort into three time periods, and studied the association with risk factors and neonatal outcome. Results: Overall, RA were detected in 21.0% (78/371) of placentas. The incidence of RA decreased from 38.8% (26/67) in the initial period to 11.7% (16/137) in the most recent period (p < 0.001). On multivariate analysis, several risk factors were independently associated with the risk of RA, including Solomon laser technique (odds ratio [OR] 0.17, 95% CI 0.09–0.33) and estimation of surgical success (OR 19.28, 95% CI 8.17–45.49). Premature delivery and neonatal morbidity occurred more often in TTS cases with RA. Conclusions: The incidence of RA after laser therapy for TTS decreased significantly in the past 15 years and is now below 15% due to the use of the Solomon technique.

Fetal Therapy: Contributors

Preface Foreword Part I. General Principles: 1. The rationale for fetal therapy 2. Insights into pathogenesis of adult cardiovascular disease from fetal animal studies 3. Human embryology: molecular mechanisms of embryonic disease 4. Ethics of fetal therapy 5. Fetal therapy choices: about risks, emotions, and the doctors role in the decision making process Part II. Fetal Disease: Pathogenesis and Principles: 6. Red cell alloimmunization: immunobiology, clinical disease, and management 7. Fetal and neonatal alloimmune thrombocytopenia 8.1. Fetal dysrhythmias: the effects of antiarrhythmic therapy on the immature heart 8.2. Fetal dysrhythmias: clinical management 9.1. Structural heart disease: embryology 9.2. Structural heart disease: genetic influences 9.3. Structural heart disease: fetal cardiac interventions 10.1. Manipulation of amniotic fluid volume: homeostasis of fluid volumes in the amniotic cavity 10.2. Manipulation of amniotic fluid volume: oligohydramnios and polyhydramnios 11.1. Twin-to-twin transfusion syndrome: scientific basis 11.2. Twin-to-twin transfusion syndrome: placental circulation 11.3. Twin-to-twin transfusion syndrome: cardiovascular manifestations 11.4. Twin-to-twin transfusion syndrome: treatment by fetoscopic laser ablation 11.5. Twin-to-twin transfusion syndrome: management of stage I disease 12.1. Twin reverse arterial perfusion (TRAP) sequence: pathophysiology 12.2. Twin reverse arterial perfusion (TRAP) sequence: in-utero treatment 13.1. Fetal infections: fetal immune responses to congenital infections 13.2. Fetal infections: clinical management 14.1. Fetal urinary tract obstruction: pathophysiology 14.2. Fetal urinary tract obstruction: prenatal assessment and prognosis 14.3. Fetal urinary tract obstruction: fetal cystoscopy 14.4. Fetal urinary tract obstruction: in-utero intervention 15.1. Fetal lung growth, development and lung fluid: physiology and pathophysiology 15.2. Fetal lung growth, development, and lung fluid: clinical management of pleural effusion and pulmonary pathology 16.1. Neural tube defects: pathophysiology and prevention 16.2. Neural tube defects: clinical management 17.1. Fetal tumors: pathophysiology 17.2. Fetal tumors: clinical management 18.1. Intrauterine growth restriction: placental basis and implications for clinical practice 18.2. Intrauterine growth restriction: differential diagnosis and management 19.1. Congenital diaphragmatic hernia: pathophysiology 19.2. Congenital diaphragmatic hernia: clinical antenatal management 20.1. Fetal stem cell transplantation: stem cell biology basics 20.2. Fetal stem cell transplantation: clinical potential 20.3. Fetal stem cell transplantation: fetal tissue engineering 21. Gene therapy: physiological principles and clinical potential 22. The future: fetal therapies and translation studies: global alignment, coordination and collaboration in perinatal research: The Global Obstetrics Network (GONet) initiative Index.

Fetal Therapy: Contents

Preface Foreword Part I. General Principles: 1. The rationale for fetal therapy 2. Insights into pathogenesis of adult cardiovascular disease from fetal animal studies 3. Human embryology: molecular mechanisms of embryonic disease 4. Ethics of fetal therapy 5. Fetal therapy choices: about risks, emotions, and the doctors role in the decision making process Part II. Fetal Disease: Pathogenesis and Principles: 6. Red cell alloimmunization: immunobiology, clinical disease, and management 7. Fetal and neonatal alloimmune thrombocytopenia 8.1. Fetal dysrhythmias: the effects of antiarrhythmic therapy on the immature heart 8.2. Fetal dysrhythmias: clinical management 9.1. Structural heart disease: embryology 9.2. Structural heart disease: genetic influences 9.3. Structural heart disease: fetal cardiac interventions 10.1. Manipulation of amniotic fluid volume: homeostasis of fluid volumes in the amniotic cavity 10.2. Manipulation of amniotic fluid volume: oligohydramnios and polyhydramnios 11.1. Twin-to-twin transfusion syndrome: scientific basis 11.2. Twin-to-twin transfusion syndrome: placental circulation 11.3. Twin-to-twin transfusion syndrome: cardiovascular manifestations 11.4. Twin-to-twin transfusion syndrome: treatment by fetoscopic laser ablation 11.5. Twin-to-twin transfusion syndrome: management of stage I disease 12.1. Twin reverse arterial perfusion (TRAP) sequence: pathophysiology 12.2. Twin reverse arterial perfusion (TRAP) sequence: in-utero treatment 13.1. Fetal infections: fetal immune responses to congenital infections 13.2. Fetal infections: clinical management 14.1. Fetal urinary tract obstruction: pathophysiology 14.2. Fetal urinary tract obstruction: prenatal assessment and prognosis 14.3. Fetal urinary tract obstruction: fetal cystoscopy 14.4. Fetal urinary tract obstruction: in-utero intervention 15.1. Fetal lung growth, development and lung fluid: physiology and pathophysiology 15.2. Fetal lung growth, development, and lung fluid: clinical management of pleural effusion and pulmonary pathology 16.1. Neural tube defects: pathophysiology and prevention 16.2. Neural tube defects: clinical management 17.1. Fetal tumors: pathophysiology 17.2. Fetal tumors: clinical management 18.1. Intrauterine growth restriction: placental basis and implications for clinical practice 18.2. Intrauterine growth restriction: differential diagnosis and management 19.1. Congenital diaphragmatic hernia: pathophysiology 19.2. Congenital diaphragmatic hernia: clinical antenatal management 20.1. Fetal stem cell transplantation: stem cell biology basics 20.2. Fetal stem cell transplantation: clinical potential 20.3. Fetal stem cell transplantation: fetal tissue engineering 21. Gene therapy: physiological principles and clinical potential 22. The future: fetal therapies and translation studies: global alignment, coordination and collaboration in perinatal research: The Global Obstetrics Network (GONet) initiative Index.