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Are choroid plexus cysts an indication for second-trimester amniocentesis?
DES-related adenocarcinoma and adenosis
Volume 162 Number 4
34. Nygren K, Johansson EDB, Wide L. Evaluation of the prognosis of threatened abortion from the peripheral plasma levels of progesterone, estradiol, and human chorionic gonadotropin. AM J OBSTET GYNECOL 1973; 116:916-22. 35. Savu L, Nunez EA. Diethylstilbestrol inhibits the estrogen-
binding activity of pregnancy plasma: possible role in DES-associated pathology. Clin Chern 1985;31:1409-10. 36. Hughes A, Jacobson HI, Wagner RK, Jungblut pw. Ovarian-independent fluctuations of estradiol receptor levels in mammalian tissues. Mol Cell Endocrinol 1976; 5:379-88.
Are choroid plexus cysts an indication for second-trimester amniocentesis? Beryl R. Benacerraf, MD, Bernard Harlow, PhD, and Fredric D. Frigoletto, Jr., MD Boston, Massachusetts Previous series that described fetuses with choroid plexus cysts have been too small to determine whether there is an association with trisomy 18 sufficiently high to warrant amniocentesis. To address this issue, we studied the incidence of choroid plexus cysts and other ultrasonographic abnormalities in 26 consecutive fetuses (13.5 to 36 weeks' gestation) with trisomy 18. Twenty of these 26 fetuses had major sonographic anomalies suggestive of aneuploidy. Seventeen of these 26 fetuses were 15 to 20 weeks and 5 of 17 (30%) had choroid plexus cysts. Six of our total 26 affected fetuses had no sonographic anomalies and therefore, on the basis of our data, 30% of these (1.8 fetuses) with trisomy 18 would have choroid plexus cysts without other findings. The incidence of choroid plexus cysts in all second-trimester fetuses (including normal fetuses and those with trisomy 18) is reportedly 1%. Given the known incidence of trisomy 18 (3/10,000), we calculated a total presumptive sample of 86,667 patients to yield our 26 fetuses wiht trisomy 18. Our hypothetical sample has 86,641 (86,667 - 26) fetuses without trisomy 18, 858 of which would have choroid plexus cysts. Thus there would be one fetus with trisomy 18 for every 477 normal fetuses with choroid plexus cysts with no other defect seen. If amniocentesis were done to seek trisomy 18 in all second-trimester fetuses with choroid plexus cysts, two normal fetuses would be lost for every one with trisomy 18 identified. (AM J OSSTET GVNECOL 1990;162:1001-6.)
Key words: Choroid plexus cysts, trisomy 18, ultrasound, cytogenetics Chudleigh et aLI first described the benign nature of choroid plexus cysts observed ultrasonographically in the second-trimester fetus. Subsequently many others have agreed that second-trimester choroid plexus cysts are usually without sequelae: most choroid plexus cysts regress by 24 weeks and the neonates are normal!-7 On occasion these cysts have been associated with aneuploidy, particularly trisomy 18. Because of this association, some investigators have recommended cytogenetic studies for second-trimester fetuses with choroid plexus cysts. "-12 The observations by Fitzsimmons et aI., 13 who studied the brains of 14 fetuses with trisomy 18 at autopsy and found a strong correlation between this abnormal karyotype and choroid plexus cysts, have From the Departments of Obstetrics and Gynecology and Radiology, Brigham and Women's Hospital, Harvard Medical School. Receivedforpublicationjune 29,1989; revised September 15,1989; accepted September 20, 1989. Reprint requests: Beryl R. Benacerraf, MD, Diagnostic Ultrasound Associates, 333 Longwood Ave., Boston, MA 02115.
611116823
fueled this controversy. To critically assess this debate, the incidence of choroid plexus cysts in secondtrimester fetuses with and without trisomy 18 as well as associated anomalies must be determined. Review of several series demonstrates considerable variation in the general incidence of second-trimester choroid plexus cysts from series to series (0.18%, 0.65%, 0.80%, and 2.5%).2.4· 5.H However, if the average of these four numbers is taken, then approximately 1% of all secondtrimester fetuses would be expected to have choroid plexus cysts, an estimate in agreement with the experience in our laboratory. Furthermore even though choroid plexus cysts are more commonly present in fetuses with trisomy 18, this is a rare chromosomal abnormality that has a known incidence of three in every 10,000 births, an important consideration in the decision to recommend amniocentesis. II Clearly, the multitude of small series describing two to 41 cases of choroid plexus cysts each is insufficient to determine whether amniocentesis is really indicated when these cysts are discovered sonographically.I-12 In
1001
1002 Benacerraf, Harlow, and Frigoletto
April 1990 Am J Obstet Gynecol
Table I. Data of 13 patients presenting for amniocentesis Patient No.
Maternal age (yr)
Gestational age (wk)
Choroid cysts
Indication for tap
38
20
No
AMA
2
40
16
No
AMA
3
37
15
No
AMA
4
39
16
No
AMA
5 6
36 24
13.5 19 (16)
Yes Yes (no)
AMA Low AFP
7 8 9
38 26 29
16 18 17
No No Yes
AMA High AFP High AFP
10
40
15
No
AMA
II
33
19
Yes
Low AFP
12 13
43 37
15 15
No Yes
AMA AMA
Other ultrasound findings
Outcome
Diaphragmatic hernia, clubfeet, fisted hands, CHD, hydrocephalus Abnormal radial ray, clubbed hands, short femurs Abnormal head shape, clubfeet Nuchal cystic hygroma (one of twins), other twin normal Large cystic hygroma At 19 wk: CHD, abnormal hands (no findings at 16 wk) None Open lumbar NTD CHD, open NTD, clubfeet, fisted hands Abnormal head shape (? NTD), diaphragmatic hernia CHD, clubfeet, fisted hands None None
TAB
TAB TAB IUFD 18 wk TAB TAB TAB TAB TAB TAB TAB TAB TAB
NTD, Neural tube defect; CHD, congenital heart defect; AFP, a-fetoprotein; AMA, advanced maternal age; IUFD, intrauterine fetal death; TAB, elective abortion.
this report, we investigate the incidence of choroid plexus cysts and other major sonographically detectable abnormalities in 26 consecutive fetuses who were subsequently discovered to have trisomy 18. With this data set, and knowing the incidence of trisomy 18 (3/10,000 cases), the incidence of choroid plexus cysts in the general population of second-trimester fetuses and in those with trisomy 18, and by knowing the overall incidence of major malformations found so no graphically in fetuses with trisomy 18, statistical analysis can determine the risk of an abnormal karyotype when a choroid plexus cyst is found prenatally. Material and methods
Cases of trios my 18 were identified from records of the five cytogenetic laboratories that serve our area, whether the diagnosis was obtained from amniotic fluid, blood, or tissue between Jan. 1, 1983 and April 1, 1989. This information was then correlated with the patient population who had prenatal ultrasound tests in our laboratory. During this period 26 consecutive fetuses with trisomy 18 were diagnosed by karyotyping either at amniocentesis or after birth. Because a number of patients had been referred because of suspected ultrasonographic anomalies on scans done elsewhere, we analyzed a subgroup of 13 consecutive fetuses (within the total 26) who were referred to our labora-
tory for a planned amniocentesis solely because of advanced maternal age or abnormal a-fetoprotein level and found to have trisomy 18. Because this smaller group of patients scheduled for amniocentesis is a finite group not referred for any so no graphic finding, this subpopulation was also analyzed separately to demonstrate lack of bias. All scans were done with an Acuson 128 phased-array system with a 3.5 MHz sector or linear transdsucer. All anomalies were recorded prospectively at the time of the original scan. The images were reviewed retrospectively only to determine the presence or absence of choroid plexus cysts. Statistical analysis was performed to determine the risk of trisomy 18 when a choroid plexus cyst was seen in a second-trimester fetus without any other sonographic abnormality. Results
Six of the 26 fetuses with trisomy 18 had no obvious sonographic anatomic malformations and the other 20 had major congenital defects suggestive of an abnormal karyotype. These malformations included congenital heart defects, neural tube defects, diaphragmatic hernia, omphalocele, hydrocephalus, clubfoot, cystic hygroma, and abnormally fisted hands (Tables I and II; Figs. 1 and 2). Similarly, in the smaller subset of 13 patients who
Choroid plexus cysts and second-trimester amniocentesis
Volume 162 Number 4
1003
Table II. Data of 13 patients not presenting for amniocentesis Indication for scan
Gestational age (wk)
Patient No.
Maternal age (yr)
14
37
36
*
IUGR (?)
15
24
32
*
Referral
16
40
16
No
Bleeding
17
32
19
No
Dating
18
40
14.5
No
Referral
19
31
14.5
No
Referral
20
42
17
No
Sizing
21
32
31
No
IUGR (?)
22
31
No
Position (?)
23
35
15
No
Referral
24
29
16
Yes
Referral
25
28
14
No
Referral
26
23
32
*
Referral
34 (32)
Other ultrasound findings
Outcome
Growth deficiency and poly. No anatomic findings Esophageal atresia, clubfeet, fisted hands, IUGR, poly Low placenta. No anatomic findings Cystic hygroma, CHD, short radial ray, clubbed hands Cystic hygroma, hydrops, clubfeet, small head Omphalocele, clubfeet, abnormal hands, ? CHD Hydrocephalus, left clubfoot, small omphalocele, NTD IUGR, poly, abnormal fisted hands, micrognathia CHD, clubfeet, growth deficiency on 2nd scan 2 wk after 1st Cystic hygroma, hydrops, small omphalocele, CHD Diaphragmatic hernia, omphalocele, fisted hands, NTD, hydrocephalus Cystic hygroma (one of twins) other twin normal Clubfoot, cerebellar hypoplasia, CHD, poly, IUGR
Neonatal death Neonatal death Neonatal death Tap and TAB Tap and TAB TAB TAB Neonatal death Neonatal death TAB TAB
IUFD 32 wk Neonatal death
NTD, Neural tube defect; CHD, congenital heart defect; IVCR, intrauterine growth retardation; POLY, polyhydramnios; TAB, elective abortion. *Images of the choroid plexus not available for review.
Table III. Likelihood that a fetus with choroid plexus cysts has trisomy 18 in the whole population Patients
With trisomy 18 Without trisomy 18 TOTAL
Other ultrasound findings (No. of patients)
With choroid cyst (No. of patients)
Without choroid cyst (No. of patient~)
Total (No. of patients)
20
1.8 858
4.2 85,783
26 86,641
20
859.8
85,787.2
86,667
There is one fetus with trisomy 18 for every 477 normal fetuses with choroid plexus cysts. were seen for planned amniocentesis, 10 fetuses had major sonographically detected malformations (Table I). In addition, one fetus in this amniocentesis group scanned initially at 16 weeks had no choroid plexus cysts or other sonographic abnormality. When the patient returned at 19 weeks for amniocentesis because of a low ex-fetoprotein value, major anatomic defects were identified consistent with trisomy 18 and choroid
plexus cysts had appeared (Table II). The other three patients in this group who had no sonographic findings were at 15 to 16 weeks' gestation at the time of sonography and it is possible that features of trisomy 18 (such as heart defects or fisted hands) may not be as apparent early as they are at 19 weeks. The similarity between results regarding the rate of major defects for this small subgroup of 13 patients (l0113 patients) and
004
Benacerraf, Harlow, and Frigoletto
April 1990 Am J Obstet Gynecol
Fig. 1. Magnified view of the fetal hand showing the characteristic overlapping index finger (arrow) seen with trisomy 18.
Fig. 2. Longitudinal view of the fetal lower leg showing a clubfoot associated with trisomy 18.
those in the total population (20/26 patients) suggests that the differences in indications for the sonograms in these two groups did not affect the results. In three of the total 26 cases, the choroid plexus was not adequately imaged, thus only 23 cases had images of the choroid plexus adequate for review. Six of these 23 had choroid plexus cysts, and these six were studied between 13.5 to 18 weeks of gestation (Figs. 3 and 4). Twenty-one of the total 26 fetuses were actually between 13.5 and 18 weeks at the time of the scan, yielding an incidence of second-trimester choroid plexus cysts of six of 21 or 28.6% in our trisomy 18 population. If only the fetuses between 15 and 20 weeks were included, choroid plexus cysts were present in five of 17 cases or 30%. Because the estimated incidence of trisomy 18 is three in 10,000 cases'an,d choroid plexus cysts occur in
Fig. 3. Fetal head showing a choroid plexus cyst (arrows) in a fetus with trisomy 18. Note that the frontal region of the head is pointed (lemon sign) in this fetus who also had a neural tube defect.
1% of second-trimester fetuses (including those with trisomy 18), the positive predictive value of choroid plexus cysts for detecting trisomy 18 can be calculated. If no other sonographic findings are considered, the sensitivity of choroid plexus cysts for the detection of trisomy 18 is 30% (from our data), the specificity 99%, and the positive predictive value 0.9%. However, 20 of the 26 fetuses with trisomy 18 in this series had major sonographic findings at the time of ultrasound scan, before knowledge of the karyotype, suggesting the need for cytogenetic evaluation. Inclusion of these other criteria changes the analysis substantially. Given the incidence of trisomy 18 (3/10,000), we estimated that 86,667 patients would have been needed to generate our 26 cases of trisomy 18 (Table III). Six of our
Volume 162 Kumber 4
Choroid plexus cysts and second-trimester amniocentesis
1005
26 affected fetuses had no major sonographic malformations suggestive of an abnormal karyotype. If 30% of these six affected fetuses have choroid plexus cysts, 1.8 fetuses with trisomy 18 would have choroid plexus cysts without other sonographic findings. Eighty-six thousand six hundred forty-one normal fetuses remain in this hypothetical population, of which 0.99% (858) would presumably have choroid plexus cysts. Thus there would be one fetus with trisomy 18 for every 477 normal fetuses with choroid plexus cysts, assuming no other sonographic abnormality. The same numbers result when the statistical analysis is used for the smaller population of 13 cases referred for amniocentesis. Comment
Most choroid plexus cysts seen in second-trimester fetuses are transient and lack clinical significance. I.H They usually regress by 24 weeks and are easily distinguished from significant intracranial abnormalities. Choroid plexus cysts can occasionally persist in neonates but only rarely cause symptoms.I'.Ih Recently a large number of reports have described small series of fetuses with choroid plexus cysts. I·I~ A key goal of such studies has been to determine if the association of choroid plexus cysts with trisomy 18 is sufficient to warrant amniocentesis for cytogenetic studies. This important question still remains unresolved because each laboratory only has a small number of these cases. Fitzsimmons et al. 13 studied 14 consecutive fetuses with trisomy 18 and showed that choroid plexus cysts were present in 35% of cases. They claimed an unusually high percentage of choroid plexus cysts in their five second-trimester fetuses (four of five); however, this was an in vitro study in which the brain of each fetus was studied with a 5 or 7.5 MHz transducer, yielding higher resolution than possible in vivo. Our study is likely to be more representative ofthe incidence of choroid plexus cysts seen sonographically in vivo in a population of second-trimester fetuses with trisomy 18. Sonographic abnormalities associated with trisomy 18 have been described and include congenital heart defect, clubfeet, fisted hands, abnormally short radial ray, neural tube defect, diaphragmatic hernia, omphalocele, hydrocephalus, micrognathia, and cystic hygroma. I4 . 17·19 These malformations can be specifically sought by experienced ultrasonographers and reliably diagnosed. 17 In this series, 20 of 26 (77%) of fetuses with trisomy 18 had such malformations identified prospectively before any knowledge of the karyotype. By use of the incidence of choroid plexus cysts in second-trimester fetuses averaged from several series (average 1%), the determined incidence of choroid plexus cysts in second-trimester trisomy 18 fetuses from the present study (30%), the known incidence of tri-
Fig. 4. Transverse view of the head of a fetus with trisomy 18 shows a very tiny choroid plexus cyst (arrow).
so my 18 (3/10,000), and the rate of identification of major malformations in our cases of trisomy 18 (77%), only one additional fetus with trisomy 18 would be identified if amniocentesis were done for choroid plexus cysts alone. 2. 1. 5. H. 14. 17 This would necessitate amniocentesis on 477 normal fetuses. The risk of losing a pregnancy from amniocentesis is approximately one per 200 cases. 20 . 21 It follows that two normal fetuses would be lost for each fetus with trisomy 18 identified if amniocentesis were done because of choroid plexus cysts in the absence of other sonographic abnormalities. This exceeds the risk currently accepted for prenatal diagnostic procedures. 22 Because one of our cases had no sonographic defect at 16 weeks but was abnormal at 19 weeks, it is possible that some of the subtle abnormalities associated with trisomy 18 are not apparent in the early part of the second trimester. Because of this, we recommend the following approach to the management of patients with second-trimester choroid plexus cysts. (l) If the gestational age is earlier than 19 weeks, the sonogram should be repeated at 19 weeks or later by a sonologist familiar with fetal malformations associated with aneuploidy. (2) If the fetus is at least 19 weeks and no other anatomic defects are identified sonographically, amniocentesis should not be necessary. REFERENCES I. Chudleigh P, Pearce JM, Campbell S. The prenatal diagnosis of transient cysts of the fetal choroid plexus. Prenat Diagn 1984;4: 135. 2. Chan L, Hixson JL, Laifer SA, et al. A sonographic and karyotypic study of second-trimester fetal choroid plexus cysts. Obstet Gynecol 1989;73:703. 3. Benacerraf BR, Laboda L. Cyst of the fetal choroid
Benacerraf, Harlow, and Frigoletto
4. 5. 6. 7. 8.
9. 10. II. 12.
plexus: a normal variant? AM J OBSTET GYNECOL 1989; 160:319. Clark SL, DeVore GR, Sabey PL. Prenatal diagnosis of cysts of the fetal choroid plexus. Obstet Gynecol 1988; 72:585. DeRoo TR, Harris RD, Sargent SK, et al. Fetal choroid plexus cysts: prevalence, clinical significance, and sonographic appearance. AJR 1988;151:1179. Benacerraf BR. Asymptomatic cysts of the fetal choroid plexus in the second trimester. J Ultrasound Med 1987; 6:475. Friday RO, Schwartz DB, Tuffli GA. Spontaneous intrauterine resolution of intraventricular cystic masses. J Ultrasound Med 1985;4:385. Chitkara U, Cogswell C, Norton K, et al. Choroid plexus cysts in the fetus: a benign anatomic variant or pathologic entity? Report of 41 cases and review of the literature. Obstet Gynecol 1988;72: 185. Farhood AI, MorrisJH, Bieber FR. Transient cysts of the fetal choroid plexus: morphology and histogenesis. AmJ Med Genet 1987;27;977. Hertzberg BS, Kay HH, Bowie JD. Fetal choroid plexus lesions: relationship of antenatal sonographic appearance to clinical outcome. J Ultrasound Med 1989;8:77. Nicolaides KH, Rodek CH, Gosden CM. Rapid karyotyping in non-lethal fetal malformation. Lancet 1986; I :283. Bundy AL, Saltzman DH, Pober B, et al. Antenatal sonographic findings in trisomy 18. J Ultrasound Med 1986;5:361.
April 1990 Am J Obstet Gynecol
13. Fitzsimmons J, Wilson D, Pascoe-Mason J, et al. Choroid plexus cysts in fetuses with trisomy 18. Obstet Gynecol 1989;73:257. 14. Jones KL. Smith's recognizable patterns of human malformation, 4th ed. Philadelphia: WB Saunders, 1988:16. 15. Giorgi C. Symptomatic cyst of the choroid plexus of the lateral ventricle. Neurosurgery 1979;5:53. 16. Fakhry J, Schechter A, Tenner MS, et al. Cysts of the choroid plexus in neonates: documentation and review of the literature. J Ultrasound Med 1985;4;561. 17. Benacerraf BR, Miller WA, Frigoletto FD. Sonographic detection of fetuses with trisomy 13 and 18: accuracy and limitations. AMJ OBSTET GYNECOL 1988;158:404. 18. Benacerraf BR. The antenatal sonographic diagnosis of congenital clubfoot: a possible indication for amniocentesis. J Clin Ultrasound 1986;14:703. 19. Benacerraf BR, Adzick S. Fetal diaphragmatic hernia: ultrasound diagnosis and clinical outcome in 19 cases. AM J OBSTET GYNECOL 1987;156:573. 20. Crandall BF, Howard J, Lebherz TB, et al. Follow-up of 2000 second trimester amniocentesis. Obstet Gynecol 1980;56:625. 21. Hanson FW, Tennant FR, Zorn EM, etal. Analysisof2136 genetic amniocentesis: experience of a single physician. AM J OBSTET GYNECOL 1985; 152:436. 22. Palomaki GE, Haddow .lE. Maternal serum a-fetoprotein, age, and Down syndrome risk. AM .l OBSTET GYNECOL 1987; 156:460.
Significance of observing no fluid at amniotomy Maurice L. Druzin, MD, and Diana M. Adams, MD New York, New York Thirty patients with oligohydramnios observed at artificial rupture of membranes were studied to determine the significance of this finding. Fifteen were subsequently found to have meconium-stained amniotic fluid and 21 had abnormal fetal heart rate tracings. This clinical observation warrants close intrapartum surveillance and preparation for delivery. (AM J OBSTET GVNECOL 1990;162:1006-7.)
Key words: Meconium, amniotomy, oligohydramnios Patients in labor often undergo artificial rupture of membranes (AROM), and the quantity and nature of amniotic fluid are considered important. In some cases no fluid is noted after AROM. Both oligohydramnios and meconium-stained amniotic fluid are associated with increased perinatal morbidity. The clinical significance of no fluid at AROM was evaluated. From the Department of Obstetrics and Gynecology, The New York Hospital-Cornell Medical Center. Received for publication September 20, 1989; accepted October 11, 1989. Reprint requests: Maurice L. Druzin, MD, 525 E. 68th St., Room M-036, New York, NY 10021. 611 117365
1006
Material and methods Thirty consecutive patients between April 1987 and August 1988 were observed by their physician to have no fluid at AROM. All patients had completed 259 days' (37 weeks) gestation, and the mean gestational age was 283.6 ± 10.9 days (40.5 weeks). Three (10%) patients were ~42 weeks' gestation, and 22 (73.3%) >40 weeks' gestation. Prior spontaneous rupture of membranes was ruled out by history and phsyical examination. At the time of the initial observation the patient's names were recorded. After delivery all 30 charts were analyzed. Abnormal fetal heart rate (FHR) patterns (fetal stress) included recurrent moderate (30 to 60 seconds duration) variable decelerations, recurrent severe (>60 seconds duration) variable decelera-
Volume 162 Number 4
34. Nygren K, Johansson EDB, Wide L. Evaluation of the prognosis of threatened abortion from the peripheral plasma levels of progesterone, estradiol, and human chorionic gonadotropin. AM J OBSTET GYNECOL 1973; 116:916-22. 35. Savu L, Nunez EA. Diethylstilbestrol inhibits the estrogen-
binding activity of pregnancy plasma: possible role in DES-associated pathology. Clin Chern 1985;31:1409-10. 36. Hughes A, Jacobson HI, Wagner RK, Jungblut pw. Ovarian-independent fluctuations of estradiol receptor levels in mammalian tissues. Mol Cell Endocrinol 1976; 5:379-88.
Are choroid plexus cysts an indication for second-trimester amniocentesis? Beryl R. Benacerraf, MD, Bernard Harlow, PhD, and Fredric D. Frigoletto, Jr., MD Boston, Massachusetts Previous series that described fetuses with choroid plexus cysts have been too small to determine whether there is an association with trisomy 18 sufficiently high to warrant amniocentesis. To address this issue, we studied the incidence of choroid plexus cysts and other ultrasonographic abnormalities in 26 consecutive fetuses (13.5 to 36 weeks' gestation) with trisomy 18. Twenty of these 26 fetuses had major sonographic anomalies suggestive of aneuploidy. Seventeen of these 26 fetuses were 15 to 20 weeks and 5 of 17 (30%) had choroid plexus cysts. Six of our total 26 affected fetuses had no sonographic anomalies and therefore, on the basis of our data, 30% of these (1.8 fetuses) with trisomy 18 would have choroid plexus cysts without other findings. The incidence of choroid plexus cysts in all second-trimester fetuses (including normal fetuses and those with trisomy 18) is reportedly 1%. Given the known incidence of trisomy 18 (3/10,000), we calculated a total presumptive sample of 86,667 patients to yield our 26 fetuses wiht trisomy 18. Our hypothetical sample has 86,641 (86,667 - 26) fetuses without trisomy 18, 858 of which would have choroid plexus cysts. Thus there would be one fetus with trisomy 18 for every 477 normal fetuses with choroid plexus cysts with no other defect seen. If amniocentesis were done to seek trisomy 18 in all second-trimester fetuses with choroid plexus cysts, two normal fetuses would be lost for every one with trisomy 18 identified. (AM J OSSTET GVNECOL 1990;162:1001-6.)
Key words: Choroid plexus cysts, trisomy 18, ultrasound, cytogenetics Chudleigh et aLI first described the benign nature of choroid plexus cysts observed ultrasonographically in the second-trimester fetus. Subsequently many others have agreed that second-trimester choroid plexus cysts are usually without sequelae: most choroid plexus cysts regress by 24 weeks and the neonates are normal!-7 On occasion these cysts have been associated with aneuploidy, particularly trisomy 18. Because of this association, some investigators have recommended cytogenetic studies for second-trimester fetuses with choroid plexus cysts. "-12 The observations by Fitzsimmons et aI., 13 who studied the brains of 14 fetuses with trisomy 18 at autopsy and found a strong correlation between this abnormal karyotype and choroid plexus cysts, have From the Departments of Obstetrics and Gynecology and Radiology, Brigham and Women's Hospital, Harvard Medical School. Receivedforpublicationjune 29,1989; revised September 15,1989; accepted September 20, 1989. Reprint requests: Beryl R. Benacerraf, MD, Diagnostic Ultrasound Associates, 333 Longwood Ave., Boston, MA 02115.
611116823
fueled this controversy. To critically assess this debate, the incidence of choroid plexus cysts in secondtrimester fetuses with and without trisomy 18 as well as associated anomalies must be determined. Review of several series demonstrates considerable variation in the general incidence of second-trimester choroid plexus cysts from series to series (0.18%, 0.65%, 0.80%, and 2.5%).2.4· 5.H However, if the average of these four numbers is taken, then approximately 1% of all secondtrimester fetuses would be expected to have choroid plexus cysts, an estimate in agreement with the experience in our laboratory. Furthermore even though choroid plexus cysts are more commonly present in fetuses with trisomy 18, this is a rare chromosomal abnormality that has a known incidence of three in every 10,000 births, an important consideration in the decision to recommend amniocentesis. II Clearly, the multitude of small series describing two to 41 cases of choroid plexus cysts each is insufficient to determine whether amniocentesis is really indicated when these cysts are discovered sonographically.I-12 In
1001
1002 Benacerraf, Harlow, and Frigoletto
April 1990 Am J Obstet Gynecol
Table I. Data of 13 patients presenting for amniocentesis Patient No.
Maternal age (yr)
Gestational age (wk)
Choroid cysts
Indication for tap
38
20
No
AMA
2
40
16
No
AMA
3
37
15
No
AMA
4
39
16
No
AMA
5 6
36 24
13.5 19 (16)
Yes Yes (no)
AMA Low AFP
7 8 9
38 26 29
16 18 17
No No Yes
AMA High AFP High AFP
10
40
15
No
AMA
II
33
19
Yes
Low AFP
12 13
43 37
15 15
No Yes
AMA AMA
Other ultrasound findings
Outcome
Diaphragmatic hernia, clubfeet, fisted hands, CHD, hydrocephalus Abnormal radial ray, clubbed hands, short femurs Abnormal head shape, clubfeet Nuchal cystic hygroma (one of twins), other twin normal Large cystic hygroma At 19 wk: CHD, abnormal hands (no findings at 16 wk) None Open lumbar NTD CHD, open NTD, clubfeet, fisted hands Abnormal head shape (? NTD), diaphragmatic hernia CHD, clubfeet, fisted hands None None
TAB
TAB TAB IUFD 18 wk TAB TAB TAB TAB TAB TAB TAB TAB TAB
NTD, Neural tube defect; CHD, congenital heart defect; AFP, a-fetoprotein; AMA, advanced maternal age; IUFD, intrauterine fetal death; TAB, elective abortion.
this report, we investigate the incidence of choroid plexus cysts and other major sonographically detectable abnormalities in 26 consecutive fetuses who were subsequently discovered to have trisomy 18. With this data set, and knowing the incidence of trisomy 18 (3/10,000 cases), the incidence of choroid plexus cysts in the general population of second-trimester fetuses and in those with trisomy 18, and by knowing the overall incidence of major malformations found so no graphically in fetuses with trisomy 18, statistical analysis can determine the risk of an abnormal karyotype when a choroid plexus cyst is found prenatally. Material and methods
Cases of trios my 18 were identified from records of the five cytogenetic laboratories that serve our area, whether the diagnosis was obtained from amniotic fluid, blood, or tissue between Jan. 1, 1983 and April 1, 1989. This information was then correlated with the patient population who had prenatal ultrasound tests in our laboratory. During this period 26 consecutive fetuses with trisomy 18 were diagnosed by karyotyping either at amniocentesis or after birth. Because a number of patients had been referred because of suspected ultrasonographic anomalies on scans done elsewhere, we analyzed a subgroup of 13 consecutive fetuses (within the total 26) who were referred to our labora-
tory for a planned amniocentesis solely because of advanced maternal age or abnormal a-fetoprotein level and found to have trisomy 18. Because this smaller group of patients scheduled for amniocentesis is a finite group not referred for any so no graphic finding, this subpopulation was also analyzed separately to demonstrate lack of bias. All scans were done with an Acuson 128 phased-array system with a 3.5 MHz sector or linear transdsucer. All anomalies were recorded prospectively at the time of the original scan. The images were reviewed retrospectively only to determine the presence or absence of choroid plexus cysts. Statistical analysis was performed to determine the risk of trisomy 18 when a choroid plexus cyst was seen in a second-trimester fetus without any other sonographic abnormality. Results
Six of the 26 fetuses with trisomy 18 had no obvious sonographic anatomic malformations and the other 20 had major congenital defects suggestive of an abnormal karyotype. These malformations included congenital heart defects, neural tube defects, diaphragmatic hernia, omphalocele, hydrocephalus, clubfoot, cystic hygroma, and abnormally fisted hands (Tables I and II; Figs. 1 and 2). Similarly, in the smaller subset of 13 patients who
Choroid plexus cysts and second-trimester amniocentesis
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1003
Table II. Data of 13 patients not presenting for amniocentesis Indication for scan
Gestational age (wk)
Patient No.
Maternal age (yr)
14
37
36
*
IUGR (?)
15
24
32
*
Referral
16
40
16
No
Bleeding
17
32
19
No
Dating
18
40
14.5
No
Referral
19
31
14.5
No
Referral
20
42
17
No
Sizing
21
32
31
No
IUGR (?)
22
31
No
Position (?)
23
35
15
No
Referral
24
29
16
Yes
Referral
25
28
14
No
Referral
26
23
32
*
Referral
34 (32)
Other ultrasound findings
Outcome
Growth deficiency and poly. No anatomic findings Esophageal atresia, clubfeet, fisted hands, IUGR, poly Low placenta. No anatomic findings Cystic hygroma, CHD, short radial ray, clubbed hands Cystic hygroma, hydrops, clubfeet, small head Omphalocele, clubfeet, abnormal hands, ? CHD Hydrocephalus, left clubfoot, small omphalocele, NTD IUGR, poly, abnormal fisted hands, micrognathia CHD, clubfeet, growth deficiency on 2nd scan 2 wk after 1st Cystic hygroma, hydrops, small omphalocele, CHD Diaphragmatic hernia, omphalocele, fisted hands, NTD, hydrocephalus Cystic hygroma (one of twins) other twin normal Clubfoot, cerebellar hypoplasia, CHD, poly, IUGR
Neonatal death Neonatal death Neonatal death Tap and TAB Tap and TAB TAB TAB Neonatal death Neonatal death TAB TAB
IUFD 32 wk Neonatal death
NTD, Neural tube defect; CHD, congenital heart defect; IVCR, intrauterine growth retardation; POLY, polyhydramnios; TAB, elective abortion. *Images of the choroid plexus not available for review.
Table III. Likelihood that a fetus with choroid plexus cysts has trisomy 18 in the whole population Patients
With trisomy 18 Without trisomy 18 TOTAL
Other ultrasound findings (No. of patients)
With choroid cyst (No. of patients)
Without choroid cyst (No. of patient~)
Total (No. of patients)
20
1.8 858
4.2 85,783
26 86,641
20
859.8
85,787.2
86,667
There is one fetus with trisomy 18 for every 477 normal fetuses with choroid plexus cysts. were seen for planned amniocentesis, 10 fetuses had major sonographically detected malformations (Table I). In addition, one fetus in this amniocentesis group scanned initially at 16 weeks had no choroid plexus cysts or other sonographic abnormality. When the patient returned at 19 weeks for amniocentesis because of a low ex-fetoprotein value, major anatomic defects were identified consistent with trisomy 18 and choroid
plexus cysts had appeared (Table II). The other three patients in this group who had no sonographic findings were at 15 to 16 weeks' gestation at the time of sonography and it is possible that features of trisomy 18 (such as heart defects or fisted hands) may not be as apparent early as they are at 19 weeks. The similarity between results regarding the rate of major defects for this small subgroup of 13 patients (l0113 patients) and
004
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April 1990 Am J Obstet Gynecol
Fig. 1. Magnified view of the fetal hand showing the characteristic overlapping index finger (arrow) seen with trisomy 18.
Fig. 2. Longitudinal view of the fetal lower leg showing a clubfoot associated with trisomy 18.
those in the total population (20/26 patients) suggests that the differences in indications for the sonograms in these two groups did not affect the results. In three of the total 26 cases, the choroid plexus was not adequately imaged, thus only 23 cases had images of the choroid plexus adequate for review. Six of these 23 had choroid plexus cysts, and these six were studied between 13.5 to 18 weeks of gestation (Figs. 3 and 4). Twenty-one of the total 26 fetuses were actually between 13.5 and 18 weeks at the time of the scan, yielding an incidence of second-trimester choroid plexus cysts of six of 21 or 28.6% in our trisomy 18 population. If only the fetuses between 15 and 20 weeks were included, choroid plexus cysts were present in five of 17 cases or 30%. Because the estimated incidence of trisomy 18 is three in 10,000 cases'an,d choroid plexus cysts occur in
Fig. 3. Fetal head showing a choroid plexus cyst (arrows) in a fetus with trisomy 18. Note that the frontal region of the head is pointed (lemon sign) in this fetus who also had a neural tube defect.
1% of second-trimester fetuses (including those with trisomy 18), the positive predictive value of choroid plexus cysts for detecting trisomy 18 can be calculated. If no other sonographic findings are considered, the sensitivity of choroid plexus cysts for the detection of trisomy 18 is 30% (from our data), the specificity 99%, and the positive predictive value 0.9%. However, 20 of the 26 fetuses with trisomy 18 in this series had major sonographic findings at the time of ultrasound scan, before knowledge of the karyotype, suggesting the need for cytogenetic evaluation. Inclusion of these other criteria changes the analysis substantially. Given the incidence of trisomy 18 (3/10,000), we estimated that 86,667 patients would have been needed to generate our 26 cases of trisomy 18 (Table III). Six of our
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Choroid plexus cysts and second-trimester amniocentesis
1005
26 affected fetuses had no major sonographic malformations suggestive of an abnormal karyotype. If 30% of these six affected fetuses have choroid plexus cysts, 1.8 fetuses with trisomy 18 would have choroid plexus cysts without other sonographic findings. Eighty-six thousand six hundred forty-one normal fetuses remain in this hypothetical population, of which 0.99% (858) would presumably have choroid plexus cysts. Thus there would be one fetus with trisomy 18 for every 477 normal fetuses with choroid plexus cysts, assuming no other sonographic abnormality. The same numbers result when the statistical analysis is used for the smaller population of 13 cases referred for amniocentesis. Comment
Most choroid plexus cysts seen in second-trimester fetuses are transient and lack clinical significance. I.H They usually regress by 24 weeks and are easily distinguished from significant intracranial abnormalities. Choroid plexus cysts can occasionally persist in neonates but only rarely cause symptoms.I'.Ih Recently a large number of reports have described small series of fetuses with choroid plexus cysts. I·I~ A key goal of such studies has been to determine if the association of choroid plexus cysts with trisomy 18 is sufficient to warrant amniocentesis for cytogenetic studies. This important question still remains unresolved because each laboratory only has a small number of these cases. Fitzsimmons et al. 13 studied 14 consecutive fetuses with trisomy 18 and showed that choroid plexus cysts were present in 35% of cases. They claimed an unusually high percentage of choroid plexus cysts in their five second-trimester fetuses (four of five); however, this was an in vitro study in which the brain of each fetus was studied with a 5 or 7.5 MHz transducer, yielding higher resolution than possible in vivo. Our study is likely to be more representative ofthe incidence of choroid plexus cysts seen sonographically in vivo in a population of second-trimester fetuses with trisomy 18. Sonographic abnormalities associated with trisomy 18 have been described and include congenital heart defect, clubfeet, fisted hands, abnormally short radial ray, neural tube defect, diaphragmatic hernia, omphalocele, hydrocephalus, micrognathia, and cystic hygroma. I4 . 17·19 These malformations can be specifically sought by experienced ultrasonographers and reliably diagnosed. 17 In this series, 20 of 26 (77%) of fetuses with trisomy 18 had such malformations identified prospectively before any knowledge of the karyotype. By use of the incidence of choroid plexus cysts in second-trimester fetuses averaged from several series (average 1%), the determined incidence of choroid plexus cysts in second-trimester trisomy 18 fetuses from the present study (30%), the known incidence of tri-
Fig. 4. Transverse view of the head of a fetus with trisomy 18 shows a very tiny choroid plexus cyst (arrow).
so my 18 (3/10,000), and the rate of identification of major malformations in our cases of trisomy 18 (77%), only one additional fetus with trisomy 18 would be identified if amniocentesis were done for choroid plexus cysts alone. 2. 1. 5. H. 14. 17 This would necessitate amniocentesis on 477 normal fetuses. The risk of losing a pregnancy from amniocentesis is approximately one per 200 cases. 20 . 21 It follows that two normal fetuses would be lost for each fetus with trisomy 18 identified if amniocentesis were done because of choroid plexus cysts in the absence of other sonographic abnormalities. This exceeds the risk currently accepted for prenatal diagnostic procedures. 22 Because one of our cases had no sonographic defect at 16 weeks but was abnormal at 19 weeks, it is possible that some of the subtle abnormalities associated with trisomy 18 are not apparent in the early part of the second trimester. Because of this, we recommend the following approach to the management of patients with second-trimester choroid plexus cysts. (l) If the gestational age is earlier than 19 weeks, the sonogram should be repeated at 19 weeks or later by a sonologist familiar with fetal malformations associated with aneuploidy. (2) If the fetus is at least 19 weeks and no other anatomic defects are identified sonographically, amniocentesis should not be necessary. REFERENCES I. Chudleigh P, Pearce JM, Campbell S. The prenatal diagnosis of transient cysts of the fetal choroid plexus. Prenat Diagn 1984;4: 135. 2. Chan L, Hixson JL, Laifer SA, et al. A sonographic and karyotypic study of second-trimester fetal choroid plexus cysts. Obstet Gynecol 1989;73:703. 3. Benacerraf BR, Laboda L. Cyst of the fetal choroid
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4. 5. 6. 7. 8.
9. 10. II. 12.
plexus: a normal variant? AM J OBSTET GYNECOL 1989; 160:319. Clark SL, DeVore GR, Sabey PL. Prenatal diagnosis of cysts of the fetal choroid plexus. Obstet Gynecol 1988; 72:585. DeRoo TR, Harris RD, Sargent SK, et al. Fetal choroid plexus cysts: prevalence, clinical significance, and sonographic appearance. AJR 1988;151:1179. Benacerraf BR. Asymptomatic cysts of the fetal choroid plexus in the second trimester. J Ultrasound Med 1987; 6:475. Friday RO, Schwartz DB, Tuffli GA. Spontaneous intrauterine resolution of intraventricular cystic masses. J Ultrasound Med 1985;4:385. Chitkara U, Cogswell C, Norton K, et al. Choroid plexus cysts in the fetus: a benign anatomic variant or pathologic entity? Report of 41 cases and review of the literature. Obstet Gynecol 1988;72: 185. Farhood AI, MorrisJH, Bieber FR. Transient cysts of the fetal choroid plexus: morphology and histogenesis. AmJ Med Genet 1987;27;977. Hertzberg BS, Kay HH, Bowie JD. Fetal choroid plexus lesions: relationship of antenatal sonographic appearance to clinical outcome. J Ultrasound Med 1989;8:77. Nicolaides KH, Rodek CH, Gosden CM. Rapid karyotyping in non-lethal fetal malformation. Lancet 1986; I :283. Bundy AL, Saltzman DH, Pober B, et al. Antenatal sonographic findings in trisomy 18. J Ultrasound Med 1986;5:361.
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13. Fitzsimmons J, Wilson D, Pascoe-Mason J, et al. Choroid plexus cysts in fetuses with trisomy 18. Obstet Gynecol 1989;73:257. 14. Jones KL. Smith's recognizable patterns of human malformation, 4th ed. Philadelphia: WB Saunders, 1988:16. 15. Giorgi C. Symptomatic cyst of the choroid plexus of the lateral ventricle. Neurosurgery 1979;5:53. 16. Fakhry J, Schechter A, Tenner MS, et al. Cysts of the choroid plexus in neonates: documentation and review of the literature. J Ultrasound Med 1985;4;561. 17. Benacerraf BR, Miller WA, Frigoletto FD. Sonographic detection of fetuses with trisomy 13 and 18: accuracy and limitations. AMJ OBSTET GYNECOL 1988;158:404. 18. Benacerraf BR. The antenatal sonographic diagnosis of congenital clubfoot: a possible indication for amniocentesis. J Clin Ultrasound 1986;14:703. 19. Benacerraf BR, Adzick S. Fetal diaphragmatic hernia: ultrasound diagnosis and clinical outcome in 19 cases. AM J OBSTET GYNECOL 1987;156:573. 20. Crandall BF, Howard J, Lebherz TB, et al. Follow-up of 2000 second trimester amniocentesis. Obstet Gynecol 1980;56:625. 21. Hanson FW, Tennant FR, Zorn EM, etal. Analysisof2136 genetic amniocentesis: experience of a single physician. AM J OBSTET GYNECOL 1985; 152:436. 22. Palomaki GE, Haddow .lE. Maternal serum a-fetoprotein, age, and Down syndrome risk. AM .l OBSTET GYNECOL 1987; 156:460.
Significance of observing no fluid at amniotomy Maurice L. Druzin, MD, and Diana M. Adams, MD New York, New York Thirty patients with oligohydramnios observed at artificial rupture of membranes were studied to determine the significance of this finding. Fifteen were subsequently found to have meconium-stained amniotic fluid and 21 had abnormal fetal heart rate tracings. This clinical observation warrants close intrapartum surveillance and preparation for delivery. (AM J OBSTET GVNECOL 1990;162:1006-7.)
Key words: Meconium, amniotomy, oligohydramnios Patients in labor often undergo artificial rupture of membranes (AROM), and the quantity and nature of amniotic fluid are considered important. In some cases no fluid is noted after AROM. Both oligohydramnios and meconium-stained amniotic fluid are associated with increased perinatal morbidity. The clinical significance of no fluid at AROM was evaluated. From the Department of Obstetrics and Gynecology, The New York Hospital-Cornell Medical Center. Received for publication September 20, 1989; accepted October 11, 1989. Reprint requests: Maurice L. Druzin, MD, 525 E. 68th St., Room M-036, New York, NY 10021. 611 117365
1006
Material and methods Thirty consecutive patients between April 1987 and August 1988 were observed by their physician to have no fluid at AROM. All patients had completed 259 days' (37 weeks) gestation, and the mean gestational age was 283.6 ± 10.9 days (40.5 weeks). Three (10%) patients were ~42 weeks' gestation, and 22 (73.3%) >40 weeks' gestation. Prior spontaneous rupture of membranes was ruled out by history and phsyical examination. At the time of the initial observation the patient's names were recorded. After delivery all 30 charts were analyzed. Abnormal fetal heart rate (FHR) patterns (fetal stress) included recurrent moderate (30 to 60 seconds duration) variable decelerations, recurrent severe (>60 seconds duration) variable decelera-