The prognostic value of ultrasound abnormalities and biological parameters in blood of fetuses infected with cytomegalovirus.

OBJECTIVE: To evaluate the prognostic value of ultrasound abnormalities and of selected biological parameters in blood of fetuses infected with cytomegalovirus (CMV). DESIGN: Retrospective observational study. SETTING: Two fetal medicine units in Paris, France. POPULATION: All fetuses infected with CMV referred between 1998 and 2006. METHODS: We retrospectively analysed data collected prospectively in 73 fetuses infected by CMV with a positive CMV polymerase chain reaction in amniotic fluid. Fetal blood sampling (FBS) was performed for evaluation of platelet count, plasma levels of aminotransferases and gamma-glutamyl transpeptidases (GGT), presence of viraemia and specific fetal immunoglobulin M. Targeted ultrasound examination was performed every fortnight. Ultrasound findings were categorised into normal examination and any ultrasound abnormality, which was further grouped as ultrasound abnormality of the fetal brain and noncerebral ultrasound abnormality. MAIN OUTCOME MEASURES: A combination of histological findings after termination of pregnancy and evidence of cytomegalic inclusion disease at birth when pregnancies were continued. Clinical symptoms at birth or histological lesions attributable to CMV were considered as poor outcome. Statistical analysis was conducted to determine the value of each parameter to predict outcome. Logistic regression was used to build up a multivariate model combining the relevant parameters. RESULTS: In univariate analysis, only thrombocytopenia and the presence of any ultrasound abnormality were associated with a poor outcome (P < 10(-4) for both abnormalities). In the multivariate analysis, both thrombocytopenia and the presence of ultrasound abnormalities remained significant independent predictors of a poor outcome. Based on univariate logistic regression, odds ratio for a poor outcome were 1.24, 7.2, 22.5 and 25.5 for each 10,000/mm(3) decrease in platelet count, the presence of noncerebral, any ultrasound and cerebral ultrasound abnormalities, respectively. CONCLUSIONS: The prognosis of CMV-infected fetuses relies independently on both targeted ultrasound examination and fetal platelet count. FBS for platelet count may therefore justify FBS in infected fetuses even in the absence of ultrasound. features of brain involvement.

Maternal administration of valaciclovir in symptomatic intrauterine cytomegalovirus infection.

OBJECTIVES: To report early experience with treatment of intrauterine cytomegalovirus (CMV) infection using maternal oral administration of valaciclovir (VACV). DESIGN: Observational study of fetuses infected with CMV with or without treatment with valaciclovir. POPULATION: Pregnancies with confirmed fetal CMV infection were treated with oral VACV (8 g/day). MAIN OUTCOME MEASURES: Fetal viral load and drug concentration were monitored in amniotic fluid and in fetal blood. Data on the course and outcome of a group of untreated symptomatic fetuses infected with CMV are also reported. RESULTS: Therapeutic concentrations were achieved in maternal and fetal bloods. The viral load in the fetal blood (VLFB) decreased significantly after 1-12 weeks of treatment (Wilcoxon paired test P = 0.02). Twenty pregnancies including 21 fetuses were treated at 28 weeks (median, range: 22-34) for 7 weeks (median, range: 1-12). Ten infants were developing normally at between 1 and 5 years of age. Two infants (both aged 2 years) had severe isolated unilateral deafness. One neonate presented with microcephaly and severe deafness but was also diagnosed with incontinentia pigmenti. Six out of seven cases that eventually required termination of pregnancy (TOP) had evidence of in utero progression of the disease with worsening cerebral lesions. One fetus died in utero. The outcome of 14/24 (58.3%) untreated symptomatic infected fetuses was poor with either TOP, intrauterine fetal demise or severe congenital infection disease of the neonate; the remaining ten infants were healthy at follow up. CONCLUSION: Maternal oral administration of VACV leads to therapeutic concentrations in the maternal and fetal compartments, with a decrease in VLFB. Our results suggest that in cases where TOP is declined, a randomised controlled trial to study this treatment option further is indicated.

[Abnormal placental caryotype in severe intrauterine growth retardations (IUGR). Case report]. / Place du caryotype placentaire dans l'enquête étiologique des retards de croissance intra-utérins sévères précoces. A propos d'un cas.

Except for cases due to maternal hypertension, severe and early intrauterine growth retardations are most usually due to fetal abnormalities. We report a case of confined placental homogenous tetraploidy associated with major fetal growth retardation leading to the premature delivery of a life born baby with a normal caryotype. We discuss the interest of chorionic villus sampling in cases of unexplained severe fetal growth retardation.

Prenatal diagnosis of HIV infection: two attempts using fetal blood sampling.

Blood samples were studied, prior to medical terminations of pregnancy, in two second trimester fetuses with HIV-positive mothers. Fetal blood was obtained from the umbilical vein under ultrasound guidance. No evidence of infection was found in either fetus. In particular, lymphocyte subpopulations were at normal levels and cultures yielded no reverse transcriptase activity. Postmortem findings were normal. Reliable means for prenatal diagnosis of HIV infection, with a minimal risk of false-negative results, have yet to be developed. However, further studies using fetal blood sampling should be useful for the management of HIV-positive pregnancies.

Absence of transplacental passage of pentosan polysulfate during mid trimester of pregnancy.

Eight women who were going to have an abortion between the 18th and 23 week of gestation for chromosomal abnormalities or haemoglobinopathies received intravenously 50 mg of pentosan polysulfate (PSP). Maternal results of haemostasis prior and after the injection of the drug were compared. Fetal coagulation parameters were tested on samples obtained by direct puncture of the umbilical cord under ultrasound guidance, 30 min after injection. Results were compared to those of normal fetuses at the same stage of gestation, obtained in the same conditions. In mothers' plasma, 30 min after injection, APTT was prolonged, factor Xa generation was markedly impaired, and factor V level was deeply decreased. By contrast, no modifications of these parameters were observed in fetal plasma, 30 min after the injection of PSP to their related mothers when compared to control fetuses. Thus the absence of biological modifications induced by PSP injection could demonstrate that this drug does not cross through the placenta.

Vitamin K dependent proteins in fetal hemostasis at mid trimester of pregnancy.

The vitamin K dependent coagulation factor activities were measured in 63 normal human fetuses from 19 to 28 weeks of pregnancy. These activities were included between 9 to 28 percent of normal adult levels. Prothrombin antigen, factor IX antigen and protein C were also measured. There is a good correlation between prothrombin procoagulant activity and antigenicity, suggesting that low level of these vitamin K dependent proteins in fetuses is probably a consequence of liver immaturity.

Placental transfer of vitamin K1 and its implications in fetal hemostasis.

Vitamin K status was evaluated using coagulation studies and/or vitamin K1 assays in a total of 53 normal fetuses and 47 neonates. Second trimester fetal blood samples were obtained for prenatal diagnosis under ultrasound guidance. Endogenous vitamin K1 concentrations (determined by high performance liquid chromatography) were substantially lower than maternal levels. The mean maternal-fetal gradient was 14-fold at mid trimester and 18-fold at birth. Despite low vitamin K levels, descarboxy prothrombin, detected by a staphylocoagulase assay, was elevated in only a single fetus and a single neonate. After maternal oral supplementation with vitamin K1, cord vitamin K1 levels were boosted 30-fold at mid trimester and 60-fold at term, demonstrating placental transfer. However, these levels were substantially lower than corresponding supplemented maternal levels. Despite elevated vitamin K1 concentrations, supplemented fetuses and neonates showed no increase in total or coagulant prothrombin activity. These results suggest that the low prothrombin levels found during intrauterine life are not due to vitamin K deficiency.

High levels of circulating thrombomodulin in human foetuses and children.

Thrombomodulin (TM) is an endothelial cell surface proteoglycan with anticoagulant functions, also implicated in cell proliferation, cell-cell adhesion and differentiation. In this study we determined circulating plasma TM (pTM) levels in human foetuses at different stages of pregnancy, at birth and in childhood. TM levels increased with gestational age, the median level reaching a peak of approximately 165 ng/ml between the 23rd and 26th week, thereafter decreasing gradually, reaching a value of 108 ng/ml at birth. pTM continues to decrease progressively during childhood, reaching in the 5-15 years group a median of 56 ng/ml which approaches the adult value. The pTM peak was statistically significant and represents a specific foetal phenomenon as it was independent of the corresponding maternal values. As a whole, the pTM pattern during foetal maturation appears totally different from that of protein C, prothrombin and other coagulation activators and inhibitors and thus, TM may play in the foetus another role in addition to its well-known anticoagulant function.

Characterization of mononuclear cell subpopulations in normal fetal peripheral blood.

It is now possible to characterize fetal peripheral blood mononuclear cells (FPBMC) from normal fetuses sampled in utero under ultrasound guidance. The surface phenotype of FPBMC from 25 fetuses, between the 20th and the 26th week of gestation, was studied using standard reagents that are known to delineate mononuclear cell subsets in adult peripheral blood. Results were compared with those obtained in neonates (cord blood) and adults. The major subsets of adult PBMC are represented in fetal blood with few qualitative differences: 20% of FPBMC are not recognized, the percentage of T cells is lower with a higher ratio T4/T8, the fraction of cells that express DR molecule is very high, and the distribution of NK antigens is different in fetuses. B cells and monocytes are in equal proportion. This work represents a prerequisite for future functional studies, and provides normal fetal values that will be useful for prenatal diagnosis of congenital immunodeficiency.

Toxoplasma gondii infection during pregnancy: T lymphocyte subpopulations in mothers and fetuses.

Prenatal diagnosis of fetal toxoplasmosis is possible with the use of fetal blood sampling, amniocentesis and ultrasound examination. The purpose of this study was to describe T lymphocyte subsets (CD3, CD4 and CD8) in mothers and their fetuses when Toxoplasma gondii infection occurred during pregnancy. Maternal and fetal blood samples were obtained in 86 cases and 9 fetuses showed T. gondii infection. Control groups consisted of 30 healthy nonpregnant women and 30 pregnant women. Pregnant women with T. gondii infection showed an increase in the suppressor (CD8) T subpopulation and a significant depression in the total helper (CD4) T cells. These alterations were more important in mothers whose fetus was infected. We showed the progressive maturation of the fetal immune system with a regular increase of all T lymphocyte subsets. Marked alterations were observed in the 9 infected fetuses (depression of CD4 population and lower CD4/CD8 ratio). In the future these differences might be used as a new marker of the severity of fetal lesions and become a useful diagnostic tool.

Free amino acids in human fetal plasma.

Free amino acids were determined on fetal plasma samples in 28 pregnancies between 20 and 33 wk gestation. No correlation can be observed between these concentrations and the age of gestation.

Changes in alpha 1-acid glycoprotein serum concentrations and glycoforms in the developing human fetus.

alpha 1-Acid glycoprotein concentrations and reactivity to concanavalin A were measured in maternal and fetal serum and amniotic fluid obtained from 24 women undergoing diagnostic cordocentesis at 20 to 33 wk gestation and in 30 additional fetal sera (19 to 34 weeks gestation). Maternal alpha 1-acid glycoprotein serum levels were five to ten times higher than fetal and amniotic levels. Fetal alpha 1-acid glycoprotein levels were found to increase with advancing gestational age. Using crossed immunoaffino electrophoresis with concanavalin A, alpha 1-acid glycoprotein patterns were identical in maternal serum and amniotic fluid but totally different in fetal serum. The fetal concanavalin A pattern changed progressively during fetal life towards that of the newborn. These data confirm earlier assumptions of fetal synthesis of alpha 1-acid glycoprotein and provide normal reference values for alpha 1-acid glycoprotein in fetal serum. In addition, the specific fetal concanavalin A pattern indicates that the alpha 1-acid glycoprotein glycosylation process during fetal life differs from that in post-natal life.

[Prenatal pharmacology of low molecular weight heparin and pentosan polysulfate]. / Pharmacologie anténatale des héparines de bas poids moléculaire (HBPM) et du polysulfate de pentosane (PSP).

The aim of prenatal pharmacology is to evaluate the biologic effects to the fetus of a drug taken during pregnancy. Development of a new technic for collection of fetal blood samples in utero under ultrasound guidance allowed, by evaluation of maternal and fetal hemostasis, study of two low molecular weight heparins, PK 10169 (Lovenox) (table I) and CY 216 (Fraxiparine) (tableau II) and of pentosan polysulfate (Hemoclar) (table III). Under the operating conditions applied, the three molecules failed to diffuse across placenta during 2nd and 3rd pregnancy trimesters. This permitted treatment of eleven women at risk for eclampsia or thromboembolism with good clinical results, white confirming absence of circulating heparinemia at birth (umbilical cord blood).

[Foetal sampling techniques]. / Techniques de prélèvements foetaux.

This article describes the current techniques of foetal sampling. All of them are actually ultrasound guided, and therefore generally very safe. Nevertheless, an elaborate learning process remains indispensable, in addition to a particular attention to the quality of the physician-patient dialogue. The choice of a technique depends on the indication and on the term of the pregnancy. The most frequently used technique is amniocentesis which presents a low risk of foetal loss, estimated between 0.2 and 0.5 percent. The interest of chorionic villus sampling is the possibility to obtain results at an earlier stage of pregnancy, with a lower risk taking when compared to early amniocentesis. We prefer the transabdominal chorionic villus sampling to the transvaginal. Foetal blood sampling is still required in some cases, but the risk of complications is higher--around 1 percent.

[Absence of transplacental passage of Fraxiparin (low molecular weight heparin) during the 3d trimester of pregnancy]. / Absence de passage transplacentaire de la fraxiparine (héparine de bas poids moléculaire) au cours du troisième trimestre de la grossesse.

Using low molecular weight fractions of heparin (HBPM) can be at least potentially useful in pregnant women for certain indications. After animal studies had been carried out for toxic effects, one HBPM, CY216, which has been put on the market under the name of Fraxiparin, was studied to see whether it crosses the placenta in pregnant women by analysing fetal blood directly. Seven women who had fetal indications for terminating their pregnancies in the third trimester received a subcutaneous injection of 17,500 Choay units of Fraxiparin (0.7 ml). The haemostatic state was assessed in the mothers before the injection and three hours after it, and in the fetus approximately three hours after the injection into the mother. The fetal blood was taken in the uterus by direct aspiration using ultrasound guidance techniques. Anti Xa, anti IIa, and cephalin-kaolin time (TCK) were estimated. The anti Xa, anti IIa and the TCK were not changed in the 7 fetuses that were studied, 3 hours after the subcutaneous injection of a large dose of CY 216 although marked changes were noted in the mothers.

[An update on the fetal circulation]. / Mise au point sur la circulation foetale.

The fetal circulation has been an exciting area of study for centuries. The principles which grew from the period of hypotheses have been demonstrated in several animal models. These experiments have shaped the major concept of fetal circulation. More recently, the improvement in ultrasound technology has allowed a non invasive study of the fetal circulation in humans. Although the general schema of the fetal circulation has been confirmed in humans, in some aspects some substantial differences have been demonstrated. They may not only reflect some inter-species differences, but also underscore the limitation of chronically instrumented animal studies.

[RU 486 and sulprostone in pregnancy termination in the 2nd and 3rd trimesters]. / RU 486 et sulprostone dans le cadre des interruptions médicales de la grossesse aux 2e et 3e trimestres.

OBJECTIVE: Describe our experience with the RU 486 (mifepristone) in case of pregnancy termination induced by sulprostone. METHOD: Prospective non controlled study in the department of Fetal Medicine of the "Institut de Puériculture de Paris". 158 women undergoing termination of pregnancy during the second and third trimester received a single dose of 600 mg of RU 486, 36 hours prior to infusion of 100 micrograms/hour of sulprostone. MAIN OUTCOME MEASURES: Delay between sulprostone therapy and diagnosis of labour duration of delivery. Prostaglandin doses used and frequency of secondary effects. RESULTS: The mean time between sulprostone administration and diagnosis of labour (146.5 +/- 106 minutes) as well delay of delivery (592.2 +/- 504 minutes) corresponded to the results reported in the literature. The primigravid women needed higher doses of prostaglandin and consequently experienced more secondary effects. No severe secondary effects were observed in this study. CONCLUSION: RU 486 is a satisfactory treatment for pregnancy termination during the second or third trimester.

[Medical termination of pregnancy for fetal anomaly: the patient's point of view]. / Interruption médicale de grossesse pour anomalie foetale. Le point de vue des patientes]

OBJECTIVES: To analyze the patient's point of view concerning pregnancy termination for fetal anomaly. METHODS: A questionnaire concerning the different steps of medical termination of pregnancy was given to 103 women on day 2 after termination. RESULTS: Most women thought that they were the ones who should make the decision (67%). Complete information prior to the procedure was greatly appreciated (81%). Physical pain remained one of the main concerns for patients given Dilapan. 94% of the women had epidural anesthesia before induction. Various mourning patterns were observed. Only 41% of the women wished to see their baby after termination; there was a correlation with age of pregnancy and social environment. Psychological assistance involved the entire team and a consultation with a pedopsychiatrist (81%). The most painful moment was the moment when breaking the new of the fetal anomaly. CONCLUSION: The women were very much in need of expressing their sorrow very soon after the event. Team work and lack of rigidity in care taking enhances the expression of individual resources, both by the medical team and the patients. Three points were highlighted by the patients.--the desire to participate in the decision making;--the importance of in-depth information on technical aspects of the procedure;--initial new breaking is recognized as a major trauma.

[Intrahepatic arteriovenous fistula. Prenatal diagnosis, physiopathological study and neonatal management]l. / Fistule artério-veineuse intrahépatique. Diagnostic anténatal, étude physiopathologique et prise en charge néonatale.

A case of arteriovenous fistula of the liver diagnosed at 30 weeks of gestation is reported. The etiologies of an hypoechogenic structure in the fetal liver are discussed showing the contribution of pulsed wave Doppler and color Doppler to the diagnosis. The clinical evolution towards heart failure led us to examine the pathophysiology of such a lesion. The prenatal management of this arteriovenous malformation is exposed.

[The passage of fluoride across the placenta. An intra-uterine study]. / Passage transplacentaire du fluor. Etude in utero.

Until now, transplacental passage of fluoride could only be checked during delivery. Recent developments in fetal blood sampling techniques in utero have made it possible to study its passage in pregnancy. Two tablets of 2.212 mg of sodium fluoride (Zymafluor) were given to 11 women with an average age of 27 1/2 years whose pregnancies on an average had lasted 22 weeks. They were having prenatal diagnosis by ultrasound guided fetal blood sampling in any case. The levels of fluoride were measured by the use of a specific electrode before the mother took fluoride and 40 minutes after she had taken it in both maternal and fetal blood samples. The results were compared with a controlled group of 11 pregnant women with similar characteristics: maternal age, duration of pregnancy and basal maternal fluoride levels. Fetal blood levels of fluorides in mothers who had taken sodium fluoride was statistically higher than in the controlled group (2.6 mumol/l and less than 1 mumol/l); this demonstrates in a statistically significant way that fluoride passes across the placenta in the fifth and sixth months of pregnancy which is the time when the milk teeth start to develop in the uterus.