- Email: [email protected]
Utility of follow-up standard sonography for fetal anomaly detection
Journal Pre-proof Utility of Follow-Up Standard Sonography for Fetal Anomaly Detection John J. Byrne, MD, MPH, Jamie L. Morgan, MD, Diane M. Twickler, MD, Donald D. Mcintire, PhD, Jodi S. Dashe, MD PII:
S0002-9378(20)30002-8
DOI:
https://doi.org/10.1016/j.ajog.2020.01.001
Reference:
YMOB 13034
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 25 September 2019 Revised Date:
24 December 2019
Accepted Date: 6 January 2020
Please cite this article as: Byrne JJ, Morgan JL, Twickler DM, Mcintire DD, Dashe JS, Utility of FollowUp Standard Sonography for Fetal Anomaly Detection, American Journal of Obstetrics and Gynecology (2020), doi: https://doi.org/10.1016/j.ajog.2020.01.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
1 1
Utility of Follow-Up Standard Sonography for Fetal Anomaly Detection
2 3
John J. BYRNE, MD, MPH
4
Jamie L. MORGAN, MD
5
Diane M. TWICKLER, MD
6
Donald D. MCINTIRE, PhD
7
Jodi S. DASHE, MD
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Departments of Obstetrics & Gynecology and Radiology University of Texas Southwestern Medical Center Parkland Health and Hospital Systems Dallas, Texas
Disclosure statement: The authors report no conflicts of interest This study was funded internally at the University of Texas Southwestern Medical Center. The paper was presented in poster format at the Society of Maternal-Fetal Medicine 39th Annual Pregnancy Meeting in Las Vegas, NV on February 11-16, 2019.
Corresponding Author: John J. Byrne, MD, MPH Department of Obstetrics and Gynecology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, Texas 75390-9032 Phone: 214-648-3113 Fax: 214-648-7262 Email: [email protected]
Word Count: Condensation 36 words, Abstract: 429 words, Manuscript: 2,851 words
2 36
Condensation: Follow-up sonography resulted in the detection of 45% of fetal anomalies
37
that had not been identified during the initial screening sonogram in a non-referred
38
population. However, more follow-up sonograms were required to detect each additional
39
anomalous fetus.
40
Short Title: Follow-Up Sonography for Fetal Anomaly Detection
41
AJOG at a Glance:
42
A. Why was this study conducted?
43
•
To determine the detection of anomalous fetuses during initial and follow-up
44
standard sonograms in an otherwise low-risk population, according to organ
45
systems involved, gestational age at follow-up sonogram, and survival to hospital
46
discharge.
47 48
B. What are the key findings? •
Follow-up sonography identified 45% of anomalous fetuses that had not been
49
identified during the initial screening sonogram, resulting in a significant increase in
50
overall anomaly detection.
51
•
majority of cases, by the organ system involved.
52 53
•
56
Infants with undetected anomalies were significantly more likely to survive to hospital discharge.
54 55
Detection was not affected by gestational age at the follow-up sonogram or in the
C. What does this study add to what is already known? •
Utility of follow-up sonography in a low-risk population is not established. We found
57
improved anomaly detection with follow-up sonography, but >400 standard
58
sonograms were needed to detect each additional anomaly.
3 59
Abstract
60
Background: In 2014, the National Institute of Child Health and Human Development
61
Fetal Imaging Workshop consensus recommended that sonograms be offered routinely to
62
all pregnant women. In the absence of another indication, this examination is
63
recommended at 18 to 22 weeks of gestation. Studies of anomaly detection often focus
64
on pregnancies at risk for anomalies and on the yield of detailed sonography – topics less
65
applicable to counseling low-risk pregnancies about the benefits and limitations of
66
standard sonography. The clinical utility of follow-up sonogram in low-risk pregnancies for
67
the purpose of fetal anomaly detection has not been established.
68
Objective: To evaluate the utility of follow-up standard sonography for anomaly detection
69
among low-risk pregnancies in a non-referred population.
70
Study Design: We performed a retrospective cohort study of singleton pregnancies that
71
underwent standard sonography at 18-21 6/7 weeks of gestation from October 2011-
72
March 2018 with subsequent delivery of a live-born infant at our hospital. Pregnancies
73
with indications for detailed sonography in our system were excluded, so as to evaluate
74
fetal anomalies first identified with standard sonography. Anomalies were categorized
75
according to the European Registration of Congenital Anomalies and Twins (EUROCAT)
76
system, with confirmation based on neonatal evaluation. Among those with no anomaly
77
detected initially, we evaluated the rate of subsequent detection according to number of
78
follow-up sonograms, gestational age at sonography, organ system(s) affected, and
79
anomaly severity. Statistical analyses were performed using χ2 and Mantel-Haenszel test.
80
Results: Standard sonography was performed in 40,335 pregnancies at 18-21 6/7
81
weeks, and 11,770 (29%) had at least 1 follow-up sonogram, with a second follow-up
4 82
sonogram in 3520 (9%). Major abnormalities were confirmed in 387 infants (1%), with 248
83
(64%) detected initially and 28 (7%) and 5 (1%) detected on the first and second follow-up
84
sonograms. Detection of residual anomalies on follow-up sonograms was significantly
85
lower than detection on the initial standard exam: 64% on initial exam, 45% for first follow-
86
up, and 45% for second follow-up, P < 0.01. A larger number of follow-up examinations
87
were required per anomalous fetus detected: 163 exams per anomalous fetus detected
88
initially, 420 per fetus detected at the first follow-up exam, and 705 per fetus detected at
89
the second follow-up sonogram, P< 0.01. The number of follow-up examinations to detect
90
each additional anomalous fetus was not affected by gestational age, P=0.7. Survival to
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hospital discharge was significantly lower for fetuses with anomalies detected on initial
92
(88%) than for fetuses with anomalies undetected until delivery (90/91, 99%), P<0.002.
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Conclusions: In a low-risk, non-referred cohort with fetal anomaly prevalence of 1%,
94
follow-up sonography resulted in detection of 45% of fetal anomalies that had not been
95
identified during the initial standard sonogram. Significantly more follow-up sonograms
96
were required to detect each additional anomalous fetus.
97 98 99 100 101 102 103 104
Key words: Anomaly detection, follow-up sonography, standard sonography
5
Introduction
105 106
In the United States, women with low-risk pregnancies typically receive at least 4
107
sonograms.1 Though seemingly ubiquitous in modern obstetrics, routine prenatal
108
sonography was not officially endorsed by national societies in the United States until
109
2014, when the National Institute of Child Health and Human Development Fetal Imaging
110
Workshop recommended that a second-trimester sonogram be offered to all pregnant
111
women.2 In the absence of another indication, this examination is recommended at 18 to
112
22 weeks of gestation for optimal timing for the evaluation of fetal anatomy.3
113
A common indication for performance of follow-up sonography in otherwise low-
114
risk pregnancies is incomplete visualization of fetal anatomy during the initial standard
115
examination. Recent series of anatomy visualization with standard sonography report
116
incomplete visualization in 13% to 21% of pregnancies – which would correspond to more
117
than 500,000 pregnancies in the U.S annually.4,5,6 Studies of anomaly detection often
118
focus on pregnancies at risk for anomalies and on the yield of detailed sonography –
119
topics less applicable to counseling low-risk pregnancies about the benefits and
120
limitations of standard sonography. The clinical utility of follow-up sonography in low-risk
121
pregnancies for the purpose of fetal anomaly detection has not been established. Indeed,
122
the Fetal Imaging Workshop identified this as an area in which further research was
123
needed.2
124
The purpose of this study was to evaluate rates of detection of anomalous fetuses
125
during initial and follow-up standard sonograms in an otherwise low-risk population,
126
according to gestational age at follow-up sonogram, organ systems involved, and survival
127
to hospital discharge.
6
Materials and Methods
128 129
This is a retrospective cohort study of women with singleton pregnancies who received
130
standard sonography between 18 and 21 6/7 weeks’ gestation as part of routine prenatal
131
care and subsequently delivered a live-born infant with a major structural anomaly at our
132
hospital. The study period was from October 2011 through March 2018. Pregnancies
133
were identified from a prospectively maintained database that contains neonatal
134
outcomes for all deliveries at our hospital, including a description of structural
135
abnormalities identified prior to hospital discharge. The European Registration of
136
Congenital Anomalies and Twins (EUROCAT) system (www.eurocat-network.eu) was
137
used for categorization. Neonatal survival to hospital discharge was evaluated as a
138
marker of anomaly severity.
139
The goal of the analysis was assessment of anomaly detection with initial and
140
follow-up standard sonography. If any major structural abnormality was identified, the
141
fetus was considered detected, and subsequent sonograms were not evaluated. Such
142
pregnancies received detailed sonography (rather than follow-up standard sonography),
143
along with counseling, prenatal diagnosis with amniocentesis if elected, and pediatric
144
subspecialty consultation as appropriate. In the absence of an anomaly, if an indication
145
for a detailed sonogram was identified (e.g. teratogen exposure, family history of
146
anomaly), that pregnancy was excluded from analysis. We did this so that our findings
147
could be used for counseling pregnancies without risk factors. Women whose initial
148
sonogram was at or beyond 22 weeks’ gestation were also excluded, to give all
149
pregnancies comparable opportunity for initial anomaly detection.
7 150
Among pregnancies in which no fetal anomaly was detected initially, we reviewed
151
records from all subsequent sonograms that were performed for standard obstetrical
152
indications and included a fetal anatomic survey.3 We recorded the indication and
153
gestational age for each follow-up exam. We grouped the gestational age at follow-up
154
sonography into 4-week intervals to facilitate comparisons. Anomaly detection was further
155
categorized according to single and multiple organ system involvement and individual
156
organ system affected. During the study period, obese women and women ages 35 and
157
older at delivery received standard sonography in the absence of another indication for a
158
detailed examination; however, such pregnancies were analyzed separately.
159
Standard sonograms were performed in accordance with national guidelines by
160
registered diagnostic medical sonographers (American Registry of Diagnostic Medical
161
Sonographers – Certified), typically within neighborhood prenatal clinics, with images
162
transmitted electronically to our hospital-based central sonography unit and read by
163
faculty who specialize in obstetrical sonography.3 Our unit was accredited by the
164
American Institute of Ultrasound in Medicine throughout the study period.
165
Our hospital serves a non-referred population in which termination for fetal
166
anomalies is rarely elected. This allowed us to calculate not only the sensitivity of
167
standard sonography but also anomaly prevalence and the false negative rate of
168
sonography (anomalies missed). To determine prevalence of anomalous fetuses
169
detected during initial and follow-up standard sonograms, we reviewed the number of
170
standard sonograms from non-anomalous singleton pregnancies delivered during the
171
study period. Statistical comparisons included Pearson’s chi-square, and Mantel-
172
Haenszel chi-square for trend. Results at P<0.05 were considered statistically significant.
8 173
Our study was approved by the Institutional Review Board of the University of Texas
174
Southwestern Medical Center and Parkland Hospital.
175 176
9 177
Results
178
During the study period, 40,335 women with singleton pregnancies received standard
179
sonography at 18 - 21 /67 weeks and delivered live born infants at our hospital. None had
180
an a-priori indication for detailed sonography in our system. Among pregnancies with no
181
abnormality detected on the initial sonogram, one or more follow-up sonograms were
182
performed in 11,770 (29%), and two follow-up sonograms were performed in 3,520 (9%).
183
Major abnormalities were confirmed in the neonatal period in 387 (1%) of these otherwise
184
low-risk pregnancies, of which 331 (86%) were anomalies of a single organ system and
185
56 (14%) involved multiple organ systems. Overall neonatal survival to hospital discharge
186
was 91%. Maternal demographic characteristics for pregnancies with anomalous fetuses
187
are shown in Table 1. Women in our study population were predominantly multiparous
188
(71%), Hispanic (82%), and non-obese (70%). Women ages 35 and older at delivery
189
accounted for 19% of our study population.
190
Detection of anomalous fetuses with initial and follow-up standard sonography is
191
presented in Figure 1. Overall, 282 anomalous fetuses (73%) were detected prenatally:
192
248 (64%) on the initial sonogram, 28 (7%) on the first follow-up sonogram, and 5 (1%)
193
on the second follow-up sonogram, with just 1 anomaly identified after the second follow-
194
up sonogram. As previously noted, follow-up sonography was performed in a minority of
195
pregnancies. When anomaly detection was considered in only those pregnancies
196
receiving follow-up sonography, 45% of residual anomalies were detected at the first
197
follow-up sonogram, and 45% of remaining anomalies were detected at the second
198
follow-up sonogram. However, detection was significantly higher at the initial sonogram
199
than at these follow-up sonograms, P < 0.001.
10 200
The addition of 1 follow-up sonogram did improve overall anomaly detection when
201
compared with an initial sonogram alone, 70% vs. 64%, P = 0.03 (Table 2). Because the
202
majority of anomalies had been detected initially, the number of follow-up sonograms
203
performed to detect an anomalous fetus (e.g. number needed to treat) was higher for
204
each subsequent examination: 163 exams per anomalous fetus detected at the initial
205
sonogram, 420 exams per fetus detected at the first follow-up sonogram, and 705 exams
206
per fetus detected at the second follow-up sonogram, P for trend < 0.001 (Figure 1). Not
207
unexpectedly, survival to hospital discharge was significantly lower for anomalous fetuses
208
detected at the initial standard sonogram (88%) than for those with anomalies detected
209
only after delivery (90/91, 99%), P = 0.002.
210
As also shown in Table 2, detection of fetuses with a single organ system anomaly
211
was comparable to detection of fetuses with anomalies of multiple organ systems, either
212
on the initial exam or first follow-up exam, both P > 0.05. When each organ system was
213
considered separately, detection on the initial exam was comparable to that for the entire
214
cohort, all P > 0.05 with one exception. For renal/genitourinary anomalies, detection with
215
follow-up sonography was significantly higher than for the overall cohort, 81% vs. 45%, P
216
< 0.004 (table 3). This may be explained by fetal renal pelvis dilatation > 7 mm, which
217
accounted for 41% of renal/genitourinary anomaly cases.
218
We next considered the indication for performing the first follow-up examination
219
and anomaly detection according to when in gestation sonography was performed. Table
220
3 lists the indication for the first follow-up sonogram among the 62 pregnancies with
221
anomalous fetuses in which no abnormality had been detected initially. The most
222
common indication was limited initial evaluation of fetal anatomy in 42%, followed by a
11 223
size-date discrepancy in 24% and fetal growth surveillance in 24%, the latter in the setting
224
of maternal hypertension, gestational diabetes, or prior pregnancy complicated by
225
demise. Table 4 depicts anomaly detection according to the gestational age at which the
226
first follow-up sonogram was performed, using 4-week intervals to facilitate comparisons.
227
The number of pregnancies with follow-up sonography at each interval ranged from just
228
less than 1000 to 3475. There was no difference in anomaly detection according to
229
gestational age, P = 0.92.
230
We were cognizant that our dataset included women 35 years of age or older
231
(advanced maternal age), as well as obese gravidas, and that both groups received
232
standard sonography in our system rather than detailed examinations. To address this
233
limitation, we analyzed fetal anomaly detection separately in these subgroups. Maternal
234
obesity was defined as body mass index greater than or equal to 30 kg/m2 prior to
235
pregnancy or at the initial prenatal visit.7 As shown in Table 5, fetal anomaly detection
236
with standard sonography did not differ according to advanced maternal age or obesity,
237
either for the initial sonogram or the first follow-up sonogram, all P > 0.05. However,
238
among those in whom anomalies were not detected during the initial sonogram, follow-up
239
sonography was more likely to be performed if the patient was obese, 27/115 (24%)
240
compared with 37/272 (13%), P = 0.009. Neonatal survival for anomalies detected
241
initially, detected at the first follow-up sonogram, or undetected after the first follow-up
242
sonogram did not differ according to advanced maternal age or obesity, all P > 0.05. If a
243
fetal abnormality was undetected after 2 standard sonograms (initial and follow-up),
244
neonatal survival was at least 95% in all groups. Undetected anomalies are included in
245
the supplemental table.
12
Comment
246 247
Principal Findings
248
There were three primary findings from our study of fetal anomaly detection with follow-up
249
sonography performed for standard indications. With either the first or second follow-up
250
examination, we identified 45% of fetuses with (residual) major structural anomalies that
251
had not been detected on prior standard sonograms. This percentage was significantly
252
lower than detection at the initial examination and corresponds to a relatively low absolute
253
percentage of pregnancies with anomalies detected during follow-up sonography – in only
254
0.2% of pregnancies was an anomalous fetus identified at the first follow-up examination.
255
Because the prevalence of anomalies is lower in a low-risk population, and because the
256
majority of anomalous fetuses are detected with the initial examination, the number of
257
follow-up examinations required to detect an anomalous fetus increased sharply with
258
each successive examination. Second, anomaly detection was not affected by the
259
gestational age at which the follow-up examination was performed, which is reassuring
260
from the perspective that its utility was not compromised at later gestational ages. Finally,
261
because severe anomalies are more likely to come to attention with standard sonography,
262
infants with undetected anomalies were significantly more likely to survive to hospital
263
discharge.
264
Results
265
The clinical utility of follow-up sonography for fetal anomaly detection in low-risk
266
pregnancies has been acknowledged as an unresolved issue and an area in which further
267
research is needed.2 The topic is challenging to study, as it requires both reliable data
268
about the prevalence of anomalous fetuses in a population receiving standard
13 269
sonography and the sensitivity of standard sonography for anomaly detection, because
270
these are needed to determine the number or proportion with residual anomalies that
271
might be detected with a follow-up sonogram. Based on birth defect registry data from the
272
United States and Europe, it is generally acknowledged that major anomalies are
273
identified in 2 to 3 percent of newborns.8,9 The prevalence is assumed to be lower in low-
274
risk pregnancies receiving standard sonography than in those receiving detailed
275
sonography. In our study population, anomaly prevalence in low-risk pregnancies and
276
detection with standard sonography were 1% and 64%, respectively. Prior data from our
277
group is consistent with that prevalence.10 Our current anomaly detection rate with
278
standard sonography is higher than we reported 10 years ago (which was 53%, 95% CI
279
45% to 62%). This may reflect the practice change of routinely offering sonography to all
280
low-risk pregnancies as well as improvements in ultrasound technology. There is limited
281
contemporary data on this topic. For example, the American College of Obstetricians and
282
Gynecologists Practice Bulletin on Ultrasound in Pregnancy includes an anomaly
283
detection rate of 40%, but that is based on a review of studies published between 20 and
284
35 years ago.3,11
285
Clinical Implications
286
There have been several recent studies of anomaly detection with follow-up sonography.
287
Most have included both detailed and standard sonograms (high-risk and low-risk
288
pregnancies) or have had the limitation of not capturing undetected anomalies –
289
precluding calculation of sensitivity and residual risk. Silvestri and colleagues (2016)
290
reviewed 1560 follow-up sonograms performed for incomplete anatomy visualization and
291
identified major abnormalities in 16 fetuses: 6 in anatomic components previously not
14 292
visualized and 10 in organ systems previously documented to appear normal.6 Detailed
293
sonograms were included in this series. We hypothesize that our lower rate of undetected
294
anomalous fetuses (0.2%) may be because we did not include detailed sonograms, such
295
that our pregnancies had lower a-priori risk in addition, potentially, to lower anomaly
296
detection. O’Brien and colleagues (2017) identified 1 major anomaly in a series of 205
297
low-risk pregnancies (0.5%) that received follow-up sonography, concluding that the
298
clinical yield of such examinations was low.12 Wood and colleagues (2018) reviewed a
299
series of 1796 follow-up sonograms – which also included detailed exams, and identified
300
major anomalies in 11 (0.6%), reporting that of all anomalies detected prenatally, more
301
than 90% were detected at the initial sonogram.13 Were we to apply this methodology to
302
our series, 90% of the anomalies that we detected prenatally (248/276) were also
303
identified at the initial sonogram. A strength of our population-based series is that we
304
were also able to evaluate undetected anomalies. We chose to analyze our data
305
according to proportion of residual anomalies detected and undetected in an effort to
306
improve counseling, realizing that even anomalies without reliable sonography detection
307
can be devastating to families.
308
Unlike other studies,6,12,14 ours did not include detection of minor aneuploidy
309
markers or findings from subsequent specialized sonography. Minor markers are
310
problematic from the standpoint of detection because they are not verified in the neonatal
311
period, and thus sensitivity cannot be calculated. Also, minor markers are intended to
312
improve aneuploidy detection, and since sonography cannot diagnose aneuploidy, we did
313
not consider minor markers in our series and excluded pregnancies that received detailed
314
sonography after detection of minor markers.
15 315
Research Implications
316
Our study differed from others in that we reviewed anomaly detection with follow-up
317
sonography that had been performed for any indication and at any point in gestation.
318
During the study period, we did not routinely perform follow-up sonography when
319
evaluation of fetal anatomy was limited, and while that was the indication for many
320
second-trimester follow-up sonograms (Table 3), anomaly detection was equally frequent
321
later in pregnancy in exams performed for other indications (Table 4). This work should
322
therefore be translated in a prospective nature. Future prospective work that identifies
323
how many follow up ultrasounds are indicated to ensure proper anatomical identification
324
is needed. Additionally, this work should be replicated in the setting of pregnancies that
325
are high risk for fetal anomalies.
326
Strengths and Limitations
327
Our study had several limitations that should be noted. Because we did not perform
328
follow-up sonography in every pregnancy, our findings apply only to those with an
329
indication, which in our series was approximately 30%. During the study period, our
330
county hospital did not have the capability to perform detailed sonography for maternal
331
age > 35 or obesity, and so we analyzed anomaly detection and neonatal survival
332
separately in these pregnancies (see Table 5). We found no statistically or clinically-
333
relevant difference in anomaly detection between our overall cohort and pregnancies
334
without these risk factors, which is reassuring in terms of the generalizability of our
335
findings to pregnancies without them. An additional limitation is that our study findings
336
only apply to anomalies detectable in the immediate neonatal period. It was not possible
337
for us to capture infants with anomalies too subtle to come to attention before the infant
16 338
was discharged from the hospital. Pregnancies identified to have minor aneuploidy
339
markers during initial standard sonograms were included in our study, because Down
340
syndrome detection was not an outcome, and we understand this might raise concern
341
that identification of minor markers led to more comprehensive evaluation. However, our
342
group recently reported detection of major anomalies in pregnancies with Down
343
syndrome, and it is comparable to our detection rate for major anomalies in the current
344
study (in the absence of Down syndrome).15 Thus, we feel that none of these limitations
345
suggests that our findings would not be applicable in other settings or centers. Strengths
346
of our series is that it is large and population-based, that we had neonatal outcomes for
347
all deliveries, and that anomalies were categorized according to a recognized system.
348
Conclusions
349
Because of our focus on standard sonography, our data may be used to counsel low-risk
350
pregnancies about the utility and limitations of routine sonography. When follow-up
351
sonography was indicated, as it was in approximately 30% of our pregnancies, additional
352
anomalous fetuses were identified. However, a larger number of follow-up examinations
353
were required: more than 400 follow-up examinations to detect a fetus with a major
354
anomaly, and if that follow-up examination was normal, more than 700 additional follow-
355
up sonograms per anomalous fetus detected. This supports the consensus-based
356
recommendation (Reddy, 2014) that a second follow-up sonogram not be performed
357
solely for better visualization. Women with low-risk pregnancies may be reassured that
358
the likelihood that the fetus has an undetected major anomaly is below 0.5% after a
359
normal standard sonogram. If follow-up sonography is indicated, knowledge that 45% of
360
residual anomalies may be detected can provide additional reassurance.
17
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Table 1: Maternal Demographic Characteristics, Pregnancies with Anomalous Fetuses N=387 Maternal age <35 >35 Race/ethnicity Black Hispanic White Other Parity Nulliparous Multiparous BMI Normal Overweight Obese class 1 Obese class 2 Obese class 3
420 421 422 423 424 425 426 427 428 429 430 431
Frequency (%)
313 (81) 74 (19) 47 (12) 316 (82) 10 (3) 14 (3) 112 (29) 275 (71) 131 (34) 141 (36) 64 (17) 32 (8) 19 (5)
20 432 433
434 435 436 437 438 439 440 441
Table 2: Proportion of Anomalous Fetuses Detected on Initial and Follow-up Sonograms
Anomalous fetuses
Detected on initial exam 248/387 (64)
Detected on follow-up exam 28/62 (45)
Detection, initial and follow-up exams 282/387 (73)a
Single organ system anomalies
208/331 (63)
24/55 (44)
232/331 (70)a
Multiple organ system anomalies
40/56 (71)
4/7 (57)
44/56 (79)
Organ system Cardiac CNS Craniofacial Gastrointestinal Pulmonary Renal/Genitourinary Skeletal Other
62/97 (64) 40/58 (69) 39/53 (74) 43/71 (61) 14/17 (82) 76/106 (72) 15/20 (75) 10/15 (67)
11/19 (55) 4/14 (29) 0 3/8 (38) 1/1 (100) 17/21 (81)b 0 2/3 (67)
73/97 (76) 44/58 (76) 39/53 (74) 46/71 (65) 15/17 (88) 93/106 (88)a 15/20 (75) 12/15 (80)
Data presented as N (%) a P<0.05 for increase in anomaly detection after follow-up sonogram compared with initial detection; bP<0.05 for comparison of individual organ systems with overall detection of anomalous fetuses
21 442
443 444 445
Table 3: Indication for First Follow-up Sonogram Indication Limited fetal anatomy evaluation Size-date discrepancy Fetal growth surveillance Hypertension Gestational diabetes Prior pregnancy with demise Decreased amniotic fluid suspected Preterm rupture of membranes Preterm labor Abnormal placentation (previa) Data presented as N (%)
N = 62 26 (42) 15 (24) 15 (24) 7 (11) 7 (11) 1 (2) 2 (3) 2 (3) 1 (2) 1 (2)
22 446 447
Table 4: Detection of anomalous fetuses according to gestational age at follow-up sonogram 18-21 6/7 wks
448 449 450 451 452 453
Anomalies detected, initial sonogram
248 anomalies, 40,335 exams, 0.6%
Anomalies detected, first followup sonogram
7 anomalies, 3475 exams, 0.2%
a
22-25 6/7 wks
26-29 6/7 wks
30-30 6/7 wks
34-37 6/7 wks
Total 248 anomalies, 40,335 exams, 163 exams per anomaly
4 anomalies, 1914 exams, 0.2%
1 anomalies, 991 exams, 0.3%
7 anomalies, 2037 exams, 0.4%
9 anomalies, 3329 exams, b 0.3%
28 anomalies, 11,779 exams, 420 exams per a anomaly
Significantly more follow-up sonograms were performed per anomalous fetus detected, compared with initial sonograms, P < 0.001; bNo significant difference in detection of anomalous fetuses during first follow-up sonogram according to gestational age, P=0.7
23 454 455
Table 5. Anomaly detection and neonatal survival according to maternal age and BMI Age < 35
Age > 35
Detected initially
313 (81) 201 (64)
Neonatal survival Detected at 1st follow-up Neonatal survival st
Undetected at 1 follow-up Neonatal survival 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472
N = 74 (19) 47 (64)
BMI < 30 kg/m2 N = 272 (70) 180 (66)
BMI > 30 kg/m2 N = 115 (30) 68 (59)
178 (89)
40 (85)
162 (90)
56 (82)
21/45 (47)
7/17 (41)
17/35 (49)
11/27 (41)
20/21 (95)
6/7 (86)
16/17 (94)
10/11 (91)
24/45 (53)
10/17 (59)
18/35 (51)
16/27 (59)
23/24 (96)
10/10 (100)
18/18 (100)
15/16 (94)
Data presented as N (%) P-values for all comparisons between maternal age cohorts and BMI cohorts all > 0.05, for anomaly detection as well as neonatal survival.
24 473
Figure 1: Flow diagram of anomaly detection by initial and follow-up sonograms.
474
a
475
exams (p=0.01). bIncreasing numbers of sonograms were required to detect a single
476
anomalous fetus at the initial exam, 1st follow-up exam, and 2nd follow-up exam,
477
respectively (p<0.001). cThose detected initially were less likely to survive to hospital
478
discharge compared to those who were undetected, p=0.002
479 480 481 482
Anomaly detection on the initial sonogram was significantly greater than on follow-up
25 483
Supplemental Table: Undetected Anomalies
Organ System Cardiac
Craniofacial
GI
GU
Muscular
Neuro
Pulmonary 484
Anomaly Ventricular septal defect (7) Tetralogy of Fallot (4) Transposition of the great vessels (3) Coarctation of the Aorta (2) Pulmonary Valve Hypoplasia (2) Anomalous pulmonary venous return (2) Tricuspid Regurgitation (1) Aortic Valve Stenosis (1) Pulmonary atresia (1) Endocardial cushion defect (1) Cleft palate (7) Cleft lip (3) Choanal Atresia (1) Absent ear canal (1) Micrognathia (1) Other congenital malformation of face/neck (1) Imperforate anus (16) Tracheo-esophageal fistula (3) Malrotation (3) Esophageal atresia (2) Ileal atresia (2) Diaphragmatic Hernia (2) Omphalocele (1) Jejunal Atresia (1) Hydronephrosis (9) Ambiguous Genitalia (2) Duplicated Collecting System (1) Cross Fused ectopia (1) Hypospadias (1) Reduction defect of upper arm (2) Achondroplasia (1) Micromelia (1) Poland anomaly (1) Microcephaly (7) Hydrocephalus (5) Lipomeningocele (1) Cerebellar hypoplasia (1) Sacral Teratoma (1) Encephalocele (1) Lymphangioma (1) Contracture (1) Cystic adenomatoid malformation (1)
S0002-9378(20)30002-8
DOI:
https://doi.org/10.1016/j.ajog.2020.01.001
Reference:
YMOB 13034
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 25 September 2019 Revised Date:
24 December 2019
Accepted Date: 6 January 2020
Please cite this article as: Byrne JJ, Morgan JL, Twickler DM, Mcintire DD, Dashe JS, Utility of FollowUp Standard Sonography for Fetal Anomaly Detection, American Journal of Obstetrics and Gynecology (2020), doi: https://doi.org/10.1016/j.ajog.2020.01.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
1 1
Utility of Follow-Up Standard Sonography for Fetal Anomaly Detection
2 3
John J. BYRNE, MD, MPH
4
Jamie L. MORGAN, MD
5
Diane M. TWICKLER, MD
6
Donald D. MCINTIRE, PhD
7
Jodi S. DASHE, MD
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Departments of Obstetrics & Gynecology and Radiology University of Texas Southwestern Medical Center Parkland Health and Hospital Systems Dallas, Texas
Disclosure statement: The authors report no conflicts of interest This study was funded internally at the University of Texas Southwestern Medical Center. The paper was presented in poster format at the Society of Maternal-Fetal Medicine 39th Annual Pregnancy Meeting in Las Vegas, NV on February 11-16, 2019.
Corresponding Author: John J. Byrne, MD, MPH Department of Obstetrics and Gynecology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, Texas 75390-9032 Phone: 214-648-3113 Fax: 214-648-7262 Email: [email protected]
Word Count: Condensation 36 words, Abstract: 429 words, Manuscript: 2,851 words
2 36
Condensation: Follow-up sonography resulted in the detection of 45% of fetal anomalies
37
that had not been identified during the initial screening sonogram in a non-referred
38
population. However, more follow-up sonograms were required to detect each additional
39
anomalous fetus.
40
Short Title: Follow-Up Sonography for Fetal Anomaly Detection
41
AJOG at a Glance:
42
A. Why was this study conducted?
43
•
To determine the detection of anomalous fetuses during initial and follow-up
44
standard sonograms in an otherwise low-risk population, according to organ
45
systems involved, gestational age at follow-up sonogram, and survival to hospital
46
discharge.
47 48
B. What are the key findings? •
Follow-up sonography identified 45% of anomalous fetuses that had not been
49
identified during the initial screening sonogram, resulting in a significant increase in
50
overall anomaly detection.
51
•
majority of cases, by the organ system involved.
52 53
•
56
Infants with undetected anomalies were significantly more likely to survive to hospital discharge.
54 55
Detection was not affected by gestational age at the follow-up sonogram or in the
C. What does this study add to what is already known? •
Utility of follow-up sonography in a low-risk population is not established. We found
57
improved anomaly detection with follow-up sonography, but >400 standard
58
sonograms were needed to detect each additional anomaly.
3 59
Abstract
60
Background: In 2014, the National Institute of Child Health and Human Development
61
Fetal Imaging Workshop consensus recommended that sonograms be offered routinely to
62
all pregnant women. In the absence of another indication, this examination is
63
recommended at 18 to 22 weeks of gestation. Studies of anomaly detection often focus
64
on pregnancies at risk for anomalies and on the yield of detailed sonography – topics less
65
applicable to counseling low-risk pregnancies about the benefits and limitations of
66
standard sonography. The clinical utility of follow-up sonogram in low-risk pregnancies for
67
the purpose of fetal anomaly detection has not been established.
68
Objective: To evaluate the utility of follow-up standard sonography for anomaly detection
69
among low-risk pregnancies in a non-referred population.
70
Study Design: We performed a retrospective cohort study of singleton pregnancies that
71
underwent standard sonography at 18-21 6/7 weeks of gestation from October 2011-
72
March 2018 with subsequent delivery of a live-born infant at our hospital. Pregnancies
73
with indications for detailed sonography in our system were excluded, so as to evaluate
74
fetal anomalies first identified with standard sonography. Anomalies were categorized
75
according to the European Registration of Congenital Anomalies and Twins (EUROCAT)
76
system, with confirmation based on neonatal evaluation. Among those with no anomaly
77
detected initially, we evaluated the rate of subsequent detection according to number of
78
follow-up sonograms, gestational age at sonography, organ system(s) affected, and
79
anomaly severity. Statistical analyses were performed using χ2 and Mantel-Haenszel test.
80
Results: Standard sonography was performed in 40,335 pregnancies at 18-21 6/7
81
weeks, and 11,770 (29%) had at least 1 follow-up sonogram, with a second follow-up
4 82
sonogram in 3520 (9%). Major abnormalities were confirmed in 387 infants (1%), with 248
83
(64%) detected initially and 28 (7%) and 5 (1%) detected on the first and second follow-up
84
sonograms. Detection of residual anomalies on follow-up sonograms was significantly
85
lower than detection on the initial standard exam: 64% on initial exam, 45% for first follow-
86
up, and 45% for second follow-up, P < 0.01. A larger number of follow-up examinations
87
were required per anomalous fetus detected: 163 exams per anomalous fetus detected
88
initially, 420 per fetus detected at the first follow-up exam, and 705 per fetus detected at
89
the second follow-up sonogram, P< 0.01. The number of follow-up examinations to detect
90
each additional anomalous fetus was not affected by gestational age, P=0.7. Survival to
91
hospital discharge was significantly lower for fetuses with anomalies detected on initial
92
(88%) than for fetuses with anomalies undetected until delivery (90/91, 99%), P<0.002.
93
Conclusions: In a low-risk, non-referred cohort with fetal anomaly prevalence of 1%,
94
follow-up sonography resulted in detection of 45% of fetal anomalies that had not been
95
identified during the initial standard sonogram. Significantly more follow-up sonograms
96
were required to detect each additional anomalous fetus.
97 98 99 100 101 102 103 104
Key words: Anomaly detection, follow-up sonography, standard sonography
5
Introduction
105 106
In the United States, women with low-risk pregnancies typically receive at least 4
107
sonograms.1 Though seemingly ubiquitous in modern obstetrics, routine prenatal
108
sonography was not officially endorsed by national societies in the United States until
109
2014, when the National Institute of Child Health and Human Development Fetal Imaging
110
Workshop recommended that a second-trimester sonogram be offered to all pregnant
111
women.2 In the absence of another indication, this examination is recommended at 18 to
112
22 weeks of gestation for optimal timing for the evaluation of fetal anatomy.3
113
A common indication for performance of follow-up sonography in otherwise low-
114
risk pregnancies is incomplete visualization of fetal anatomy during the initial standard
115
examination. Recent series of anatomy visualization with standard sonography report
116
incomplete visualization in 13% to 21% of pregnancies – which would correspond to more
117
than 500,000 pregnancies in the U.S annually.4,5,6 Studies of anomaly detection often
118
focus on pregnancies at risk for anomalies and on the yield of detailed sonography –
119
topics less applicable to counseling low-risk pregnancies about the benefits and
120
limitations of standard sonography. The clinical utility of follow-up sonography in low-risk
121
pregnancies for the purpose of fetal anomaly detection has not been established. Indeed,
122
the Fetal Imaging Workshop identified this as an area in which further research was
123
needed.2
124
The purpose of this study was to evaluate rates of detection of anomalous fetuses
125
during initial and follow-up standard sonograms in an otherwise low-risk population,
126
according to gestational age at follow-up sonogram, organ systems involved, and survival
127
to hospital discharge.
6
Materials and Methods
128 129
This is a retrospective cohort study of women with singleton pregnancies who received
130
standard sonography between 18 and 21 6/7 weeks’ gestation as part of routine prenatal
131
care and subsequently delivered a live-born infant with a major structural anomaly at our
132
hospital. The study period was from October 2011 through March 2018. Pregnancies
133
were identified from a prospectively maintained database that contains neonatal
134
outcomes for all deliveries at our hospital, including a description of structural
135
abnormalities identified prior to hospital discharge. The European Registration of
136
Congenital Anomalies and Twins (EUROCAT) system (www.eurocat-network.eu) was
137
used for categorization. Neonatal survival to hospital discharge was evaluated as a
138
marker of anomaly severity.
139
The goal of the analysis was assessment of anomaly detection with initial and
140
follow-up standard sonography. If any major structural abnormality was identified, the
141
fetus was considered detected, and subsequent sonograms were not evaluated. Such
142
pregnancies received detailed sonography (rather than follow-up standard sonography),
143
along with counseling, prenatal diagnosis with amniocentesis if elected, and pediatric
144
subspecialty consultation as appropriate. In the absence of an anomaly, if an indication
145
for a detailed sonogram was identified (e.g. teratogen exposure, family history of
146
anomaly), that pregnancy was excluded from analysis. We did this so that our findings
147
could be used for counseling pregnancies without risk factors. Women whose initial
148
sonogram was at or beyond 22 weeks’ gestation were also excluded, to give all
149
pregnancies comparable opportunity for initial anomaly detection.
7 150
Among pregnancies in which no fetal anomaly was detected initially, we reviewed
151
records from all subsequent sonograms that were performed for standard obstetrical
152
indications and included a fetal anatomic survey.3 We recorded the indication and
153
gestational age for each follow-up exam. We grouped the gestational age at follow-up
154
sonography into 4-week intervals to facilitate comparisons. Anomaly detection was further
155
categorized according to single and multiple organ system involvement and individual
156
organ system affected. During the study period, obese women and women ages 35 and
157
older at delivery received standard sonography in the absence of another indication for a
158
detailed examination; however, such pregnancies were analyzed separately.
159
Standard sonograms were performed in accordance with national guidelines by
160
registered diagnostic medical sonographers (American Registry of Diagnostic Medical
161
Sonographers – Certified), typically within neighborhood prenatal clinics, with images
162
transmitted electronically to our hospital-based central sonography unit and read by
163
faculty who specialize in obstetrical sonography.3 Our unit was accredited by the
164
American Institute of Ultrasound in Medicine throughout the study period.
165
Our hospital serves a non-referred population in which termination for fetal
166
anomalies is rarely elected. This allowed us to calculate not only the sensitivity of
167
standard sonography but also anomaly prevalence and the false negative rate of
168
sonography (anomalies missed). To determine prevalence of anomalous fetuses
169
detected during initial and follow-up standard sonograms, we reviewed the number of
170
standard sonograms from non-anomalous singleton pregnancies delivered during the
171
study period. Statistical comparisons included Pearson’s chi-square, and Mantel-
172
Haenszel chi-square for trend. Results at P<0.05 were considered statistically significant.
8 173
Our study was approved by the Institutional Review Board of the University of Texas
174
Southwestern Medical Center and Parkland Hospital.
175 176
9 177
Results
178
During the study period, 40,335 women with singleton pregnancies received standard
179
sonography at 18 - 21 /67 weeks and delivered live born infants at our hospital. None had
180
an a-priori indication for detailed sonography in our system. Among pregnancies with no
181
abnormality detected on the initial sonogram, one or more follow-up sonograms were
182
performed in 11,770 (29%), and two follow-up sonograms were performed in 3,520 (9%).
183
Major abnormalities were confirmed in the neonatal period in 387 (1%) of these otherwise
184
low-risk pregnancies, of which 331 (86%) were anomalies of a single organ system and
185
56 (14%) involved multiple organ systems. Overall neonatal survival to hospital discharge
186
was 91%. Maternal demographic characteristics for pregnancies with anomalous fetuses
187
are shown in Table 1. Women in our study population were predominantly multiparous
188
(71%), Hispanic (82%), and non-obese (70%). Women ages 35 and older at delivery
189
accounted for 19% of our study population.
190
Detection of anomalous fetuses with initial and follow-up standard sonography is
191
presented in Figure 1. Overall, 282 anomalous fetuses (73%) were detected prenatally:
192
248 (64%) on the initial sonogram, 28 (7%) on the first follow-up sonogram, and 5 (1%)
193
on the second follow-up sonogram, with just 1 anomaly identified after the second follow-
194
up sonogram. As previously noted, follow-up sonography was performed in a minority of
195
pregnancies. When anomaly detection was considered in only those pregnancies
196
receiving follow-up sonography, 45% of residual anomalies were detected at the first
197
follow-up sonogram, and 45% of remaining anomalies were detected at the second
198
follow-up sonogram. However, detection was significantly higher at the initial sonogram
199
than at these follow-up sonograms, P < 0.001.
10 200
The addition of 1 follow-up sonogram did improve overall anomaly detection when
201
compared with an initial sonogram alone, 70% vs. 64%, P = 0.03 (Table 2). Because the
202
majority of anomalies had been detected initially, the number of follow-up sonograms
203
performed to detect an anomalous fetus (e.g. number needed to treat) was higher for
204
each subsequent examination: 163 exams per anomalous fetus detected at the initial
205
sonogram, 420 exams per fetus detected at the first follow-up sonogram, and 705 exams
206
per fetus detected at the second follow-up sonogram, P for trend < 0.001 (Figure 1). Not
207
unexpectedly, survival to hospital discharge was significantly lower for anomalous fetuses
208
detected at the initial standard sonogram (88%) than for those with anomalies detected
209
only after delivery (90/91, 99%), P = 0.002.
210
As also shown in Table 2, detection of fetuses with a single organ system anomaly
211
was comparable to detection of fetuses with anomalies of multiple organ systems, either
212
on the initial exam or first follow-up exam, both P > 0.05. When each organ system was
213
considered separately, detection on the initial exam was comparable to that for the entire
214
cohort, all P > 0.05 with one exception. For renal/genitourinary anomalies, detection with
215
follow-up sonography was significantly higher than for the overall cohort, 81% vs. 45%, P
216
< 0.004 (table 3). This may be explained by fetal renal pelvis dilatation > 7 mm, which
217
accounted for 41% of renal/genitourinary anomaly cases.
218
We next considered the indication for performing the first follow-up examination
219
and anomaly detection according to when in gestation sonography was performed. Table
220
3 lists the indication for the first follow-up sonogram among the 62 pregnancies with
221
anomalous fetuses in which no abnormality had been detected initially. The most
222
common indication was limited initial evaluation of fetal anatomy in 42%, followed by a
11 223
size-date discrepancy in 24% and fetal growth surveillance in 24%, the latter in the setting
224
of maternal hypertension, gestational diabetes, or prior pregnancy complicated by
225
demise. Table 4 depicts anomaly detection according to the gestational age at which the
226
first follow-up sonogram was performed, using 4-week intervals to facilitate comparisons.
227
The number of pregnancies with follow-up sonography at each interval ranged from just
228
less than 1000 to 3475. There was no difference in anomaly detection according to
229
gestational age, P = 0.92.
230
We were cognizant that our dataset included women 35 years of age or older
231
(advanced maternal age), as well as obese gravidas, and that both groups received
232
standard sonography in our system rather than detailed examinations. To address this
233
limitation, we analyzed fetal anomaly detection separately in these subgroups. Maternal
234
obesity was defined as body mass index greater than or equal to 30 kg/m2 prior to
235
pregnancy or at the initial prenatal visit.7 As shown in Table 5, fetal anomaly detection
236
with standard sonography did not differ according to advanced maternal age or obesity,
237
either for the initial sonogram or the first follow-up sonogram, all P > 0.05. However,
238
among those in whom anomalies were not detected during the initial sonogram, follow-up
239
sonography was more likely to be performed if the patient was obese, 27/115 (24%)
240
compared with 37/272 (13%), P = 0.009. Neonatal survival for anomalies detected
241
initially, detected at the first follow-up sonogram, or undetected after the first follow-up
242
sonogram did not differ according to advanced maternal age or obesity, all P > 0.05. If a
243
fetal abnormality was undetected after 2 standard sonograms (initial and follow-up),
244
neonatal survival was at least 95% in all groups. Undetected anomalies are included in
245
the supplemental table.
12
Comment
246 247
Principal Findings
248
There were three primary findings from our study of fetal anomaly detection with follow-up
249
sonography performed for standard indications. With either the first or second follow-up
250
examination, we identified 45% of fetuses with (residual) major structural anomalies that
251
had not been detected on prior standard sonograms. This percentage was significantly
252
lower than detection at the initial examination and corresponds to a relatively low absolute
253
percentage of pregnancies with anomalies detected during follow-up sonography – in only
254
0.2% of pregnancies was an anomalous fetus identified at the first follow-up examination.
255
Because the prevalence of anomalies is lower in a low-risk population, and because the
256
majority of anomalous fetuses are detected with the initial examination, the number of
257
follow-up examinations required to detect an anomalous fetus increased sharply with
258
each successive examination. Second, anomaly detection was not affected by the
259
gestational age at which the follow-up examination was performed, which is reassuring
260
from the perspective that its utility was not compromised at later gestational ages. Finally,
261
because severe anomalies are more likely to come to attention with standard sonography,
262
infants with undetected anomalies were significantly more likely to survive to hospital
263
discharge.
264
Results
265
The clinical utility of follow-up sonography for fetal anomaly detection in low-risk
266
pregnancies has been acknowledged as an unresolved issue and an area in which further
267
research is needed.2 The topic is challenging to study, as it requires both reliable data
268
about the prevalence of anomalous fetuses in a population receiving standard
13 269
sonography and the sensitivity of standard sonography for anomaly detection, because
270
these are needed to determine the number or proportion with residual anomalies that
271
might be detected with a follow-up sonogram. Based on birth defect registry data from the
272
United States and Europe, it is generally acknowledged that major anomalies are
273
identified in 2 to 3 percent of newborns.8,9 The prevalence is assumed to be lower in low-
274
risk pregnancies receiving standard sonography than in those receiving detailed
275
sonography. In our study population, anomaly prevalence in low-risk pregnancies and
276
detection with standard sonography were 1% and 64%, respectively. Prior data from our
277
group is consistent with that prevalence.10 Our current anomaly detection rate with
278
standard sonography is higher than we reported 10 years ago (which was 53%, 95% CI
279
45% to 62%). This may reflect the practice change of routinely offering sonography to all
280
low-risk pregnancies as well as improvements in ultrasound technology. There is limited
281
contemporary data on this topic. For example, the American College of Obstetricians and
282
Gynecologists Practice Bulletin on Ultrasound in Pregnancy includes an anomaly
283
detection rate of 40%, but that is based on a review of studies published between 20 and
284
35 years ago.3,11
285
Clinical Implications
286
There have been several recent studies of anomaly detection with follow-up sonography.
287
Most have included both detailed and standard sonograms (high-risk and low-risk
288
pregnancies) or have had the limitation of not capturing undetected anomalies –
289
precluding calculation of sensitivity and residual risk. Silvestri and colleagues (2016)
290
reviewed 1560 follow-up sonograms performed for incomplete anatomy visualization and
291
identified major abnormalities in 16 fetuses: 6 in anatomic components previously not
14 292
visualized and 10 in organ systems previously documented to appear normal.6 Detailed
293
sonograms were included in this series. We hypothesize that our lower rate of undetected
294
anomalous fetuses (0.2%) may be because we did not include detailed sonograms, such
295
that our pregnancies had lower a-priori risk in addition, potentially, to lower anomaly
296
detection. O’Brien and colleagues (2017) identified 1 major anomaly in a series of 205
297
low-risk pregnancies (0.5%) that received follow-up sonography, concluding that the
298
clinical yield of such examinations was low.12 Wood and colleagues (2018) reviewed a
299
series of 1796 follow-up sonograms – which also included detailed exams, and identified
300
major anomalies in 11 (0.6%), reporting that of all anomalies detected prenatally, more
301
than 90% were detected at the initial sonogram.13 Were we to apply this methodology to
302
our series, 90% of the anomalies that we detected prenatally (248/276) were also
303
identified at the initial sonogram. A strength of our population-based series is that we
304
were also able to evaluate undetected anomalies. We chose to analyze our data
305
according to proportion of residual anomalies detected and undetected in an effort to
306
improve counseling, realizing that even anomalies without reliable sonography detection
307
can be devastating to families.
308
Unlike other studies,6,12,14 ours did not include detection of minor aneuploidy
309
markers or findings from subsequent specialized sonography. Minor markers are
310
problematic from the standpoint of detection because they are not verified in the neonatal
311
period, and thus sensitivity cannot be calculated. Also, minor markers are intended to
312
improve aneuploidy detection, and since sonography cannot diagnose aneuploidy, we did
313
not consider minor markers in our series and excluded pregnancies that received detailed
314
sonography after detection of minor markers.
15 315
Research Implications
316
Our study differed from others in that we reviewed anomaly detection with follow-up
317
sonography that had been performed for any indication and at any point in gestation.
318
During the study period, we did not routinely perform follow-up sonography when
319
evaluation of fetal anatomy was limited, and while that was the indication for many
320
second-trimester follow-up sonograms (Table 3), anomaly detection was equally frequent
321
later in pregnancy in exams performed for other indications (Table 4). This work should
322
therefore be translated in a prospective nature. Future prospective work that identifies
323
how many follow up ultrasounds are indicated to ensure proper anatomical identification
324
is needed. Additionally, this work should be replicated in the setting of pregnancies that
325
are high risk for fetal anomalies.
326
Strengths and Limitations
327
Our study had several limitations that should be noted. Because we did not perform
328
follow-up sonography in every pregnancy, our findings apply only to those with an
329
indication, which in our series was approximately 30%. During the study period, our
330
county hospital did not have the capability to perform detailed sonography for maternal
331
age > 35 or obesity, and so we analyzed anomaly detection and neonatal survival
332
separately in these pregnancies (see Table 5). We found no statistically or clinically-
333
relevant difference in anomaly detection between our overall cohort and pregnancies
334
without these risk factors, which is reassuring in terms of the generalizability of our
335
findings to pregnancies without them. An additional limitation is that our study findings
336
only apply to anomalies detectable in the immediate neonatal period. It was not possible
337
for us to capture infants with anomalies too subtle to come to attention before the infant
16 338
was discharged from the hospital. Pregnancies identified to have minor aneuploidy
339
markers during initial standard sonograms were included in our study, because Down
340
syndrome detection was not an outcome, and we understand this might raise concern
341
that identification of minor markers led to more comprehensive evaluation. However, our
342
group recently reported detection of major anomalies in pregnancies with Down
343
syndrome, and it is comparable to our detection rate for major anomalies in the current
344
study (in the absence of Down syndrome).15 Thus, we feel that none of these limitations
345
suggests that our findings would not be applicable in other settings or centers. Strengths
346
of our series is that it is large and population-based, that we had neonatal outcomes for
347
all deliveries, and that anomalies were categorized according to a recognized system.
348
Conclusions
349
Because of our focus on standard sonography, our data may be used to counsel low-risk
350
pregnancies about the utility and limitations of routine sonography. When follow-up
351
sonography was indicated, as it was in approximately 30% of our pregnancies, additional
352
anomalous fetuses were identified. However, a larger number of follow-up examinations
353
were required: more than 400 follow-up examinations to detect a fetus with a major
354
anomaly, and if that follow-up examination was normal, more than 700 additional follow-
355
up sonograms per anomalous fetus detected. This supports the consensus-based
356
recommendation (Reddy, 2014) that a second follow-up sonogram not be performed
357
solely for better visualization. Women with low-risk pregnancies may be reassured that
358
the likelihood that the fetus has an undetected major anomaly is below 0.5% after a
359
normal standard sonogram. If follow-up sonography is indicated, knowledge that 45% of
360
residual anomalies may be detected can provide additional reassurance.
17
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Reddy UM, Abuhamad AZ, Levine D, Saade GR. Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology and Society of Radiologists in Ultrasound fetal imaging workshop. Obstet Gynecol 2014; 123(5):1070-82.
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Ultrasound in Pregnancy. Practice Bulletin No. 175 American College of Obstetricians and Gynecologists. Obstet Gynecol 2016;128:e241-56.
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Chung JH, Pelayo R, Hatfield TJ, Speir VJ, Wu J, Caughey AB. Limitations of the fetal anatomic survey via ultrasound in the obese obstetrical population. J MaternFetal Neonatal Med 2012;25:1945-9.
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Pasko DN, Wood SL, Jenkins SM, Owen J, Harper LM. Completion and sensitivity of the second-trimester fetal anatomic survey in obese gravidas. J Ultrasound Med 2016;35:2449-57.
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Silvestri MT, Pettker CM, Raney JH, Xu X, Ross JS. Frequency and Importance of Incomplete Screening Fetal Anatomic Sonography in Pregnancy. J Ultrasound Med 2016;35:2665-73.
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Weight gain during pregnancy. Committee Opinion No. 548. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:210-2.
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Cragan JD, Gilboa SM. Including prenatal diagnoses in birth defects monitoring: experience of the Metropolitan Atlanta Congenital Defects Program. Birth Defects Res A Clin Mol Teratol 2009;85:20-9.
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Dolk H, Loane M, Garne E: The prevalence of congenital anomalies in Europe. Adv Exp Med Biol 2010; 686;349-64.
10. Dashe JD, McIntire DD, Twickler DM. Effect of maternal obesity on the ultrasound detection of anomalous fetuses. Obstet Gynecol 2009;113:1001-7. 11. Levi S. Ultrasound in prenatal diagnosis: polemics around routine ultrasound screening for second trimester fetal malformations. Prenat Diagn 2002;22:285–95. 12. O’Brien K, Shainker SA, Modest AM, Spiel MH, Rsetkova N, Shah N, et al. Cost analysis of following up incomplete low-risk fetal anatomy ultrasounds. Birth 2017; 44(1);35-40.
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13. Wood SL, Owen J, Jenkins SM, Harper LM. The utility of repeat midtrimester anatomy ultrasound for anomaly detection. Am J Perinatol 2018; 35(14):1346-51. 14. Waller SA, O’Connell K, Carter A, Gravett MG, Dighe M, Richardson ML, et al. Incidence of fetal anomalies after incomplete anatomic surveys between 16 and 22 weeks. Ultrasound Q 2013;29(4):307-12. 15. Hussamy DJ, Herrera CL, Twickler DM, McIntire DD, Dashe JS. Number of risk factors in Down syndrome pregnancies. Am J Perinatol 2019;36(1):79-85.
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Table 1: Maternal Demographic Characteristics, Pregnancies with Anomalous Fetuses N=387 Maternal age <35 >35 Race/ethnicity Black Hispanic White Other Parity Nulliparous Multiparous BMI Normal Overweight Obese class 1 Obese class 2 Obese class 3
420 421 422 423 424 425 426 427 428 429 430 431
Frequency (%)
313 (81) 74 (19) 47 (12) 316 (82) 10 (3) 14 (3) 112 (29) 275 (71) 131 (34) 141 (36) 64 (17) 32 (8) 19 (5)
20 432 433
434 435 436 437 438 439 440 441
Table 2: Proportion of Anomalous Fetuses Detected on Initial and Follow-up Sonograms
Anomalous fetuses
Detected on initial exam 248/387 (64)
Detected on follow-up exam 28/62 (45)
Detection, initial and follow-up exams 282/387 (73)a
Single organ system anomalies
208/331 (63)
24/55 (44)
232/331 (70)a
Multiple organ system anomalies
40/56 (71)
4/7 (57)
44/56 (79)
Organ system Cardiac CNS Craniofacial Gastrointestinal Pulmonary Renal/Genitourinary Skeletal Other
62/97 (64) 40/58 (69) 39/53 (74) 43/71 (61) 14/17 (82) 76/106 (72) 15/20 (75) 10/15 (67)
11/19 (55) 4/14 (29) 0 3/8 (38) 1/1 (100) 17/21 (81)b 0 2/3 (67)
73/97 (76) 44/58 (76) 39/53 (74) 46/71 (65) 15/17 (88) 93/106 (88)a 15/20 (75) 12/15 (80)
Data presented as N (%) a P<0.05 for increase in anomaly detection after follow-up sonogram compared with initial detection; bP<0.05 for comparison of individual organ systems with overall detection of anomalous fetuses
21 442
443 444 445
Table 3: Indication for First Follow-up Sonogram Indication Limited fetal anatomy evaluation Size-date discrepancy Fetal growth surveillance Hypertension Gestational diabetes Prior pregnancy with demise Decreased amniotic fluid suspected Preterm rupture of membranes Preterm labor Abnormal placentation (previa) Data presented as N (%)
N = 62 26 (42) 15 (24) 15 (24) 7 (11) 7 (11) 1 (2) 2 (3) 2 (3) 1 (2) 1 (2)
22 446 447
Table 4: Detection of anomalous fetuses according to gestational age at follow-up sonogram 18-21 6/7 wks
448 449 450 451 452 453
Anomalies detected, initial sonogram
248 anomalies, 40,335 exams, 0.6%
Anomalies detected, first followup sonogram
7 anomalies, 3475 exams, 0.2%
a
22-25 6/7 wks
26-29 6/7 wks
30-30 6/7 wks
34-37 6/7 wks
Total 248 anomalies, 40,335 exams, 163 exams per anomaly
4 anomalies, 1914 exams, 0.2%
1 anomalies, 991 exams, 0.3%
7 anomalies, 2037 exams, 0.4%
9 anomalies, 3329 exams, b 0.3%
28 anomalies, 11,779 exams, 420 exams per a anomaly
Significantly more follow-up sonograms were performed per anomalous fetus detected, compared with initial sonograms, P < 0.001; bNo significant difference in detection of anomalous fetuses during first follow-up sonogram according to gestational age, P=0.7
23 454 455
Table 5. Anomaly detection and neonatal survival according to maternal age and BMI Age < 35
Age > 35
Detected initially
313 (81) 201 (64)
Neonatal survival Detected at 1st follow-up Neonatal survival st
Undetected at 1 follow-up Neonatal survival 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472
N = 74 (19) 47 (64)
BMI < 30 kg/m2 N = 272 (70) 180 (66)
BMI > 30 kg/m2 N = 115 (30) 68 (59)
178 (89)
40 (85)
162 (90)
56 (82)
21/45 (47)
7/17 (41)
17/35 (49)
11/27 (41)
20/21 (95)
6/7 (86)
16/17 (94)
10/11 (91)
24/45 (53)
10/17 (59)
18/35 (51)
16/27 (59)
23/24 (96)
10/10 (100)
18/18 (100)
15/16 (94)
Data presented as N (%) P-values for all comparisons between maternal age cohorts and BMI cohorts all > 0.05, for anomaly detection as well as neonatal survival.
24 473
Figure 1: Flow diagram of anomaly detection by initial and follow-up sonograms.
474
a
475
exams (p=0.01). bIncreasing numbers of sonograms were required to detect a single
476
anomalous fetus at the initial exam, 1st follow-up exam, and 2nd follow-up exam,
477
respectively (p<0.001). cThose detected initially were less likely to survive to hospital
478
discharge compared to those who were undetected, p=0.002
479 480 481 482
Anomaly detection on the initial sonogram was significantly greater than on follow-up
25 483
Supplemental Table: Undetected Anomalies
Organ System Cardiac
Craniofacial
GI
GU
Muscular
Neuro
Pulmonary 484
Anomaly Ventricular septal defect (7) Tetralogy of Fallot (4) Transposition of the great vessels (3) Coarctation of the Aorta (2) Pulmonary Valve Hypoplasia (2) Anomalous pulmonary venous return (2) Tricuspid Regurgitation (1) Aortic Valve Stenosis (1) Pulmonary atresia (1) Endocardial cushion defect (1) Cleft palate (7) Cleft lip (3) Choanal Atresia (1) Absent ear canal (1) Micrognathia (1) Other congenital malformation of face/neck (1) Imperforate anus (16) Tracheo-esophageal fistula (3) Malrotation (3) Esophageal atresia (2) Ileal atresia (2) Diaphragmatic Hernia (2) Omphalocele (1) Jejunal Atresia (1) Hydronephrosis (9) Ambiguous Genitalia (2) Duplicated Collecting System (1) Cross Fused ectopia (1) Hypospadias (1) Reduction defect of upper arm (2) Achondroplasia (1) Micromelia (1) Poland anomaly (1) Microcephaly (7) Hydrocephalus (5) Lipomeningocele (1) Cerebellar hypoplasia (1) Sacral Teratoma (1) Encephalocele (1) Lymphangioma (1) Contracture (1) Cystic adenomatoid malformation (1)