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Fetoscopic surgery for the treatment of congenital anomalies.

Fetoscopic techniques may broaden the indications for prenatal surgical intervention by obviating the risks of hysterotomy. For example, congenital obstructive uropathy has been treated by open vesicostomy and percutaneous catheter placement. The open approach is appropriate only for highly selected fetuses because of the inherent risks, whereas catheter drainage, though a safer procedure, is only useful for short-term therapy late in gestation due to frequent catheter obstruction and migration. The natural history of congenital obstructive uropathy mandates the need for improved therapy earlier in gestation, in order to salvage fetuses who would otherwise die of renal failure and pulmonary hypoplasia. We have developed a potential solution to this problem in which surgery is performed on the fetus without the risks of hysterotomy. Endoscopic fetal surgery uses a telescopic lens and operating instruments that are passed through small "ports" in the uterus. A bubble of CO2 is used to displace amniotic fluid and provides excellent visualization in a magnified field. This approach is considerably less invasive than open fetal surgery and, therefore, is less likely to provoke preterm labor. In this study we corrected obstructive uropathy in midgestation fetal lambs using a new, expandable wire mesh stent that is placed endoscopically and should provide more reliable bladder drainage than existing catheters. The fetoscopic surgical approach can potentially expand the indications for in utero surgery by decreasing fetal risks, facilitating intervention earlier in gestation, and reducing preterm labor. As a consequence, the potential now exists to correct non-life-threatening malformations in utero.

Animals

The "fetoscope"--a new clinical tool for prenatal genetic diagnosis.

Our experience in 65 patients using a "fetoscope" and local anesthesia prior to saline abortion is described. Visualization of the intrauterine contents improved with experience, was optimum at 16 to 18 weeks' gestation, and was superior to the quality of photographic records. Four fetal skin biopsies and 6 amnion biopsies were done. Six blood samples were taken from the fetal surface of the placenta. The limitations of this instrument are described. No significant complications have occurred. Current and probable future indications for fetoscopy are reviewed. Until both the safety of the procedure is proved and problems of visualization due to limitation of visual field are solved, extreme caution is urged in the employment of this instrument in genetic high-risk pregnancy.

Abortion, Therapeutic

[Clinical experience with fetoscopy (author's transl)].

A fetoscope with a trocar of an external diameter of 3.9 and internal diameter of 2.9 mm was used. The optical equipment of the fetoscope had lenses with external diameters of 2.2 and 2.7 mm. The fetoscope can be inserted into the uterine cavity through the abdominal wall with local anaesthesia and insertion controlled by ultrasound. This type of insertion is uncomplicated and relatively free of risks. Thus an essential prerequisite for a successful fetoscopy is fulfilled. For the success of the fetoscopy, it is important to know what the diagnostic value of the procedure is and what can be seen through the fetoscope. The direct intrauterine visualization of the fetus or parts of the fetus is with the fetoscope under evaluation possible and was successful in 23 of 26 fetuses. The field of visualization is limited to 50 degrees by the optical system and only small parts of the fetus can be seen at a time. The extent of visualization of the fetus depends besides the optical system, on the quality of the amniotic fluid and the optimal timing of the fetoscopy in the second trimester between 15 and 18 weeks. Success is also dependant on the endoscopic experience and the technical training of the observer. After 13 of 26 fetoscopies the improvement was approximately 70%. Inspection of some parts of the fetus, for intance, the face is successful in every detail but still more or less fortuitous. Fetoscopy can only be deemed to be successful when a more or less total visualization of the fetus has heen accomplished. This was the case in 39% of the cases. Fetoscopy was used for diagnostic purpose in one case with the term delivery of a healthy infant. Fetal blood sampling by puncture of placental vessels under visualization is in its infancy. Fetoscopy is a justified procedure at this time in cases with a high genetic risk and for the avoidance of an abruptio.

Amniotic Fluid

Fetoscopy--a new endoscopic approach.

A total of 105 fetoscopies were performed either prior to therapeutic abortions or, in 29 cases, for diagnostic purposes. In these latter cases the fetuses were at increased risk for congenital syndromes, limb deformities, cleft lip and palate or neural-tube defects. The procedure is performed transabdominally under local anaesthesia. The studies confirmed the practicability of the fetoscopic technique as described. Done under direct vision, using simultaneous real-time ultrasound-scanning, the fetoscope can be introduced without damage to fetus and placenta. In diagnostic cases, a total visualization of the entire fetus is not always necessary, as recognition and examination of specific fetal parts is often sufficient for prenatal diagnosis. Viewed in this way, the rate of diagnostic fetoscopies reached 78%. In these cases, the targets chosen for inspection could, in fact, be reached by the fetoscope. A total inspection of the fetus was aimed at in those fetoscopies performed prior to planned abortions in order to gain practice, and this was achieved in 42% of cases. In 5 of the 29 patients already mentioned, the pregnancy was terminated immediately after fetoscopy, and in 24 cases pregnancy was continued. Abortions have so far been recorded in 4 cases, not all of which were necessarily due to the fetoscopy, however. In general, fetoscopy appears to hold less danger for mother and child than had previously been anticipated.

Abortion, Therapeutic

[Fetoscopy under ultrasound control (author's transl)].

Under local anaesthesia and ultrasound control (beta-mode; Vidoson) the fetoscope was introduced into the amniotic cavity in 23 women, 13-20 weeks pregnant. Used before planned surgical abortion the method decisively reduced the dangers of damage to the fetus. In 21 women introduction of the fetoscope was without problem, but twice obesity made it difficult. Placental surface, umbilical cord, fetal head and fetal limbs were more commonly seen than other fetal parts. In one instance fetoscopy made it possible to exclude Mohr's syndrome. Preliminary attempts to obtain fetal blood by puncture of placental vessels under fetoscopy were successful. The described technique seems highly promising. Further experience will demonstrate whether it is without danger and simple enough to be used routinely in the prenatal diagnosis of congenital anomalies.

Anesthesia, Local

Sampling the fetoplacental circulation. II. Combined laparoscopy-fetoscopy in the pregnant ovine.

Induction of pneumoperitoneum, laparoscopy, and intrauterine endoscopy (fetoscopy) were successfully accompished in 23 pregnant sheep at 45 to 60 days' gestational age. The fetoscope, a conventional 2.7 mm. Hopkins straightforward wide-angle telescope (Stortz 27018A) encased in a prototype 3.1 mm. eccentric cannula, incorporates a 25 gauge needle channel. Multiple pregnancy was encountered in 11 animals. Forty-two separate fetoscopic trials were accomplished; a fetoplacental blood sample was obtained in 52 per cent of the trials. A mean interval of 19 +/- 9 days (+/- S.D., range 6 to 37 days) was allowed between fetoscopy trials. Fetal deaths occurred in nine animals (39 per cent). We believe that laparoscopy permits preselection of the proposed fetoscopy puncture site and will permit the operator to thereby avoid the placenta and/or uterine vessels.

Animals

Fetal laser surgery in genetic polydactyly mice.

The first digital ray of the hindlimb plate in Slc:ICR mouse fetus was irradiated with 2 watts argon laser beam for 0.3 sec after releasing from the abdominal cavity and envelop of uterine myometrium on day 13 of gestation, and then the fetuses were allowed to develop in the abdominal cavity contacting with the uterus via the placenta exo utero until term. ICR mouse fetuses which received fetal laser surgery lost their first digits completely, resulting in 4-digit hindfoot on day 18 of gestation. The homozygous Polydactyly Nagoya (Pdn/Pdn) mice exhibit 1-3 extra digits both in the fore- and hindlimbs preaxially. The extra digital rays in the left hindlimbs of Pdn/Pdn fetuses were irradiated with 2 watts argon laser beam for 0.3 sec on day 13 of gestation exo utero. The left hindlimbs of the Pdn/Pdn fetuses which received fetal laser surgery lost their preaxial extra digits on day 18 of gestation, resulting in 5 digits, though their 1st digit was triphalangia. The combination of a laser instrument with the fetoscope and/or ultrasound scanner may promote the fetal surgery of congenital anomalies in humans.

Animals

Fetoscopy in continuing pregnancies.

A total of 34 fetoscopic procedures were performed in 28 patients whose fetuses were at risk for hemoglobinopathies (22 cases) or short-limbed dwarfism (three cases). An adequate sample of fetal blood for study of globin-chain synthesis was obtained in 23 of the 25 cases (92%), and valuable diagnostic information was obtained in all three cases at risk for an anomalous fetus. Six patients elected to terminate their pregnancies based on the studies, and in the 22 patients continuing their pregnancies there have been no losses. Thus far, data from this series suggest that fetoscopy is associated with low maternal and fetal morbidity.

Dwarfism

Early prenatal diagnosis of neural-tube defects by ultrasound-guided fetoscopy.

In three fetuses with neural-tube defects (N.T.D.s) the lesions were clearly seen by fetoscopy in the second trimester. In a fourth fetus, in which the diagnosis of N.T.D. was suspected because of raised amniotic-fluid alpha-fetoprotein, spina bifida was excluded by fetoscopic examination and a normal baby was delivered at term. Ultrasound-guided fetoscopy has a place in the diagnosis of N.T.D.s when the results of other investigations are conflicting or inconclusive, and may be useful in assessing the severity of a lesion.

Amniocentesis

The steroid hormonal milieu of the undisturbed human fetus and mother at 16-20 weeks gestation.

The interrelations of steroid hormone levels in plasma and amniotic fluid from mothers and their undisturbed fetuses at early midgestation of human pregnancy have not been defined previously. We, therefore, studied 12 healthy mothers and their fetuses undergoing termination of pregnancy for social reasons at 16-20 weeks gestation. Fetal arterial and venous blood was obtained by direct vessel puncture through a fetoscope in the conscious sedated mothers immediately before termination of pregnancy. Simultaneously, maternal peripheral venous blood and amniotic fluid were collected. Aldosterone (Aldo), corticosterone (B), 11-deoxycorticosterone, progesterone (P), 17-hydroxyprogesterone (17OHP), 11-deoxycortisol, cortisol (F), and cortisone were simultaneously determined by specific RIA after extraction and chromatography. Positive fetal arterio-venous differences were found for F, B, and Aldo, whereas arteriovenous differences were negative for P and 17OHP. In amniotic fluid, six of the eight corticosteroids showed significantly lower levels during fetoscopy than during routine amniocentesis, as reported previously using the same analytical methods. The present study demonstrates that the undisturbed human fetus at 16-20 weeks gestation actively secretes the most important gluco- and mineralocorticoids, F, B, and Aldo, independent of the mother. P and 17OHP were shown to be primarily derived from placental production and supplied to the fetus as a source of F and Aldo biosynthesis. The fetoscopy procedure with premedication seemed to give rise to less stress to the fetus than routine amniocentesis without sedation. Fetoscopy is, therefore, an ideal method to study feto-maternal steroid interrelations in human pregnancy.

17-alpha-Hydroxyprogesterone

[Expression of cytokeratins during embryogenesis and in pathologic epithelia].

Epithelial cell intermediate filaments, or cytokeratins, are excellent markers for cell differentiation. During embryogenesis, cytokeratins specific of a stage of differentiation step always become detectable before corresponding morphologic changes: for instance, cytokeratins 5 and 14 are found around the eight week, shortly before stratification of the epithelium occurs, and cytokeratins 1 and 10 are produced before morphologic evidence of keratinization becomes detectable. Among potential diagnostic applications, analysis of cytokeratin patterns of epidermal cells desquamated in the amniotic fluid may provide earlier and less invasive diagnosis than fetoscopic biopsies. Similarly, a review of cytokeratins expressed in a variety of epithelial diseases (involving the epidermis, digestive tract, respiratory tract, urogenital tract, or breast) demonstrated persistence of the original tissue pattern in some instances (this was the case for the majority of simple epithelia) but not in others (complex epithelia). This suggests that cytokeratins may prove valuable as markers for specific tumor stages or types and may provide earlier information than morphologic studies.

Breast Neoplasms

[The Harlequin Baby syndrome. A new case].

The Harlequin baby syndrome is a rare but lethal ichtyosis. We report a new case of a primiparous woman of 28 years of age who had a pregnancy that progressed normally with the delivery of a child of 2,450 grams whose Apgar was 9 at one minute and 10 at three minutes, but who died after living just 24 hours. The reason for this work is to try to analyse the features that are known about possible treatment and antenatal diagnosis of the Harlequin baby syndrome. It has been suggested that vitamin A supplements should be given for several years because the skin state may be improved. On the other hand morbidity is likely to remain serious particularly from the point of view of growth and psychomotor development. Antenatal diagnosis using skin biopsy can be obtained after 23 weeks of amenorrhoea using a fetoscope; it shows the 25% of cases recur. At present the only treatment if a recurrence does occur is to terminate the pregnancy.

Abortion, Therapeutic

Endoscopic fetal surgery by excimer laser. An experimental study in premature lambs.

Fetal malformations are detected early in pregnancy by means of ultrasound challenging fetal therapy. While open fetal surgery has been preformed during preliminary clinical trials we evaluated fetoscopic therapy avoiding laparotomy and uterotomy. We used a laser fibre (900 mu) which was introduced into the uterus by an endoscope. During animal experiments in five fetal lambs with a gestational age of 120-122 days we used an excimer laser (Technolas, x) with a wave-length of 308 nm. Laser incisions were compared with the conventional cutting technique using a scapel. During histological evaluation the tissue effect was morphometricly analysed. The zone of devitalisation was characterized by pycnosis of the nuclei and in a change of cytoplasma volume. The excimer laser incisions using a frequency of 40 HZ had a mean zone of devitalisation of 50.3 +/- 4.5 mu. Using the excimer laser with a frequency of 10 HZ we found a tissue alteration of only 11.2 +/- 3.4 mu. The incisions by scapel showed a extended traumatisation with a mean tissue effect of 153.2 +/- 16.3 mu. From these results we conclude, that endoscopic surgery may be come a usefull additional tool for fetal therapy.

Animals

[The antenatal diagnosis of haemoglobinopathies. A preliminary study (author's transl)].

From now on antenatal diagnosis of haemoglobinopathies is possible. Fetal blood can be taken from the uterus from the 17th to the 20th week of the pregnancy by direct puncture of the placenta or placentocentesis or by selective puncture of a straight vein close to its insertion in the cord on the fetal surface of the placenta, using a fetoscope. Biochemical techniques today allow us to detect beta thalassaemia major (with total absence of synthesis or with synthesis of less than 2 per cent of the beta A chain of haemoglobin by the fetus) and drepanocytosis (which is the synthesis of the chain beta S by the in the absence of production of the chain beta A). It is possible in cases where the fetal blood that has been taken is seriously contaminated by maternal blood (which is often the case with direct punctures) by using purification methods to increase the proportion of fetal red blood cells in the sample by eliminating adult reticulocytes which could cause errors in diagnosis. There are several centres where this type of diagnosis is being carried out. Some of them now have two years' experience and their results are encouraging. In spite of their difficulty these methods of investigation can allow couples at risk to have normal children or heterozygous infants. They can help them to avoid the need for termination of pregnancy or permanent contraception.

Anemia, Sickle Cell

[Fetoscopy. A new method in prenatal diagnosis (author's transl)].

Fetoscopes are now being developed which make possible the inspection of human fetuses as well as withdrawal of a fetal blood sample in the early mid-trimester of pregnancy. The preliminary experiences of several groups are presented in this report. In addition, a fetoscopy including fetal blood sampling in a 24 week pregnancy prior to therapeutic abortion is described. The first prenatal diagnoses which have been made using this novel technique, concern defects of the fetal erythrocytes (sickle cel Hb, thalassemia). The fetal blood sample that was obtained in the present case was studied by appropriate methods. As expected, there was no evidence of either of these anomalies.

Anemia, Sickle Cell

Techniques for in utero endoscopic surgery. A new approach for fetal intervention.

In utero open surgery can salvage many fetuses with life-threatening anomalies. This approach carries risks, especially from preterm labor induced by the hysterotomy incision. In an effort to decrease uterine injury during hysterotomy, we developed techniques for endoscopic manipulation of the fetus. We developed these methods in fetal lambs. The uterus was exposed and insufflated with CO2. As a model for in utero surgery, a simulated cleft lip was created and immediately repaired using intracorporeal suturing and knot-tying procedures. The techniques for endoscopic suture placement and knot-tying were based on microsurgical principles. We also designed and created several specialized instruments to facilitate precise work in this highly magnified surgical field. The novel techniques of endoscopic fetal surgery described here offer an alternate approach to fetal intervention. Our future goals include the application of these techniques to a nonhuman primate model and the development of percutaneous access methods.

Animals