- Email: [email protected]
Factors associated with fetal demise in fetal echogenic bowel
Factors associated with fetal demise in fetal echogenic bowel Huda B. Al-Kouatly, MD, Stephen T. Chasen, MD, Amer K. Karam, MD, Regine Ahner, MD, and Frank A. Chervenak, MD New York, NY OBJECTIVE: The purpose of this study was to determine risk factors associated with intrauterine fetal demise in fetuses with unexplained echogenic bowel that is diagnosed in the second trimester. STUDY DESIGN: A retrospective case-control study compared fetuses with echogenic bowel and fetal demise with fetuses with echogenic bowel who were live born. Fetuses affected with cystic fibrosis, aneuploidy, or congenital infection and fetuses diagnosed with major anomalies were excluded. Variables examined in the determination of risk factors for intrauterine fetal demise included intrauterine growth restriction, oligohydramnios, elevated maternal serum alpha-fetoprotein levels, and elevated maternal serum β-hCG levels. Statistical analysis was performed with the Fisher exact test, Student t test, and logistic regression analysis. RESULTS: One hundred fifty-six fetuses met the inclusion criteria. There were 9 cases of intrauterine fetal demise and 147 live born control fetuses. The median gestational age of intrauterine fetal demise was 22.0 weeks (range, 17-39 weeks). Intrauterine growth restriction occurred more frequently in cases of intrauterine fetal demise than in live born infants (22.2% vs 0.7%; P = .009), as did oligohydramnios (44.4% vs 2.0%; P < .001) and elevated maternal serum alpha-fetoprotein levels (80.0% vs 7.7%; P = .001). With the use of logistic regression analysis, elevated maternal serum alpha-fetoprotein was the strongest independent risk factor that was associated with intrauterine fetal demise (odds ratio, 39.48; 95% CI, 11.04%-141.25%). CONCLUSION: In our series, there was a 5.8% incidence of intrauterine fetal demise in fetuses with unexplained echogenic bowel. Elevated maternal serum alpha-fetoprotein is the strongest predictor of fetal demise in fetal echogenic bowel. (Am J Obstet Gynecol 2001;185:1039-43.)
Key words: Echogenic bowel, fetal demise, maternal serum alpha-fetoprotein, oligohydramnios, growth restriction
There are few studies in the literature that address the risk factors for intrauterine fetal demise (IUFD) in fetuses with echogenic bowel and absent major congenital anomalies. The range of the rate of fetal demise that has been reported in previous studies is 3.8% to 8.0%.1-7 The associated factors for fetal demise that have been mentioned in previous studies are intrauterine growth restriction (IUGR) and elevated maternal serum alpha-fetoprotein (MSAFP) levels.2-5, 7, 8 Risk factors for fetal demise have been addressed as a separate study so far only by Achiron et al.8 Our objective was to determine the risk factors that are associated with IUFD in second trimester fetuses with unexplained echogenic bowel. From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, New York Presbyterian Hospital-Weill Medical College of Cornell University. Presented at the Twenty-first Annual Meeting of the Society for MaternalFetal Medicine, Reno, Nev, February 5-10, 2001. Reprints not available from author. Correspondence: Huda B. Al-Kouatly, MD, New York Hospital-Weill Medical College of Cornell University, Department of Obstetrics and Gynecology, 525 East 68th St, J-130, New York, NY 10021. E-mail: [email protected]. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/6/117641 doi:10:1067/mob.2001.117641
Material and methods All cases of fetal echogenic bowel that were diagnosed in our ultrasound unit from 1993 to 2000 were identified. Our study population included only those pregnant patients who received prenatal care and planned delivery at our institution. Patients who were referred from other hospitals or who did not deliver at our institution were excluded. Cases with associated major fetal anomalies that were diagnosed with ultrasound scanning were excluded. Fetuses with minor anomalies like club foot or other sonographic findings of aneuploidy (such as choroid plexus cysts or echogenic intracardiac foci) were included. Patients who were diagnosed with fetal echogenic bowel after 24 weeks of gestation and patients who underwent intrauterine transfusion were excluded. Pregnancy terminations were excluded. Only cases in which bowel echogenicity was as bright or brighter than the adjacent bone, with the use of appropriate gain settings, were included. To accomplish this, the sonographic images were reviewed separately by a sonographer and a perinatologist, neither of whom had knowledge of fetal outcome. Cases in which echogenicity was less than that of bone were excluded. Interobserver differences in the assessment of echogenicity was determined. Cases in 1039
1040 Al-Kouatly et al
which the images were unclear or unavailable for review were excluded. Ultrasound examinations were performed with Acuson equipment (128 XP/4 and 128 XP/10; Acuson, Mountain View, Calif) with curvilinear 3.5 or 5.0 MHz transducers. We offer routinely complete anatomic survey for all our patients. Our standard for the evaluation of the fetal abdomen with echogenic bowel was by serial transverse, sagittal, and coronal sections. If the bowel still looks as bright as bone or brighter with the minimal gain needed to visualize the adjacent bone, then we diagnose echogenic bowel. Echogenicity was classified as either focal or multifocal. Focal was defined as an isolated contiguous region of echogenicity within the fetal abdomen; multifocal was defined as more than 1 echogenic focus noted in separate regions of the fetal abdomen. Prominent bowel loops were defined as fluid-filled loops of bowel that were highlighted within echogenic walls. Pregnancy outcomes and neonatal outcomes were determined by a review of medical records. Our recommendation for patients who were diagnosed with fetal echogenic bowel is to offer amniocentesis, parental DNA cystic fibrosis testing, and maternal serologic testing for cytomegalovirus and toxoplasmosis. Cases that were affected with cystic fibrosis, aneuploidy, and congenital infection were excluded. Cases of IUFD were identified. Our control group consisted of those fetuses that were diagnosed with echogenic bowel who were live born. Neonates with congenital anomalies that were identified at birth were excluded. Variables that were examined in the determination of risk factors for IUFD in fetuses with echogenic bowel included IUGR and oligohydramnios (which were diagnosed at the same ultrasound examination in which echogenic bowel was detected), elevated MSAFP levels, and elevated maternal serum ß-hCG levels. We defined IUGR as an estimated fetal weight of less than the 10th percentile for a given gestational age. Oligohydramnios was defined subjectively by experienced sonographers. Both elevated MSAFP and elevated ß-hCG levels were defined as >2.50 multiples of median. Placental pathologic features of fetuses with IUFD were reviewed, when available, for the presence or absence of placental infarcts. Maternal history of first trimester bleeding or evidence of subchorionic collection by ultrasound examination was recorded. Statistical comparison was performed with the Fisher exact test and Student t test; a probability value of <.05 was considered statistically significant. Logistic regression analysis was performed to account for confounding variables with the use of the SPSS 9.0 calculation package (SPSS, Inc, Chicago, Ill). Results Echogenic bowel was diagnosed in 318 fetuses in 314 pregnant patients during the study period. One hundred fifty-six fetuses in 152 pregnancies met the inclusion cri-
November 2001 Am J Obstet Gynecol
Table I. Indications for ultrasound scan at the time that echogenic bowel was diagnosed Indication Anatomy Amniocentesis Abnormal triple screen Bleeding Preterm labor TOTAL
Frequency
Percent
107 27 16 1 1 152
70.4 17.8 10.4 0.7 0.7 100.0
Table II. Demographic characteristics and gestational age of echogenic bowel diagnosis between cases and live born control subjects Characteristic
Demise (n = 9)
Control subjects (n = 147)
Maternal age* (y) 31.3 ± 5.1 32.7 ± 5.3 Class† Private (n) 6/9 (66.7%) 126/143 (88.1%) Clinic (n) 3/9 (33.3%) 17/143 (11.9%) Ethnic background† White (n) 2/7 (28.6%) 107/138 (77.5%) Nonwhite (n) 5/7 (71.4%) 31/138 (22.5%) Gestational age at diagnosis* (wk) 17.3 ± 2.1 18.6 ± 1.9
P value .44 .098
.011 .046
*P < .05 was considered significant, determined by Student t test. †P < .05 was considered significant, determined by the Fisher exact test.
teria. The incidence of echogenic bowel in our patient population was 0.7%. The indications for ultrasound examination at the time echogenic bowel was diagnosed for these patients are shown in Table I. The reasons for the exclusion of 162 pregnancies were as follows: patients referred from other institutions (89 patients), images unavailable or unclear (26 patients), bowel echogenicity not as bright as bone (12 patients), major structural anomalies (9 patients), aneuploidy (5 patients), cystic fibrosis (5 patients), congenital cytomegalovirus infection (1 patient), diagnosis after 24 weeks (4 patients), fetuses that required intrauterine transfusion (3 patients), pregnancies that were not delivered at our hospital (4 patients), pregnancy terminations (3 patients; 1 termination for club foot and 2 terminations for IUGR, oligohydramnios, and elevated MSAFP levels), and congenital anomalies that were identified at birth (1 patient). In the first 80 cases, images were reviewed for bowel echogenicity by 2 examiners, with 95% interobserver concordance. Because of the high rate of concordance, subsequent films were evaluated by only 1 examiner. Of 156 fetuses with echogenic bowel, there were 9 cases of IUFD for an incidence of 5.8%. Six cases involved singleton pregnancies; fetal death occurred in a single fetus with second trimester echogenic bowel in 2 twin pregnancies and in 1 triplet pregnancy. Thus, the control group of live-born infants included 147 fetuses. One hundred
Al-Kouatly et al 1041
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Table III. Characteristics of fetuses with echogenic bowel who experienced IUFD and the risk factors for demise Patient 1 2 3 4 5 6‡ 7§ 8§ 9
Maternal GA at echogenic age (y) bowel diagnosis (wk) 38 34 33 30 24 30 35 23 35
16.0 20.0 17.0 14.0 17.0 20.0 15.0 19.0 18.0
IUGR
Oligohydramnios
GA of fetal demise (wk)
No Yes No No No No No Yes No
Yes Yes No Yes No No No Yes No
22.0 22.0 19.0 17.0 25.0 32.0 39.0 26.0 20.0
MSAFP ∆ weeks* level† (MoM) 6.0 2.0 2.0 3.0 8.0 12.0 24.0 7.0 2.0
Not done 6.4 5.0 > 23 3.53 Not done Not done Not done 0.86
ß-hCG level† (MoM)
Placental infarcts
Not done 0.28 1.22 NA 6.94 Not done Not done Not done 0.944
Yes NA Yes Yes Yes Yes Yes Yes NA
GA, Gestational age; MoM, multiples of the median; NA, not available. *The difference between the gestational age at which echogenic bowel was diagnosed by ultrasound scan and the gestational age of fetal demise. †Multiples of the median. ‡Triplet gestation. §Twin gestation.
twenty-four patients underwent prenatal cytogenetic testing. One hundred twenty-four mothers and 75 fathers underwent cystic fibrosis testing. One hundred one patients underwent cytomegalovirus serologic testing. Table II compares the demographic characteristics and gestational age at diagnosis of echogenic bowel between case patients and control subjects. The mean maternal age was similar between case patients and control subjects. A higher proportion of mothers with IUFD were nonwhite compared with control subjects (71.4% vs 22.5%; P = .011). Echogenic bowel was also diagnosed at an earlier gestational age in cases of IUFD than in control subjects (17.3 ± 2.1 weeks vs 18.6 ± 1.9 weeks; P = .046). Table III depicts the characteristics of the 9 fetuses who died in utero and the risk factors that were associated with the deaths. The median gestational age at the time of fetal demise was 22.0 weeks (range, 17-39 weeks). The median interval between the gestational age at diagnosis of echogenic bowel and IUFD was 6 weeks (range, 2-24 weeks). Only 1 of these patients had an additional finding (a unilateral clubfoot) on ultrasound examination. Of the 9 cases of IUFD, IUGR was suspected in 2 cases and oligohydramnios was present in 4 cases, all of which were identified at the same ultrasound examination in which echogenic bowel was diagnosed. Follow-up ultrasound examination revealed IUGR in 2 other patients, 3 weeks after echogenic bowel was diagnosed. Oligohydramnios was noted in 1 additional patient, at 29 weeks of gestation. MSAFP level was elevated in 4 of 5 mothers who were tested. ß-hCG level was elevated in 1 of 4 mothers who were tested. Table IV depicts the risk factors that were identified in the cases with IUFD compared with the live born control subjects. IUGR was present more frequently in cases of IUFD than in live born fetuses (22.2% vs 0.7%; P = .009), as was oligohydramnios (44.4% vs 2.0%; P < .001) and elevated MSAFP levels (80.0% vs 7.7%; P = .001). Elevated ß-hCG level was not significantly more common in cases of IUFD. Logistic regression analysis was used to determine
Table IV. The risk factors for demise in those cases with IUFD versus live born control subjects Risk factors for demise IUGR (%) Oligohydramnios (%) Elevated MSAFP level (%)† Elevated β-hCG level (%)†
Fetuses with demise (n = 9)
Live born infants (n = 147)
P value*
22.2 (2/9)
0.7 (1/147)
.009
44.4 (4/9)
2.0 (3/147)
<.001
80.0 (4/5)
7.7 (6/78)
.001
25.0 (1/4)
9.3 (7/75)
.353
*Determined by the Fisher exact test for comparison of categoric variables; P < .05 was considered significant. †Serum screening was not performed for all patients.
Table V. Logistic regression analysis of the risk factors for fetal demise in fetuses who were diagnosed with echogenic bowel Risk factor IUGR Oligohydramnios Elevated MSAFP level
Odds ratio
95% CI
5.18 9.51 39.48
0.18-152.15 (NS) 1.79-50.64 11.04-141.25
NS, Not significant.
independent risk factors for IUFD. The variables entered into the logistic regression analysis were IUGR, oligohydramnios, and MSAFP level. Oligohydramnios and elevated MSAFP levels were found to be independently associated with IUFD, as shown in Table V. The strongest predictor factor for demise was an elevated MSAFP level (odds ratio, 39.48; 95% CI, 11.04%-141.25%). Not all 9 patients who had IUFD underwent an amniocentesis. Only 4 patients underwent amniocentesis; the gestational age difference between the time that the amniocentesis was performed and the demise was 3, 8, 12, and 23 weeks. Fetal tissue karyotype was performed on 3 other cases with IUFD, and the test results were normal.
1042 Al-Kouatly et al
Fetal death occurred in 2 patients in the third trimester. Patient 6 had a trichorionic triamnionic triplet gestation with severe preeclampsia, and patient 7 had a dichorionic diamnionic twin gestation with no complications. The 2 other triplet fetuses and the twin fetus also had echogenic bowel and were normal live born infants. There was no difference in the pattern of bowel echogenicity between fetuses with IUFD and live born control subjects. Bowel echogenicity was multifocal in 66.6% of fetuses with IUFD and 81.0% of the live born group (P = .383). Bowel loops were not more prominent in the IUFD group compared with live born control infants (11.1% vs 10.2%; P = 1.0). Seven mothers underwent dilatation and evacuation. Autopsy was available in 5 cases and did not show evidence of anomalies, although examination was limited by fetal fragmentation. Detailed autopsy for the 32-week IUFD showed no anomalies, and gross examination of the 39-week IUFD was normal. Placental examination was performed on 7 of the 9 fetuses with fetal demise, as shown in Table III. There was evidence of placental infarcts in all 7 placentas that were examined. Because placental examination was performed mainly for clinical indications (such as IUFD), we cannot comment on the rate of placental infarction in control subjects. Maternal history of first trimester bleeding or evidence of subchorionic collection by ultrasound examination was not different between the case patients with IUFD and the live born control infants (11.1% vs 17.7%; P = 1.0). Comment The prenatal diagnosis of fetal echogenic bowel in the absence of major anomalies, aneuploidy, cystic fibrosis, and congenital infection is associated with a high incidence of IUFD. Our 5.8% incidence of IUFD with fetal echogenic bowel could be an underestimate because there were 2 pregnancy terminations because of IUGR, oligohydramnios, and elevated MSAFP levels. Had these patients continued their pregnancies, IUFD was likely. In fetuses with echogenic bowel, the presence of IUGR, oligohydramnios, or elevated MSAFP levels was associated with fetal demise. The strongest association was with elevated MSAFP levels. No specific pattern of bowel echogenicity was associated with IUFD. IUFD is an uncommon event, but it is more common in multiple gestations than in singleton gestations. Fetal surveillance in the third trimester was not recommended for cases of isolated echogenic bowel alone. We did recommend fetal surveillance in those cases that were associated with oligohydramnios, IUGR, elevated MSAFP levels, or other standard indications. We can only speculate about the reason that echogenic bowel occurs before demise. Possible explanations include uteroplacental ischemia and intra-amniotic bleeding. Because there was evidence of placental infarcts in
November 2001 Am J Obstet Gynecol
the 7 placentas that were examined, a placental abnormality may explain the association between elevated MSAFP level, growth restriction, oligohydramnios, and echogenic bowel. The elevation of MSAFP levels in these cases could be due to an alteration of the maternalplacental barrier. Placental infarcts could lead to placental and fetal hypoperfusion, which could subsequently lead to oligohydramnios and growth restriction. Fetal redistribution of blood flow may contribute to gut ischemia that could manifest itself as echogenic bowel. Only 1 mother of the 9 cases of IUFD reported vaginal bleeding and had a 1.2- × 2.9-cm subchorionic collection noted on ultrasound examination. The absence of a history of vaginal bleeding in the remaining 8 cases does not exclude intra-amniotic bleeding. Objective determination of intra-amniotic bleeding has been shown to be associated with echogenic bowel.9 One strength of our study is our rigid inclusion criteria. Twenty-eight percent of the patients who were diagnosed in our ultrasound unit with fetal echogenic bowel were excluded because they were referred from other institutions or for a second opinion. Because these patients may be at risk for adverse outcomes, the exclusion of these cases avoided an overestimate of the actual incidence of IUFD in fetuses that were diagnosed with echogenic bowel. Another strength is our large sample size and the inclusion of only those cases in which bowel echogenicity was as bright as bone. Cases with lesser degrees of echogenicity that are less likely to involve abnormalities were not included in our series.10 Limitations to our study include the exclusion of a significant number of patients (8.2%) because their ultrasound images were unavailable or unclear. Serum screening was also not performed in 4 of the 9 fetuses with demise. This limited the logistic regression analysis, because those cases not undergoing serum screening were not included. It is thus not clear whether the strong association between elevated MSAFP level and IUFD in these fetuses would be applicable to the entire cohort. Testing for aneuploidy, cystic fibrosis, and congenital infection were not performed on all cases. Routine examination of all neonates was performed, and there were no morphologic abnormalities suggestive of aneuploidy, so we are confident that no cases of aneuploidy were missed in the control group. It is possible that there were some cases of cystic fibrosis or congenital infection that were missed. In conclusion, most fetuses with echogenic bowel and absent major congenital anomalies in the second trimester that are not affected by aneuploidy, cystic fibrosis, or congenital infection will be liveborn. When IUGR, oligohydramnios, or elevated MSAFP level is present, however, there is a significant risk of fetal demise. It is unclear whether these demises can be prevented by serial ultrasound examinations and antepartum fetal surveillance. This information is useful in counseling patients
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with second-trimester echogenic bowel and elevated MSAFP levels. REFERENCES
1. Yaron Y, Hassan S, Geva E, Kupferminc MJ, Yavetz H, Evans MI. Evaluation of fetal echogenic bowel in the second trimester. Fetal Diagn Ther 1999;14:176-80. 2. MacGregor SN, Tamura R, Sabbagha R, Brenhofer JK, Kambich MP, Pergament E. Isolated hyperechoic fetal bowel: significance and implications for management. Am J Obstet Gynecol 1995;173:1254-8. 3. Bromley B, Doubilet P, Frigoletto FD, Krauss C, Estroff JA, Benacerraf BR. Is fetal hyperechoic bowel on second-trimester sonogram an indication for amniocentesis? Obstet Gynecol 1994;83:647-51. 4. Nyberg DA, Dubinsky T, Resta RG, Mahony BS, Hickok DE, Luthy DA. Echogenic fetal bowel during the second trimester: clinical importance. Radiology 1993;188:527-31.
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5. Ghose I, Mason GC, Martinez D, Harrison KL, Evans JA, Ferriman EL, et al. Hyperechogenic fetal bowel: a prospective analysis of sixty consecutive cases. Br J Obstet Gynaecol 2000;107:426-9. 6. Muller F, Dommergues M, Aubry MC, Simon-Bouy B, Gautier E, Oury JF, et al. Hyperechogenic fetal bowel: an ultrasonographic marker for adverse fetal and neonatal outcome. Am J Obstet Gynecol 1995;173:508-13. 7. Strocker AM, Snijders RJ, Carlson DE, Greene N, Gregory KD, Walla CA, et al. Fetal echogenic bowel: parameters to be considered in differential diagnosis. Ultrasound Obstet Gynecol 2000;16:519-23. 8. Achiron R, Seidman DS, Horowitz A, Mashiach S, Goldman B, Lipitz S. Hyperechogenic fetal bowel and elevated serum alpha-fetoprotein: a poor fetal prognosis. Obstet Gynecol 1996;88:368-71. 9. Sepulveda W, Reid R, Nicolaidis P, Prendiville O, Chapman RS, Fisk NM. Second-trimester echogenic bowel and intraamniotic bleeding: association between fetal bowel echogenicity and amniotic fluid spectrophotometry at 410nm. Am J Obstet Gynecol 1996;174:839-42. 10. Slotnick RN, Abuhamad AZ. Prognostic implications of fetal echogenic bowel. Lancet;347:85-7.
Key words: Echogenic bowel, fetal demise, maternal serum alpha-fetoprotein, oligohydramnios, growth restriction
There are few studies in the literature that address the risk factors for intrauterine fetal demise (IUFD) in fetuses with echogenic bowel and absent major congenital anomalies. The range of the rate of fetal demise that has been reported in previous studies is 3.8% to 8.0%.1-7 The associated factors for fetal demise that have been mentioned in previous studies are intrauterine growth restriction (IUGR) and elevated maternal serum alpha-fetoprotein (MSAFP) levels.2-5, 7, 8 Risk factors for fetal demise have been addressed as a separate study so far only by Achiron et al.8 Our objective was to determine the risk factors that are associated with IUFD in second trimester fetuses with unexplained echogenic bowel. From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, New York Presbyterian Hospital-Weill Medical College of Cornell University. Presented at the Twenty-first Annual Meeting of the Society for MaternalFetal Medicine, Reno, Nev, February 5-10, 2001. Reprints not available from author. Correspondence: Huda B. Al-Kouatly, MD, New York Hospital-Weill Medical College of Cornell University, Department of Obstetrics and Gynecology, 525 East 68th St, J-130, New York, NY 10021. E-mail: [email protected]. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/6/117641 doi:10:1067/mob.2001.117641
Material and methods All cases of fetal echogenic bowel that were diagnosed in our ultrasound unit from 1993 to 2000 were identified. Our study population included only those pregnant patients who received prenatal care and planned delivery at our institution. Patients who were referred from other hospitals or who did not deliver at our institution were excluded. Cases with associated major fetal anomalies that were diagnosed with ultrasound scanning were excluded. Fetuses with minor anomalies like club foot or other sonographic findings of aneuploidy (such as choroid plexus cysts or echogenic intracardiac foci) were included. Patients who were diagnosed with fetal echogenic bowel after 24 weeks of gestation and patients who underwent intrauterine transfusion were excluded. Pregnancy terminations were excluded. Only cases in which bowel echogenicity was as bright or brighter than the adjacent bone, with the use of appropriate gain settings, were included. To accomplish this, the sonographic images were reviewed separately by a sonographer and a perinatologist, neither of whom had knowledge of fetal outcome. Cases in which echogenicity was less than that of bone were excluded. Interobserver differences in the assessment of echogenicity was determined. Cases in 1039
1040 Al-Kouatly et al
which the images were unclear or unavailable for review were excluded. Ultrasound examinations were performed with Acuson equipment (128 XP/4 and 128 XP/10; Acuson, Mountain View, Calif) with curvilinear 3.5 or 5.0 MHz transducers. We offer routinely complete anatomic survey for all our patients. Our standard for the evaluation of the fetal abdomen with echogenic bowel was by serial transverse, sagittal, and coronal sections. If the bowel still looks as bright as bone or brighter with the minimal gain needed to visualize the adjacent bone, then we diagnose echogenic bowel. Echogenicity was classified as either focal or multifocal. Focal was defined as an isolated contiguous region of echogenicity within the fetal abdomen; multifocal was defined as more than 1 echogenic focus noted in separate regions of the fetal abdomen. Prominent bowel loops were defined as fluid-filled loops of bowel that were highlighted within echogenic walls. Pregnancy outcomes and neonatal outcomes were determined by a review of medical records. Our recommendation for patients who were diagnosed with fetal echogenic bowel is to offer amniocentesis, parental DNA cystic fibrosis testing, and maternal serologic testing for cytomegalovirus and toxoplasmosis. Cases that were affected with cystic fibrosis, aneuploidy, and congenital infection were excluded. Cases of IUFD were identified. Our control group consisted of those fetuses that were diagnosed with echogenic bowel who were live born. Neonates with congenital anomalies that were identified at birth were excluded. Variables that were examined in the determination of risk factors for IUFD in fetuses with echogenic bowel included IUGR and oligohydramnios (which were diagnosed at the same ultrasound examination in which echogenic bowel was detected), elevated MSAFP levels, and elevated maternal serum ß-hCG levels. We defined IUGR as an estimated fetal weight of less than the 10th percentile for a given gestational age. Oligohydramnios was defined subjectively by experienced sonographers. Both elevated MSAFP and elevated ß-hCG levels were defined as >2.50 multiples of median. Placental pathologic features of fetuses with IUFD were reviewed, when available, for the presence or absence of placental infarcts. Maternal history of first trimester bleeding or evidence of subchorionic collection by ultrasound examination was recorded. Statistical comparison was performed with the Fisher exact test and Student t test; a probability value of <.05 was considered statistically significant. Logistic regression analysis was performed to account for confounding variables with the use of the SPSS 9.0 calculation package (SPSS, Inc, Chicago, Ill). Results Echogenic bowel was diagnosed in 318 fetuses in 314 pregnant patients during the study period. One hundred fifty-six fetuses in 152 pregnancies met the inclusion cri-
November 2001 Am J Obstet Gynecol
Table I. Indications for ultrasound scan at the time that echogenic bowel was diagnosed Indication Anatomy Amniocentesis Abnormal triple screen Bleeding Preterm labor TOTAL
Frequency
Percent
107 27 16 1 1 152
70.4 17.8 10.4 0.7 0.7 100.0
Table II. Demographic characteristics and gestational age of echogenic bowel diagnosis between cases and live born control subjects Characteristic
Demise (n = 9)
Control subjects (n = 147)
Maternal age* (y) 31.3 ± 5.1 32.7 ± 5.3 Class† Private (n) 6/9 (66.7%) 126/143 (88.1%) Clinic (n) 3/9 (33.3%) 17/143 (11.9%) Ethnic background† White (n) 2/7 (28.6%) 107/138 (77.5%) Nonwhite (n) 5/7 (71.4%) 31/138 (22.5%) Gestational age at diagnosis* (wk) 17.3 ± 2.1 18.6 ± 1.9
P value .44 .098
.011 .046
*P < .05 was considered significant, determined by Student t test. †P < .05 was considered significant, determined by the Fisher exact test.
teria. The incidence of echogenic bowel in our patient population was 0.7%. The indications for ultrasound examination at the time echogenic bowel was diagnosed for these patients are shown in Table I. The reasons for the exclusion of 162 pregnancies were as follows: patients referred from other institutions (89 patients), images unavailable or unclear (26 patients), bowel echogenicity not as bright as bone (12 patients), major structural anomalies (9 patients), aneuploidy (5 patients), cystic fibrosis (5 patients), congenital cytomegalovirus infection (1 patient), diagnosis after 24 weeks (4 patients), fetuses that required intrauterine transfusion (3 patients), pregnancies that were not delivered at our hospital (4 patients), pregnancy terminations (3 patients; 1 termination for club foot and 2 terminations for IUGR, oligohydramnios, and elevated MSAFP levels), and congenital anomalies that were identified at birth (1 patient). In the first 80 cases, images were reviewed for bowel echogenicity by 2 examiners, with 95% interobserver concordance. Because of the high rate of concordance, subsequent films were evaluated by only 1 examiner. Of 156 fetuses with echogenic bowel, there were 9 cases of IUFD for an incidence of 5.8%. Six cases involved singleton pregnancies; fetal death occurred in a single fetus with second trimester echogenic bowel in 2 twin pregnancies and in 1 triplet pregnancy. Thus, the control group of live-born infants included 147 fetuses. One hundred
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Table III. Characteristics of fetuses with echogenic bowel who experienced IUFD and the risk factors for demise Patient 1 2 3 4 5 6‡ 7§ 8§ 9
Maternal GA at echogenic age (y) bowel diagnosis (wk) 38 34 33 30 24 30 35 23 35
16.0 20.0 17.0 14.0 17.0 20.0 15.0 19.0 18.0
IUGR
Oligohydramnios
GA of fetal demise (wk)
No Yes No No No No No Yes No
Yes Yes No Yes No No No Yes No
22.0 22.0 19.0 17.0 25.0 32.0 39.0 26.0 20.0
MSAFP ∆ weeks* level† (MoM) 6.0 2.0 2.0 3.0 8.0 12.0 24.0 7.0 2.0
Not done 6.4 5.0 > 23 3.53 Not done Not done Not done 0.86
ß-hCG level† (MoM)
Placental infarcts
Not done 0.28 1.22 NA 6.94 Not done Not done Not done 0.944
Yes NA Yes Yes Yes Yes Yes Yes NA
GA, Gestational age; MoM, multiples of the median; NA, not available. *The difference between the gestational age at which echogenic bowel was diagnosed by ultrasound scan and the gestational age of fetal demise. †Multiples of the median. ‡Triplet gestation. §Twin gestation.
twenty-four patients underwent prenatal cytogenetic testing. One hundred twenty-four mothers and 75 fathers underwent cystic fibrosis testing. One hundred one patients underwent cytomegalovirus serologic testing. Table II compares the demographic characteristics and gestational age at diagnosis of echogenic bowel between case patients and control subjects. The mean maternal age was similar between case patients and control subjects. A higher proportion of mothers with IUFD were nonwhite compared with control subjects (71.4% vs 22.5%; P = .011). Echogenic bowel was also diagnosed at an earlier gestational age in cases of IUFD than in control subjects (17.3 ± 2.1 weeks vs 18.6 ± 1.9 weeks; P = .046). Table III depicts the characteristics of the 9 fetuses who died in utero and the risk factors that were associated with the deaths. The median gestational age at the time of fetal demise was 22.0 weeks (range, 17-39 weeks). The median interval between the gestational age at diagnosis of echogenic bowel and IUFD was 6 weeks (range, 2-24 weeks). Only 1 of these patients had an additional finding (a unilateral clubfoot) on ultrasound examination. Of the 9 cases of IUFD, IUGR was suspected in 2 cases and oligohydramnios was present in 4 cases, all of which were identified at the same ultrasound examination in which echogenic bowel was diagnosed. Follow-up ultrasound examination revealed IUGR in 2 other patients, 3 weeks after echogenic bowel was diagnosed. Oligohydramnios was noted in 1 additional patient, at 29 weeks of gestation. MSAFP level was elevated in 4 of 5 mothers who were tested. ß-hCG level was elevated in 1 of 4 mothers who were tested. Table IV depicts the risk factors that were identified in the cases with IUFD compared with the live born control subjects. IUGR was present more frequently in cases of IUFD than in live born fetuses (22.2% vs 0.7%; P = .009), as was oligohydramnios (44.4% vs 2.0%; P < .001) and elevated MSAFP levels (80.0% vs 7.7%; P = .001). Elevated ß-hCG level was not significantly more common in cases of IUFD. Logistic regression analysis was used to determine
Table IV. The risk factors for demise in those cases with IUFD versus live born control subjects Risk factors for demise IUGR (%) Oligohydramnios (%) Elevated MSAFP level (%)† Elevated β-hCG level (%)†
Fetuses with demise (n = 9)
Live born infants (n = 147)
P value*
22.2 (2/9)
0.7 (1/147)
.009
44.4 (4/9)
2.0 (3/147)
<.001
80.0 (4/5)
7.7 (6/78)
.001
25.0 (1/4)
9.3 (7/75)
.353
*Determined by the Fisher exact test for comparison of categoric variables; P < .05 was considered significant. †Serum screening was not performed for all patients.
Table V. Logistic regression analysis of the risk factors for fetal demise in fetuses who were diagnosed with echogenic bowel Risk factor IUGR Oligohydramnios Elevated MSAFP level
Odds ratio
95% CI
5.18 9.51 39.48
0.18-152.15 (NS) 1.79-50.64 11.04-141.25
NS, Not significant.
independent risk factors for IUFD. The variables entered into the logistic regression analysis were IUGR, oligohydramnios, and MSAFP level. Oligohydramnios and elevated MSAFP levels were found to be independently associated with IUFD, as shown in Table V. The strongest predictor factor for demise was an elevated MSAFP level (odds ratio, 39.48; 95% CI, 11.04%-141.25%). Not all 9 patients who had IUFD underwent an amniocentesis. Only 4 patients underwent amniocentesis; the gestational age difference between the time that the amniocentesis was performed and the demise was 3, 8, 12, and 23 weeks. Fetal tissue karyotype was performed on 3 other cases with IUFD, and the test results were normal.
1042 Al-Kouatly et al
Fetal death occurred in 2 patients in the third trimester. Patient 6 had a trichorionic triamnionic triplet gestation with severe preeclampsia, and patient 7 had a dichorionic diamnionic twin gestation with no complications. The 2 other triplet fetuses and the twin fetus also had echogenic bowel and were normal live born infants. There was no difference in the pattern of bowel echogenicity between fetuses with IUFD and live born control subjects. Bowel echogenicity was multifocal in 66.6% of fetuses with IUFD and 81.0% of the live born group (P = .383). Bowel loops were not more prominent in the IUFD group compared with live born control infants (11.1% vs 10.2%; P = 1.0). Seven mothers underwent dilatation and evacuation. Autopsy was available in 5 cases and did not show evidence of anomalies, although examination was limited by fetal fragmentation. Detailed autopsy for the 32-week IUFD showed no anomalies, and gross examination of the 39-week IUFD was normal. Placental examination was performed on 7 of the 9 fetuses with fetal demise, as shown in Table III. There was evidence of placental infarcts in all 7 placentas that were examined. Because placental examination was performed mainly for clinical indications (such as IUFD), we cannot comment on the rate of placental infarction in control subjects. Maternal history of first trimester bleeding or evidence of subchorionic collection by ultrasound examination was not different between the case patients with IUFD and the live born control infants (11.1% vs 17.7%; P = 1.0). Comment The prenatal diagnosis of fetal echogenic bowel in the absence of major anomalies, aneuploidy, cystic fibrosis, and congenital infection is associated with a high incidence of IUFD. Our 5.8% incidence of IUFD with fetal echogenic bowel could be an underestimate because there were 2 pregnancy terminations because of IUGR, oligohydramnios, and elevated MSAFP levels. Had these patients continued their pregnancies, IUFD was likely. In fetuses with echogenic bowel, the presence of IUGR, oligohydramnios, or elevated MSAFP levels was associated with fetal demise. The strongest association was with elevated MSAFP levels. No specific pattern of bowel echogenicity was associated with IUFD. IUFD is an uncommon event, but it is more common in multiple gestations than in singleton gestations. Fetal surveillance in the third trimester was not recommended for cases of isolated echogenic bowel alone. We did recommend fetal surveillance in those cases that were associated with oligohydramnios, IUGR, elevated MSAFP levels, or other standard indications. We can only speculate about the reason that echogenic bowel occurs before demise. Possible explanations include uteroplacental ischemia and intra-amniotic bleeding. Because there was evidence of placental infarcts in
November 2001 Am J Obstet Gynecol
the 7 placentas that were examined, a placental abnormality may explain the association between elevated MSAFP level, growth restriction, oligohydramnios, and echogenic bowel. The elevation of MSAFP levels in these cases could be due to an alteration of the maternalplacental barrier. Placental infarcts could lead to placental and fetal hypoperfusion, which could subsequently lead to oligohydramnios and growth restriction. Fetal redistribution of blood flow may contribute to gut ischemia that could manifest itself as echogenic bowel. Only 1 mother of the 9 cases of IUFD reported vaginal bleeding and had a 1.2- × 2.9-cm subchorionic collection noted on ultrasound examination. The absence of a history of vaginal bleeding in the remaining 8 cases does not exclude intra-amniotic bleeding. Objective determination of intra-amniotic bleeding has been shown to be associated with echogenic bowel.9 One strength of our study is our rigid inclusion criteria. Twenty-eight percent of the patients who were diagnosed in our ultrasound unit with fetal echogenic bowel were excluded because they were referred from other institutions or for a second opinion. Because these patients may be at risk for adverse outcomes, the exclusion of these cases avoided an overestimate of the actual incidence of IUFD in fetuses that were diagnosed with echogenic bowel. Another strength is our large sample size and the inclusion of only those cases in which bowel echogenicity was as bright as bone. Cases with lesser degrees of echogenicity that are less likely to involve abnormalities were not included in our series.10 Limitations to our study include the exclusion of a significant number of patients (8.2%) because their ultrasound images were unavailable or unclear. Serum screening was also not performed in 4 of the 9 fetuses with demise. This limited the logistic regression analysis, because those cases not undergoing serum screening were not included. It is thus not clear whether the strong association between elevated MSAFP level and IUFD in these fetuses would be applicable to the entire cohort. Testing for aneuploidy, cystic fibrosis, and congenital infection were not performed on all cases. Routine examination of all neonates was performed, and there were no morphologic abnormalities suggestive of aneuploidy, so we are confident that no cases of aneuploidy were missed in the control group. It is possible that there were some cases of cystic fibrosis or congenital infection that were missed. In conclusion, most fetuses with echogenic bowel and absent major congenital anomalies in the second trimester that are not affected by aneuploidy, cystic fibrosis, or congenital infection will be liveborn. When IUGR, oligohydramnios, or elevated MSAFP level is present, however, there is a significant risk of fetal demise. It is unclear whether these demises can be prevented by serial ultrasound examinations and antepartum fetal surveillance. This information is useful in counseling patients
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