Marc Dommergues

Twin-to-Twin Transfusion Syndrome : Role of the Fetal Renin-Angiotensin System

The twin-to-twin transfusion syndrome (TTS) results from an unbalanced blood supply through placental anastomoses in monochorionic twins. It induces growth restriction, renal tubular dysgenesis, and oliguria in the donor and visceromegaly and polyuria in the recipient. A better understanding of its pathophysiology could contribute to improving the management of TTS, which still carries a high perinatal mortality in both twins. As well as several other candidates, the renin-angiotensin system might be involved in TTS. To evaluate its role in the pathogenesis of the syndrome, we studied the kidneys of 21 twin pairs who died from TTS at 19 to 30 weeks, compared with 39 individuals in a control group, using light microscopy, immunohistochemistry, and in situ hybridization. The overexpression of the renin protein and transcript with frequent evidence of renin synthesis by mesangial cells was observed in the donor kidneys, presumably as a consequence of chronic renal hypoperfusion. This upregulation of renin synthesis might be beneficial to restore euvolemia. In severe cases of TTS, however, angiotensin-II-induced vasoconstriction acts as an additional deleterious factor by further reducing the renal blood flow in donors. In recipients, renin expression was virtually absent, possibly because it was down-regulated by hypervolemia. However, in addition to congestion and hemorrhagic infarction, there were severe glomerular and arterial lesions resembling those observed in polycythemia- or hypertension-induced microangiopathy. We speculate that fetal hypertension in the recipient might be partly mediated by the transfer of circulating renin produced by the donor, through the placental vascular shunts.

Efficacy of second-trimester selective termination for fetal abnormalities: International collaborative experience among the world's largest centers

OBJECTIVE Our goal was to develop the most comprehensive database possible to counsel patients about selective termination for fetal abnormalities, because no one center has sufficient data to assess much more than crude loss rates. STUDY DESIGN A total of 183 completed cases of selective termination from 9 centers in 4 countries were combined (169 twins, 11 triplets, 3 quadruplets). Variables included indications, methods, (potassium chloride, exsanguination, air embolus), gestational age at procedure, pregnancies lost (< or = 24 weeks), gestational age at delivery, and neonatal outcome. RESULTS Indications for selective termination were 96 chromosomal, 76 structural, and 11 mendelian. Selective termination was technically successful in 100% of cases. In 23 of 183 (12.6%) miscarriage occurred before 24 weeks; 2 of 37 (5.4%) occurred when the procedure done at < or = 16 weeks and 21 of 146 (14.4%) when it was done thereafter. Air embolization had a higher loss rate: 10 of 24 (41.7%) compared with 13 of 156 (8.3%) by potassium chloride (chi 2 = 117, p < 0.0001). Three cases of selective termination performed in monochorionic pregnancies all resulted in pregnancy loss. Among 183 potentially viable deliveries, 7 occurred before 28 weeks, 19 at 29 to 32 weeks, 41 at 33 to 36 weeks, and 93 at > or = 37 weeks. Gestational age at delivery was not influenced by the technique used or the indication but was negatively correlated with gestational age at the time of selective termination. No coagulopathy or ischemic damage was observed in survivors. There was no maternal morbidity. CONCLUSIONS (1) Selective termination in experienced hands for a dizygotic abnormal twin is safe and effective when done with potassium chloride. A total of 83.8% of viable deliveries occurred after 33 weeks and only 4.3% at 25 to 28 weeks. (2) Gestational age at the procedure correlated positively with loss rate and inversely with gestational age at delivery; this emphasizes the need for early diagnosis in multifetal pregnancies. (3) Coagulopathy tests are probably unnecessary.

Pathogenesis of Twin-Twin Transfusion Syndrome: The Renin-Angiotensin System Hypothesis

In spite of active perinatal management, twin-twin transfusion syndrome (TTTS) remains a severe disease with a high risk of neonatal mortality and morbidity. TTTS initially results from an unbalanced blood flow from a donor to a recipient twin. However, its pathogenesis remains unclear, although cardiovascular disturbances and regulation of fetal volemia and diuresis seem central in this syndrome. Previously, we demonstrated that the renin-angiotensin system (RAS) was up-regulated in donor twins as a consequence of hypovolemia, and down-regulated in recipients. This was the first evidence of the implication of the RAS in TTTS. We hypothesize that the RAS plays a key role in the pathogenesis of TTTS. In the donor, RAS up-regulation aggravates oligohydramnios and may increase arterial resistance, which could contribute to placental dysfunction leading to intrauterine growth restriction. In the recipient, paradoxical RAS activation, due to transfer of effectors such as angiotensin II through placental shunts, could explain fetal vascular disturbances and cardiomyopathy. According to our hypothesis, TTTS would appear similar to the classical model of hypertension referred to as ‘2 kidneys-1 clip’ with a donor twin, comparable to the clipped kidney, intoxicating its cotwin, comparable to the normal kidney.

Transabdominal versus transcervical and transvaginal multifetal pregnancy reduction: International collaborative experience of more than one thousand cases * ** *

OBJECTIVES Two major approaches for multifetal pregnancy reduction have been developed over the past several years: transabdominal potassium chloride by injection and pelvic procedures by either transcervical aspiration or transvaginal potassium chloride injection or by an automated spring-loaded puncture device. The purpose of this study was to create the largest database from among the worlds largest centers to assess possible differences in efficacy and complication rates by transabdominal or transcervical or multifetal pregnancy reduction. STUDY DESIGN Data on over 1000 completed pregnancies that underwent multifetal pregnancy reduction by both methods from major centers with among the highest worldwide experience were combined. Transabdominal cases were divided temporally (1986 through 1991 and 1991 through 1993). RESULTS Transabdominal multifetal pregnancy reduction was successfully performed on 846 patients and transcervical or transvaginal on 238 patients. Transcervical or transvaginal reduction is performed earlier and starts and finishes with fewer embryos. In 12.6% of cases transcervical or transvaginal reduction left a singleton as opposed to 4.4% for transabdominal reduction. Pregnancy losses (up to 24 weeks) were observed in 13.1% of transcervical or transvaginal cases and in 16.2% of transabdominal cases early in the series and 8.8% of late transabdominal cases. Transcervical or transvaginal reduction may be safer very early in gestation and transabdominal safer later in the first trimester. Premature deliveries were comparable, with only about 5% delivered between 25 and 28 weeks. The smaller starting numbers for transcervical and transvaginal reduction may explain a slightly higher term delivery rate. The transabdominal route tends to reduce the fundal embryos and the transcervical and transvaginal the lower ones. The significance of this is not clear. CONCLUSIONS (1) Multifetal pregnancy reduction by either method is a relatively safe and efficient method for improving outcome in multifetal pregnancies. (2) More than 84% are delivered at > 33 weeks. (3) The experience and preference of the operator are probably the key determinants for an individual patient. (4) An inverse relationship of starting and finishing number to loss rates and gestational age at delivery suggests that there still is a cost of iatrogenic multifetal pregnancies, even if multifetal pregnancy reduction can be successfully performed.

Congenital adenomatoid malformation of the lung: When is active fetal therapy indicated?☆☆☆★

OBJECTIVE Although aggressive fetal therapies such as thoracoamniotic shunting can be applied to cystic adenomatoid malformations of the lung diagnosed in utero, there is no clear consensus regarding their indications. Our purpose was to evaluate a management policy in which aggressive fetal therapy was restricted to those cases complicated by major polyhydramnios or hydrops; all other cases were managed conservatively. STUDY DESIGN A prospective cohort study of 33 cases with a prenatal diagnosis of cystic adenomatoid malformations of the lung was performed. Thoracoamniotic shunting was offered only in nine macrocystic cases with acute polyhydramnios or hydrops. RESULTS Four cases were diagnosed postnatally as sequestrations. Of 12 cases complicated by acute polyhydramnios or hydrops, 5 survived (1 type III with spontaneous incomplete resolution in utero, 4 type I with substantial volume reduction after shunting). The 17 cases without acute polyhydramnios or hydrops were managed conservatively and survived. CONCLUSION Conservative management is indicated in cases of cystic adenomatoid malformations of the lung without acute polyhydramnios or hydrops.

Detection of maternal cells in human fetal blood during the third trimester of pregnancy using allele‐specific PCR amplification

Using a highly sensitive allele‐specific PCR amplification method, we have previously shown that maternal cells could be detected in all 10 cord bloods tested. This raised the question of whether maternal cells are released into cord blood during the process of delivery or whether they are already present during pregnancy. We have now used the same PCR method to detect the presence of maternal cells in nine fetal blood samples collected at different gestational ages. Maternal cells were detected in eight samples obtained between 24 and 35 weeks of gestation. They were estimated to amount between 10−4 and 10−5 of nucleated fetal blood cells. In two cases mononuclear and polymorphonuclear cell fractions were separated by Ficoll gradient centrifugation and maternal cells were detected as comparable levels in both fractions. Maternal cells could not be detected in the one fetal blood sample obtained at 20 weeks of gestation, suggesting that maternal cells could appear at detectable levels in fetal blood during the third trimester of pregnancy. These results are discussed in terms of materno‐fetal immune tolerance and of transmission of viruses (and more specifically of the human immunodeficiency virus) from mother to child.

Fetal Lung Volume Estimated by 3-Dimensional Ultrasonography and Magnetic Resonance Imaging in Cases With Isolated Congenital Diaphragmatic Hernia

Objective. To assess the agreement of 3‐dimensional ultrasonography and magnetic resonance imaging in estimating fetal lung volume in cases with isolated congenital diaphragmatic hernia. Methods. Fetal lung volume was measured in 11 cases of congenital diaphragmatic hernia (10 left and 1 right) by 3‐dimensional ultrasonography and magnetic resonance imaging. These examinations were performed during the same week. The operators were blinded to each others results. Intraclass correlation was used to evaluate the agreement between 3‐dimensional ultrasonography and magnetic resonance imaging estimations of the ipsilateral, contralateral, and total fetal lung volume. A Bland‐Altman graph was plotted to detect possible discordant observations. Results. The global intraclass correlation coefficient between magnetic resonance imaging and 3‐dimensional ultrasonographic measurement of fetal lung volume was 0.94 (95% confidence interval, 0.78–0.98) with no outliers observed on the Bland‐Altman plot. Conclusions. There is a good agreement between 3‐dimensional ultrasonography and magnetic resonance imaging for fetal lung volume estimation in cases with congenital diaphragmatic hernia.

Hyperechogenic fetal bowel: an ultrasonographic marker for adverse fetal and neonatal outcome.

OBJECTIVE Fetal hyperchogenic bowel is associated with a variety of conditions, the incidence of which has yet to be studied. STUDY DESIGN The outcomes of 182 cases of fetal hyperechogenic bowel were reviewed. Screening for maternal toxoplasmosis, fetal karyotyping, and amniotic fluid digestive enzyme assays were performed in all cases. Eight mutations associated with cystic fibrosis were analyzed in 116 cases. RESULTS Of 135 newborns, 121 were normal, but nine underwent surgery for gastrointestinal obstruction, three had cytomegalovirus or parvovirus infection, one had a triple X chromosome, and one died from sudden infant death syndrome. In utero fetal death was observed in 24 cases. Elective termination of pregnancy was performed in 23 cases for associated anomalies. CONCLUSIONS Hyperechogenic fetal bowel was associated with increased risk for adverse outcome. Prenatal management should include ultrasonographic surveillance, fetal karyotyping, amniotic digestive enzyme assays, and screening for cystic fibrosis and infectious disease.

International, collaborative experience of 1789 patients having multifetal pregnancy reduction: a plateauing of risks and outcomes.

Objective: To develop the most up-to-date, complete data base of multifetal pregnancy reduction (MFPR) from cases, and to provide the best counseling for couples with multifetal pregnancies. Methods: From nine centers in five countries, 1789 completed MFPR cases were collected and outcomes evaluated. Pregnancy losses were defined as through 24 weeks and deliveries categorized in groups of 25-28, 29-32, 33-36, and 37 or more weeks. Results: Overall, the pregnancy loss rate was 11.7% but varied from a low of 7.6% for triplets to twins and increased with each additional starting number to 22.9% for sextuplets or higher. Early premature deliveries (25-28 weeks) were 4.5% and varied with starting number. Loss rates by finishing number were highest for triplets and lowest for twins, but gestational age at delivery was highest for singletons. Conclusions: Multifetal pregnancy reduction has been shown to be a safe and effective method to improve outcome in multifetal pregnancies. Outcomes are worse with higher-order gestations and support the need for continued vigilance of fertility therapy.

Can Three-Dimensional Ultrasound Be Used for the Assessment of the Fetal Lung Volume in Cases of Congenital Diaphragmatic Hernia?

We report on 2 fetuses with congenital diaphragmatic hernia (CDH) in whom the fetal lung volumes were estimated by three-dimensional ultrasound and the results compared with the postmortem lung volume measurements. Both examiners (sonographer and pathologist) were blinded to each other’s results. The 1st case was a right CDH diagnosed at 20 weeks of gestation. The 2nd case was a left CDH diagnosed at 22 weeks of gestation. Both pregnancies were terminated upon request of the parents. Three-dimensional ultrasound estimation of the fetal lung volume was performed 1 day before termination of pregnancy using the technique of rotation of the three perpendicular planes. The left and right lung volumes estimated by three-dimensional ultrasound were 3.88 and 1.87 cm3, respectively, in the 1st case and 0 and 5.52 cm3, respectively, in the 2nd case. On postmortem examination, the left and right lung volumes were 3.0 and 2.2 cm3, respectively, in case 1 and 1.1 and 5.6 cm3, respectively, in case 2. This suggests that a three-dimensional estimation of pulmonary volumes may be correlated with postmortem findings in cases with CDH.