Oral concurrent session E

ORAL CONCURRENT SESSION E Prenatal Diagnosis Fetal Therapy Saturday, February 7, 1998 8:00 am - 10:30 am

Moderators: Isabelle A. Wilkins, MD Mark Evans, MD Charles Kleinman, MD

Judges:

Richard L. Berkowitz, MD Dale P. Reisner, MD Joshua A. Copel, MD

Fontainebleau Ballroom A/B Abstract Numbers 57-66

$ 2 6 SPO Abstracts

January 1998 A m J Obstet Gynecol

57

C E R V I C A L L E N G T H ASSESSMENT: A U S E F U L ADDITION T O T H E S C R E E N I N G O B S T E T R I C A L U L T R A S O U N D EXAMINATION. RS Smith.l, ~ C H Comstock, J.a J S KirkJ B Brod.~ky, Ix G TatemJ x W Lee. 1.2 Division of Fetal Imaging, Department of Obstetrics & Gynecology, William Beaumont Hospital,1 Royal Oak, Michigan and Department of Obstetrics and Gynecology, Wayne State University,2 Detroit, Michigan. OBJECTIVE: The usefulness of cervical length assessment in low-risk patients remains controversial because previous studies have included patients with risk factors for preterm delivery. Our objective is to determine if the addition of cervical length assessment to all transabdominal sonograms can identify low-risk patients who may deliver preterm. STUDY DESIGN: All patients <35 weeks gestation presenting to our Fetal Imaging Unit between 1990 and 1996 had cervical length assessment attempted prospectively using transabdominal sonography. A cervical length <3.0 cm was considered abnormal. The primary outeot~e examined was spontaneous preterm delivery after preterm labor or rupture of mernbranes between 20 and 34 completed weeks. Patients with abnormal cervical lengths were divided into low and high-risk groups with regard to other risk factors for preterm delivery. Rates of pretem'l delivery were compared using chi-square, (P< 0.05). Patients were excluded if they delivered at another hospital or delivered preterm due to other complications. RESULTS: During the 7-year study period, 72,000 scans had cervical length routinely assessed. Abnormal cervical lengths were found on 497 patients; 99 were excluded. O f the remaining 398 patient.s, 158 (40%) were low-risk and 240 (60%) were high-risk. Spontaneous preterm delivery occurred in 120 of 398 patients (30%). In the low-risk group, 40 of 155 (25%) patients delivered preterm compared to 80 of 240 (33%) patients in the high-risk group (25% vs 33%, P = 0.08). C O N C L U S I O N S : The routine addition of cervical length assessment to the obstetrical ultrasound examination is useful in identifying otherwise low-risk patients who may deliver preterm.

59 ELECTROSPRAY MASS S P E C T R O M E T R Y O F PCR PRODUCTS: A POWERFUL NEW TECHNIQUE FOR GENETIC SCREENING AND MUTATION DETECTION. C. NelsonJ x L Nelson, 2~ K. Ward, 1,2 Depts. of Human Geneticsl and Ob-Gyn,a Univ. of Utah, Salt Lake City, UT. OBJECTIVE: Recent advances in mass spectrometry now provide a highlyaccurate and sensitive means to determine the molecular weight of relatively large nucleic acids, proteins, and other biopolymers. Elcctrospray mass spectrometry is demonstrated as a viable approach for identification of mutations through analysis of PCR products. STUDY DESIGN: The electrospray ionization process generates a seres of multiply-charged molecular ions from which very accurate mass assignments are derived for each strand of DNA in a PCR product. As a resnlt, the exact nucleotide composition of each allele is determined, pinpointing whether a mutation is present. PCR products were generated using standard methods and were prepared by simple extraction and precipitation procedures for direct analysis by mass spectrometry. RESULTS: Assays, with only 1-2 minutes analysis time, have been developed for several disease-causing mutations. For example, cystic fibrosis, factor V Leiden, and angiotensinogen polymorpbisms were studied. The technique affords unambiguous identification of single-base substitutions in PCR products up to 55100 bp (substitution dependent). Single-base pair deletions are easily characterized in 150-200 bp products. Advantages of analyzing multiple mutations within a single experiment are discussed. CONCLUSIONS: Mass spectrometry offers great potential for rapid, lowcost, large-scale genetic screening in obstetrics.

58

MULTICENTER INTERNATIONAL ASSESSMENT - 142,367 PRENATAL KARYOTYPES, C H R O M O S O M A L S P E C I F I C P R O B E S (CSP), AND FLUORESCENT IN SITU HYBRIDIZATION (FISH) LIMITATIONS. M I Evo~l,~

60 CEMAT (CANADIAN EARLY tEA) VS. M1DTREVIESTER (MA) AMNIOCENTESIS TRIAL) P R O S P E C T I V E R A N D O M I Z E D EVALUATION: COMPARISON OF AMNIOTIC FLUID CULTURE CHARACTERISTICS BETWEEN EA AND MA. xE.J,T. Wi~t~or, R.D. Wilson for the CEMAT Group. OBJECITVE: The objective was to compare the culture success rate, time in culture, maternal cell contamination (MCC) and frequency of mosaicism in fluids at 110-126 weeks with 150-166 weeks. STUDY DESIGN: This multicentered (12), prospective, randomized clinical trial compared continuous ultrasound-guided EA and MA (22-gauge needle) in patients at a late maternal age (-< 35 years). Amniotic fluid was obtained from 2107 women having EA and 1999 women having MA. Approximately 10 ml of amniotie fluid was obtained from EA patients and 20 ml from MA patients. RESULTS: No karyotype was reported from 28 (1.3%) EA fluids compared with 1 (0.05%) of the MA fluids p<.001. On average, results were reported one day later for the EA fluids. Mosaicism (Levels I, II and III combined) was found more frequently in MA fluids 253/1998 (12.7%) than in EA fluids 215/2079 (I0.3%). There was a discrepancy between the fluid karyotype (46,XX) and the baby's gender (male) in one EA and no discrepancies in MA. CONCLUSION: The culture failure rate for EA fluids was higher than for MA fluids (1.3% vs 0.05%) and the time required in culture was slightly longer for EA fluids. MCC was not significantly different in the two groups.

GP Heat3; x W Miller, x T-H Bui, x R Snijders, x R J Wapne); P Miny,-v M P Johnson, D Pealonan, x A Johnson, g Nicolaides, x W Holzgreve, x SA Ebrahhn, x R. Baba, x L .lackson. x Depts. of OB/GYN, Molecuar Medicine & Genetics, and Pathology,

Wayne State University, Detroit, MI., Reproductive Genetics Center, Denver, CO, Prenatal Diagnosis Center, Lexington, MA, Karolinska Institute, Stockholm, Sweden, Kings College, Loodon, England, Jefferson Medical College. Philadelphia, PA, University of Basel, Basel, Switzerland, Quest/Nichols, Inc., California. OBJECTIVE: With increasing availability of CSP FISH, we sought to assess the theoretical limitations an.d continued need for actual karyotyping in prenatal caseS.

METHODS: 142,367 prenatal karyotypes from 8 centers in 4 countries over a 5 year period were compared with predicted detection by commercially available probes for chromosomes 13, 18, 21, X , and Y. 1009'odetection efficiency was assumed, although in practice, lower percentages are routine. RESULTS: 3,807 Abnommlities were found (2.67%), of which 2,459 (64.6%) would have been detectable, while 36.4% would have been missed with the above mentioned probes. Detectable abnormalities included: 1322-T21,538-T18, 171T13; 199-45,X; 62-47,XXX; 69-47,XXu 50-47,XYY, and 4 8 - 6 9 , X X X / Y . Aberrations not detectable with these probes included 364 mosaics, 5 i0 translccations (61 unbalanced de novo, 124 balanced de novo), 45 duplication/deletions, 842 inversions (34 unbalanced de hurt), and 68 marker ehromosontes. CONCLUSION: CSP FISH is becoming more commonly nsod in prenatal diagnosis. Some centers perform it routinely, and report out results based on CSPFISII results alone. While some of the eytogeaetie aberrations which would have been missed using CSP FISH alone are not as phenotypically important as the classle trisomies, at least half would be expected to have potential clinical significance. Our data thus suggest a significant percentage of abnormalities detected by karyotype may be missed by CSP-FISH alone, and could be the source of problems in patient management. Therefore, until more sophisticated nrethods become perfatted, CSP FISH must remain an adjunct in prenatal diagnosis, as too many potentially significant abnormalities will otherwise be missed.

V o l u m e 178, N u m b e r 1, Part 2 A m J Obstet G y n e c o l

SPO Abstracts S27

61 EFFICACY OF UUI'RASOUND FOR PRENATAL DIAGNOSIS OF OPEN NEURAL TUBE AND VENTRAL WALL DEFECTS. C. Lenaon. x D. Gray. .~ Dept. Ob/Gyn, Washington Univ. School of Medicine, St. Louis, MO. OBJECTIVE: To assess the effectiveness of sonography for the prenatal diagnosis of open neural tube and ventral wall defects in a high risk population. STUDY DESIGN: From August 1988 to June 1997, 2257 consecutive patients at risk for neural tube defects (NTD) were evaluated at our institution. Indications for referral included an elevated maternal serum alpha fetal protein (msAFP) (n = 1757) an/or a family history of NTD (n = 516). Study subjects were prospectively evaluated by sonography alone and genetic amniocentesis (GA) was employed only for the following: fetal anatomy inadequately imaged, markedly elevated msAFP, patient request, or increased risk for chromosomal disorder based on previous history, serum screening or ultrasound findings. Pregnancy outcome data was collected for all 2257 study patients. RESULTS: Fourteen ventral wall defects (1/161 incidance) and 66 open neural tube defects (1/34 incidence - 44 open spina bifida, 19 enencephaly, 3 encephaloceles) occurred in the study population. Sonography alone for our "at risk" population demonstrated 97% (64166) sensitivity and 99.9% (225512257) specificity for the prenatal diagnosis of open neural tube defects and was 100% sensitive and specific for ventral wall defects. Two open spina bi fida lesions were confirmed by amniocentesis after suspicious sonographic findings. Of the 204 GA's performed in the study population, 175 (86%) were performed for a risk of chromosomal disorder. In the remaining 29 pregnancies GA was performed for technically inadequate scans, patient request, or marked elevation of msAFP. Assuming a 1 in 200 risk of spontaneous abortion attributable to GA, avoidance of invasive testing in 2053 patients may have prevented the loss of I0 - 11 normal pregnancies. CONCLUSION: Our experience suggests that sonography can serve as a highly reliable tool for the prenatal diagnosis of neural tube and ventt'al wall defects in a high risk population.

63 MULTICENTER EXPERIENCE OF FETAL B L A D D E R S H U N T S . O. Davis. S.F. Duly, J. Yang, x M. Kal~nann, x R.J. Wapner. Dept o f Ob/Gyn, Jefferson Medical College of Thomas Jefferson Univ, Phila, PA. OBJECTIVE: Reports from single institutions on the success of fetal bladder shunts may not represent the experience and complications seen in general use. To determine this we established a database to collate the overall experience with the Harrison fetal bladder shunt. STUDY DESIGN: Data sheets were forwarded to every physician who requested a Harrison fetal shunt from Cook Ob/Gyn requesting information on the indication for insertion, procedural and postprocedural complications and outcomes of the shunt procedure. Procedure related complications are those which occurred within 14 days of insertion. Success was defined as a continuing pregnancy more than 14 days after shunt placement with the bladder draining until delivery. Experience with those shunts placed in the fetal bladder are reported here. RESULTS: Completed data sheets with followup have been received for 52 shunts placed in 42 fetuses. Data has been collected from 16 institutions, in g of those institutions there was only 1 shunt placed. The indication was suspected posterior urethral valves in 36 (86%), ureteropelvic junction obstruction in 2 eases(4.8%) and one ease each of urethral atresia, hydronephrosis, Prune belly syndrome and one undocumented case. The mean age at initial placement was 24.8 (5.0) weeks. Of the 52 procedures 18 (34.6%) were successful, there was unsuccessful placement in 3 cases (5.7%). The shunt became dislodged in 11(21.2%), obstructed in 8 (15.4%), migrated into the bladder in 5 (9.6%) and into the fetal pofitonium in 1 case (1.9%). Delivery occurred within two weeks of placement in 5 cases (9.6%). There were no perinntaI complications in 30 cases (71.4%). Perinatnl complications included 6 preterm labors, 4 episodes of premature rupture of membranes and 2 cases of infection. Pregnancy outcome included 5 terminations (12%), 3 intrauterine demises (7%), 13 neonatal deaths (31%), and 21 live neonates (50%). Five of the neonatal deaths died from pulmonary hypoplasia, 4 had additional anomalies, 2 died at <26 weeks, in 2 cases the cause of death was unclear. CONCLUSION: While potentially beneficial in many cases, fetal bladder shunting is associated with significant pednatal and shunt related problems. In this muhlcentcr review ooly 50% of the fetuses survived the neonatal period. Further evaluation is required to investigate if outcome may be retated to operator experience, case selection or other unidentified factors.

6 2 ANTENATAL S O N O G R A P H I C DETECTION O F FETAL HYDRONEPHROSIS AS A PREDICTOR OF POSTNATAL HYDRONEPHROSIS. R. Bonebrake.X A. Fleming, K. Dutton. -~Dept. OblGyn, Creighton University School of Medicine, Omaha, NE. OBJECTIVE: According to current criteria (renal anterior-posterior(A-P) diameter ->4ram <33 weeks estimated gestational age (EGA) and ~ 7mm ;~ 33 weeks EGA), neonates are oftentimes needlessly subjected to expensive and possibly invasive evaluations. The objective was to reassess by ultrasound the critical antenatal A-P diameter of the renal pelvis that predicts postnatal (PN) hydronephrosis and, therefore, the need for PN ewduation. STUDY DESIGN: A retrospective cohort study was conducted. For a period of 48 months, charts of all the patients with the diagnosis of antenatal congenital hydronephrosis (CH) were reviewed. All of the following were met tbr inclusion: CH after 20 wks EGA, unresolved CH prior to delivery, singleton gestation, and PN follow-up (ultrasound ~72 hours after delivery and telephone survey of the parents). The antenatal renal A-P diameter of those with and without PN hydronephrosis were then evaluated by gestational age (<33 wks and >_.33wks). RESULTS: Fifty-three antenatal charts were identified. Of the 53 neonates, 38% (20) had confimaed PN hydronephrosis. In the entire population, 10 mm was found to be statistically significant for predicting PN hydronepbrosls (OR=8.96 [3.23 10 ram, whereas only 2/33 neonates without PN hydronephrosis had renal A-P diameters >10 ram. At an EGA ~:33 wks, the renal A-P diameter of 10 mm was statistically significant (OR=139.50 [14.3 < OR < 1711.83], P = 0.0001) with a sensitivity, specificity, positive predictive value, and a negative predictive value of 90%, 94%, 90%, and 94% respectively. A ROC curve confirmed the cutoff of 10 mm with PN hydronephrosis. In the subgroup of <33 wks EGA, 10 mm was found not to be statistically significant. CONCLUSIONS: An antenatal evaluation of renal A-P diameter at >-33 wks EGA is a highly valid screening test for PN hydronephrosis. A measurement of 10 mm (previously accepted as 7 ram) at >33 weeks EGA indicates the critical need for postnatal follow-up.

64 DEREGULATED EXPRESSION OF T H E cYR6L I M M E D I A T E - E A R L Y GENE IN CONGENIC MICE: A M O D E L F O R THE S T U D Y O F G E N E T I C REGULATORS O F I N T R A U T E R I N E G R O W T H . J. Santolava-For~as. A Koures, x L. Lau.x Depts of OB/Gyn and Genetics, Univ. of II., Chicago, IL. OBJECTIVE: Currently we have rudimentary knowledge concerning the regulation of normal fetal growth. The growth factor inducible gene c y r r l has been characterized and the endogenous developmental expression in the outhreed mouse embryo determined. Our objective was to create m~ animal model in which both the environment and the genome could be under control. Congenle BL57-heta-actincyr61 mice were created to determine if an exclusive de-regulated expression of this gene had any effect on perinatal mortality, birthweight and post-natal growth. STUDY DESIGN: 10 outbred transgenic beta-actin-cyr61 were paired with 10 BL57 inbred female mice. Transgenic male newborns, recognized by their curly tails, From 4 consecutive generations were allowed to reach maturity and then back crossed with their mothers. Newborn weight, survival rate and growth pattern up to 50 days of development were dete~nined in study and control litter-mates. PCR analysis was used to demonstrate the presence of the beta-acttn- cyt61 transgane in the study group. RESULTS: Curly-tail transgenic newborns were consistently smaller than controls throughout the generations (ANOVA p< 0.001). Transgenic newborns from F2 to F5 generations had a survival rate at day 4 of llfe of 40% vs 84% for control (p<0.01). The growth patterns from birth to day 50 was significantly greater for controls than for F3-4 surviving transgenic animals (slopes. P<0.001) CONCLUSION: Deregulated expression of the cyr61 gene associates greater perinatal mortality, decreased newborn weight and postnatal growth. This animal model can be used to bring stone insight into the molecular basis of intrauterine growth.

$ 2 8 SPO Abstracts

January 1998 A m J Obstet Gynecol

6 5 A M N I O R E D U C T I O N IN TWIN-TWIN T R A N S F U S I O N SYNDROME - A M U L T I C E N T E R R E G I S T R Y , EVALUATION O F 579 P R O C E D U R E S . International q'~S Registry Group, Maternal Fetal Medicine, Yale University, New Haven, CT, USA. OBJECTIVE: To report the results of a multieenter registry established in 1995 to evaluate fetal morbidity and mortality in pregnancies treated with amniomduction because of twin-twin transfusion syndrome ('ITS). S T U D Y DESIGN: Twelve centers from the United States, Europe, and Oceania, participated in the registry. 579 amnioreductions were peffornaed on 175 pregnancies complicated by TTS. Each procedure was reported to the registry and evaluated for gestational age at diagnosis and delivery, number of amnioreductions performed, fetal survival rate, morbidity, and Doppler of the umbilical artery (UA). RESULTS: Gestational age at diagnosis ranged from 14 to 34 weeks (median" 21 weeks); whereas it was between 18 and 38 weeks at delivery (median: 30 weeks). The median number of amnioredoctions per patient was 2 and the median volume ofamniotic fluid removed per patient was 1420 ml. Delivery occurred because of fetal distress in 22% of the patients. The total survival rate was 66%; with survival rate in recipient and donor of 70% and 61%, respectively. In 75% of the cases, at least one twin survived; whereas the survival rate of both twins was 55%. Absent end diastolic velocity in the UA waS associated with a worst survival rate for both the recipients (44%) and the donors (31%) (p<.05). Survival was also worse with a greater number of amnioreductions (p<.05). Major abnormalities in the neonatal head sonograms were observed in 20% of the recipients and in 19% of the donors, respectively. CONCLUSIONS: Amnioreduction used in TTTS is associated with a poor perinatal outcome when there is absence of end diastolic velocity in the UA and/or when repeated procedures are necessary. Overall the survival rate is similar to that reperted for laser therapy.

6 6 OPEN FETAL SURGERY F O R CONGENITAL CYSTIC ADENOMATOID MALFORMATION O F THE LUNG. Scott Adztclr Michael Harrison, Timothy Cromblehobne, Alan Flake, Lori Howell. Children's Hospital of Philadelphia, Philadelphia, PA, Univ. of California, San Francisco, CA. OBJECTIVE: Hydrops in the fetus with a large congenital cystic adenomatold malformation (CCAM) of the lung is highly predictive for fetal or neonatal demise. We report results with open fetal surgery to treat this problem. STUDY DESIGN: From 1983-1997, we followed more than 150 fetal lung mass cases from the time of prenatsl diagnosis. This is a retrospective review of 13 cases of fetal CCAM associated with hydrops treated by open fetal surgery between 1990-1997. RESULTS: 13 hydropic fetuses with life-threatening CCAM were selected for fetal surgical resection of the massively enl,'u'ged pulmonary lobe (fetal lobectomy) at 21-29 weeks gestation. In the 8 fetuses that survived, fetal CCAM resection led to hydrops resolution in 1-2 weeks, return of the mediastinum to the midline within 3 weeks, and impressive in utero lung growth. Mean postoperative pregnancy, duration was 7.5 weeks (range 2-13 weeks). Developmental testing was normal in an 8 survivors (follow-up pedod of 6 months to 7 years). All 5 fetal deaths occurred in massively hydropie fetuses either immediately before (I), during (2) or shortly after (2) the fetal operation. Maternal complications were limited to a wound infection and a wound seroma. CONCLUSION: Fetal surgery is a therapeutic option for fetal CCAM associated with non- immune hydrops at less than 30 weeks gestation.