Research

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OBSTETRICS

First-trimester detection of fetal anomalies in pregestational

diabetes using nuchal translucency, ductus venosus
Doppler, and maternal glycosylated hemoglobin
Jena L. Miller, MD; Margarita de Veciana, MS, MD; Sifa Turan, MD; Michelle Kush, MD;
Anita Manogura, MD; Christopher R. Harman, MD; Ahmet A. Baschat, MD

tional diabetes correlates with their glycemic control. This study aimed
to assess the predictive performance of first-trimester fetal nuchal
translucency (NT), ductus venosus (DV) Doppler, and hemoglobin A1c
(HbA1c) to predict fetal anomalies in women with pregestational
diabetes.

(r2, 0.15; P .001) and 8.35% was the optimal cutoff for prediction
of anomalies with an area under the curve of 0.72 (95% confidence interval, 0.57 0.88). Therefore, first-trimester prediction of anomalies
was best in women with increased NT or HbA1c 8.3% (sensitivity
70.6%, specificity 77.4%, positive predictive value 16.2%, negative
predictive value 97.7%, P .001).

STUDY DESIGN: This was a prospective observational study of patients

CONCLUSION: In women with pregestational diabetes and poor glyce-

undergoing first-trimester NT with DV Doppler. Screening performance

was tested for first-trimester parameters to detect fetal anomalies.

mic control, an increased NT increases risks for major fetal anomalies.

Second-trimester follow-up is required to achieve accurate prenatal
diagnosis.

OBJECTIVE: The frequency of fetal anomalies in women with pregesta-

RESULTS: Of 293 patients, 17 had fetal anomalies (11 cardiac, 7 ma-

jor, 3 multisystem). All anomalous fetuses were suspected prenatally.

One had NT 95th centile, 2 had reversed DV a-wave, and 13 had
HbA1c 7.0%. The HbA1c was the primary determinant of anomalies

Key words: diabetes, ductus venosus Doppler, first trimester,

glycosylated hemoglobin, nuchal translucency

Cite this article as: Miller JL, de Veciana M, Turan S, et al. First-trimester detection of fetal anomalies in pregestational diabetes using nuchal translucency,
ductus venosus Doppler, and maternal glycosylated hemoglobin. Am J Obstet Gynecol 2013;208:385.e1-8.

omen with pregestational diabetes mellitus are at substantially

increased risk for having a fetus with
congenital anomalies. This risk is related
to periconceptional glycemic control as
From the Department of Obstetrics,
Gynecology, and Reproductive Sciences,
University of Maryland School of Medicine,
Baltimore, MD (Drs Miller, Turan, Kush,
Manogura, Harman, and Baschat), and the
Department of Obstetrics and Gynecology,
Eastern Virginia Medical School, Norfolk, VA
(Drs Miller and de Veciana).
Received Oct. 7, 2012; revised Jan. 2, 2013;
accepted Jan. 19, 2013.
The authors report no conflict of interest.
Presented at the 29th annual meeting of the
Society for Maternal-Fetal Medicine, San
Diego, CA, Jan. 26-31, 2009.
Reprints: Ahmet A. Baschat, MB, BCh,
Department of Obstetrics, Gynecology, and
Reproductive Sciences, University of Maryland,
Baltimore, 22 S. Greene St., N6E12, Baltimore,
MD 21201. abaschat@umm.edu.
0002-9378/$36.00
2013 Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2013.01.041

evidenced by the higher frequency of fetal anomalies in women with raised glycosylated hemoglobin (HbA1c) levels at
the beginning of pregnancy.1-3 Fetal
anomalies predominantly involve cardiac, musculoskeletal, urogenital, and
central nervous systems and of these cardiovascular anomalies comprise the
highest proportion and are the greatest
contributor to perinatal mortality.4-6 In
recognition of the frequency and pattern
of anomalies, typical prenatal screening
for women with pregestational diabetes
consists of a targeted second-trimester
ultrasound followed by fetal echocardiography. However, since the risk for fetal
anomalies in pregestational diabetes can
already be estimated in early pregnancy
by the HbA1c level these women may
benefit from potential early detection of
fetal anomalies in the first trimester.7,8
Such early detection can offer the advantage of early consideration of management options, early risk stratification, and, if pregnancy termination is
desired, the advantage of increased pri-

vacy and decreased cost, morbidity,

and mortality.9
First-trimester ultrasound measurement of the fetal nuchal translucency
(NT) thickness and integration of this
measurement with additional parameters not only identifies risk for
aneuploidy with greater accuracy than
second-trimester screening but also predicts fetal anomalies.10-12 In addition to
fetal aneuploidy, an increased NT and
abnormal ductus venosus (DV) flow velocity waveform can independently predict cardiovascular and renal anomalies
and adverse perinatal outcome.13-16 As
many of the anomalies observed in pregestational diabetes are also associated
with an increased NT and since the dimension of the NT appears to be independent of the HbA1c or the degree of
glycemic control,17-19 first-trimester
screening using NT thickness and
DV Doppler may lead to their early
identification.
Accordingly, it was the aim of this
study to test the hypothesis that either an

MAY 2013 American Journal of Obstetrics & Gynecology

385.e1

Research

Obstetrics

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TABLE 1

Maternal characteristics, first-trimester

parameters, and perinatal outcomes
Parameter

Data

Maternal characteristics

.....................................................................................................................................................................................................................................

Age, y

30 (1845)

.....................................................................................................................................................................................................................................

Gravidity

2 (117)

Parity

1 (014)

.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................

Ethnicity, n (%)

............................................................................................................................................................................................................................

African American

159 (53.6)

White

122 (41.5)

Asian

5 (1.7)

Hispanic

3 (1)

Asian Indian

1 (0.3)

Undocumented

3 (1)

............................................................................................................................................................................................................................
............................................................................................................................................................................................................................
............................................................................................................................................................................................................................
............................................................................................................................................................................................................................
............................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................
2

BMI (kg/m )

34.6 (18.576.4)

.....................................................................................................................................................................................................................................
2
a

BMI (kg/m ) 30, n (%)

127 (68.6)

BMI (kg/m ) 40, n (%)

48 (25.9)

.....................................................................................................................................................................................................................................
2
a
..............................................................................................................................................................................................................................................

First-trimester parameters

.....................................................................................................................................................................................................................................

HbA1c, g/dL

7.0 (4.815.4)

.....................................................................................................................................................................................................................................

GA, wk

12.5 (11.114.4)

CRL, mm

64.6 (42.686)

NT, mm

1.4 (1.07.7)

DVPI

1.07 (0.92.37)

.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................
b

Perinatal outcomes

.....................................................................................................................................................................................................................................

GA at delivery (wk), median (interquartile range)

37.6 (36.138.5)

.....................................................................................................................................................................................................................................

Birthweight (g), median (interquartile range)

3298 (26483725)

.....................................................................................................................................................................................................................................

Live birth

279 (95.2)

.....................................................................................................................................................................................................................................

Spontaneous miscarriage

7 (2.4)

Elective termination

5 (1.7)

FDIU

2 (0.7)

.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................

Cesarean delivery

180 (61.4)

Apgar 5 at 5 min

1 (0.4)

.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................

NICU admission

73 (24.9)

..............................................................................................................................................................................................................................................

This table describes study population at enrollment, variables measured at time of first-trimester screening, and perinatal
outcomes. Data are median (range) unless otherwise specified.
BMI, body mass index; CRL, crown-rump length; DVPI, ductus venosus pulsatility index; FDIU, fetal demise in utero; GA,
gestational age; HbA1c, glycosylated hemoglobin; NICU, neonatal intensive care unit; NT, nuchal translucency.
a

Percent of 185 patients with recorded BMI; b Data are n (%) unless otherwise specified.

Miller. First-trimester screening for fetal anomalies in women with pregestational diabetes. Am J Obstet Gynecol 2013.

increased first-trimester NT or abnormal DV Doppler will detect fetal anomalies in women with pregestational diabetes, especially in association with an
elevated HbA1c.
385.e2

M ATERIALS AND M ETHODS

This is a prospective, observational study
of women with pregestational diabetes
presenting for first-trimester screening
at the University of Maryland Center for

American Journal of Obstetrics & Gynecology MAY 2013

Advanced Fetal Care and the Division of

Maternal-Fetal Medicine, Eastern Virginia Medical School, from April 2003
through June 2009. The study protocol
was approved by the institutional review
boards of both institutions. Inclusion
criteria were preexisting diabetes mellitus requiring medical therapy with confirmed viable intrauterine pregnancy in
women who presented for first-trimester
screening. Maternal demographics, pregnancy/diabetes history, and HbA1c
were obtained as a part of routine clinical
practice. Patients agreed to follow-up
evaluation as part of the study.
Women underwent a standardized
first-trimester ultrasound examination
between 110 and 136 weeks gestation (crown-rump length [CRL], 45-84
mm). The gestational age was calculated
from the last menstrual period based on
the Naegele rule. If there was a 1 week
discrepancy between the calculated gestational age and the CRL, the dates were
adjusted to the latter. In addition to the
CRL measurement, the examination included measurement of the NT; documentation of the head, brain, stomach,
abdomen, bladder, and extremities; and
4-chamber heart view. The DV waveform was assessed by pulsed wave Doppler as previously described and the length
of the examination was limited to 2 minutes with power settings adjusted to minimize fetal exposure.13,20 When the typical DV waveform was obtained, the
image was frozen, the pulsatility index
was measured, and the direction of
blood flow during atrial systole was visually assessed as antegrade, absent, or retrograde. NT and DV Doppler measurements were performed by certified
sonographers according to Fetal Medicine Foundation21 or NT Quality Review
Program.12,22 Either transabdominal or
transvaginal approach was used and time
to complete the examination was at the
discretion of the examiner to optimize
visualization of all structures.
Following the first-trimester ultrasound, women with continuing pregnancies underwent second-trimester
targeted ultrasound at 18-20 weeks gestation and fetal echocardiography at
22-24 weeks gestation according to
recommendations of the International

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Research

TABLE 2

First-trimester characteristics and outcome of 17 anomalous fetuses

Case

GA,
wk

BMI,
kg/m2

CRL,
mm

HbA1c,
%

11.6

49.7

55

8.7

13.2

41

70.7

7.1

NT,
mm

DV
PI

DV
a-wave

GA Dx,
wk

Outcome

Anomaly

Positive

22

Live birth

TOF

1.5

1.14

Positive

23.4

Live birth

TOF, holoprosencephaly, cleft

lip/palate

................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

12.8

76.4

73

12.1

27.5

56.6

8.6

2.6

Positive

29.3

Live birth

TOF, AV canal defect

15.4

1.6

1.27

Positive

25.1

Live birth

ASD/VSD, pulmonary stenosis,

hypospadiasa

................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

12.3

39.6

66.1

na

1.6

13.6

28.9

73

12.1

1.3

na

Reversed

12.3

TOP

Encephalocele

Positive

13.6

TOP

Omphalocele, VACTERL association,

cerebellar hypoplasiab

................................................................................................................................................................................................................................................................................................................................................................................

1.12

................................................................................................................................................................................................................................................................................................................................................................................

12

29.3

56.5

9.5

2.7

1.06

Positive

16

TOP

Fused thalami, VSD,

ventriculomegaly, 2VC, megacystis

................................................................................................................................................................................................................................................................................................................................................................................

12.5

26.7

65.1

12.1

1.8

13.1

31.6

69.9

9.6

2.4

10

14.2

36

83

10.7

1.5

11

12.3

23.9

63.4

5.8

12

12.4

na

59.6

5.5

13

13.6

33

71

10.4

1.2

14

12.6

na

51.8

9.2

1.3

15

13.5

32.5

73.7

10.8

1.2

16

12.4

55

59

8.4

1.4

0.95

Positive

26.4

Live birth

Bicuspid aortic valve, mild RVH

Positive

19.1

Live birth

VSD

1.06

Positive

19.6

Live birth

VSD

1.2

0.9

Positive

19

Live birth

VSD

1.4

0.83

Positive

21.5

Live birth

VSD, pericardial effusion

2.3

Reversed

24.1

FDIU

2VC, echogenic bowel

1.04

Positive

19

Live birth

2VC, placental vascular mass

0.99

Positive

19.5

Live birth

2VC, hydrocele

0.62

Positive

18.6

Live birth

Pulmonary stenosis, liver

calcifications

................................................................................................................................................................................................................................................................................................................................................................................

na

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
a

................................................................................................................................................................................................................................................................................................................................................................................

17

11.5

24.7

53.2

5.7

1.6

0.6

Positive

24.3

Live birth

Persistent right umbilical vein

................................................................................................................................................................................................................................................................................................................................................................................

This table describes case of each fetal anomaly and measurements taken at first-trimester evaluation and perinatal outcome.
ASD, atrial septal defect; AV, atrioventricular; BMI, body mass index; CRL, crown-rump length; DV, ductus venosus; Dx, diagnosis; FDIU, fetal demise in utero; GA, gestational age; HbA1c, hemoglobin
A1c; na, not available; NT, nuchal translucency; PI, pulsatility index; RVH, right ventricular hypertrophy; TOF, tetralogy of Fallot; TOP, termination of pregnancy; VACTERL, association of vertebral
anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, renal and limb defects; VSD, ventricular septal defect; 2VC, 2-vessel cord.
a

Finding diagnosed postnatally; b Omphalocele was diagnosed in first trimester, additional anomalies were diagnosed early in second trimester prior to elective termination of pregnancy.

Miller. First-trimester screening for fetal anomalies in women with pregestational diabetes. Am J Obstet Gynecol 2013.

Society of Ultrasound in Obstetrics

and Gynecology.23,24 Subsequent ultrasounds for growth and fetal assessment
were performed as clinically indicated.
At the first-trimester sonogram, fetal
anomalies were only reported if the diagnosis was certain. Patients with suspected anomalies were informed of the
findings with a caveat that a follow-up
sonogram would focus on a more complete evaluation of the suspected anomaly. For patients where a prenatal diagnosis was possible with a reasonable
amount of certainty, fetal anomalies
were documented and classified according to organ system. An anomaly was defined as a malformation resulting from
abnormal development. Major fetal
anomalies were defined as malforma-

tions that are lethal, cause serious impairment, or require intervention. Those
that were present but anticipated to have
minimal functional implications were
defined as minor. Additional ultrasound
markers and findings were recorded if
observed. Patients were managed according to the standard of care regardless
of study participation.
Pregnancy outcome and delivery details were obtained from patient records
or obstetric providers. An attending pediatrician performed the neonatal evaluation prior to hospital discharge. Anomalies were confirmed and any additional
findings were documented.
NT thickness 95th centile for CRL
and reversal of the a-wave in the DV were
evaluated as first-trimester predictors of

fetal anomalies. According to the recommendations of the American Diabetes

Association, HbA1c 7% defined poor
glycemic control. The presence of either
an abnormal NT or DV was tested as a
predictor of any fetal anomaly, major
anomalies, and specific organ system
anomalies. The predictive accuracy was
also evaluated stratified by an abnormal
HbA1c. Fisher exact test and 2 test were
used as appropriate for analysis of categorical variables. Mann Whitney U test
was used for comparison of continuous
variables. Receiver operating characteristic (ROC) curves were constructed to
identify if cutoffs with superior first-trimester screening performance could be
identified for continuous variables. Area
under the ROC curves and 95% confi-

MAY 2013 American Journal of Obstetrics & Gynecology

385.e3

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TABLE 3

Characteristics of pregnancies with and without anomalies

Characteristic

Anomaly (n 17)

No anomaly (n 276)

P value

Age, y

31.1 6.4

30.2 5.8

.508

BMI, kg/m

37.2 13.6

34.9 8.8

.938

HbA1c, %

9.4 2.6

7.3 1.9

.001

NT, mm

1.6 0.5

1.5 0.6

.425

NT 95th percentile

1 (6)

4 (1)

.277

DV PI

1.1 0.4

1.1 0.3

.172

DV reversed a-wave

2 (12)

6 (2)

.77

..............................................................................................................................................................................................................................................
2
..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................
a
..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................
a
..............................................................................................................................................................................................................................................

GA at delivery, wk

33.5 6.5

36.4 4.2

.009

..............................................................................................................................................................................................................................................

Birthweight, g

2470 1311

3183 882

.045

..............................................................................................................................................................................................................................................
a

Live birth

13 (76)

266 (96)

.005

Cesarean delivery

8 (47)

172 (62)

.189

NICU admission

9 (53)

64 (23)

.021

..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................

Data are mean SD or n (%).

BMI, body mass index; DV, ductus venosus; GA, gestational age; HbA1c, glycosylated hemoglobin; NICU, neonatal intensive
care unit; NT, nuchal translucency; PI, pulsatility index.
a

Fisher exact test; all others are 2 or Mann-Whitney U tests.

Miller. First-trimester screening for fetal anomalies in women with pregestational diabetes. Am J Obstet Gynecol 2013.

dence intervals were compared and logistic regression was used to identify the
primary predictors of fetal anomalies. A
P value .05 was considered statistically
significant. Statistical software IBM SPSS
Statistics 20 (SPSS Inc., Chicago, IL) was
used for the analysis.

R ESULTS
From April 2003 through June 2009, 341
women consented for study participation. The first-trimester ultrasound revealed miscarriage in 3, and a fetal CRL
outside the gestational age criteria in 23
women. In 10 women, NT or DV Doppler could not be obtained; 11 women
were lost to follow-up and 1 patient
withdrew participation leaving 293 patients for final analysis (Table 1).
Seventeen women had an anomalous
fetus, of which 7 cases were major anomalies and 10 were minor anomalies. Major anomalies were diagnosed at each examination with most of them being
identified in the first trimester (n 2,
28.6%) or at the time of fetal echocardiogram (n 3, 42.9%). The second-trimester detailed anatomy scan and interval growth scan each identified 1 fetus
with a major anomaly. The second-trimester ultrasound examination was
385.e4

most important for identifying minor

anomalies (n 6, 60%) but additional
minor anomalies were detected at fetal
echocardiogram (n 3, 30%) and at the
interval growth scan (n 1, 10%) As a
single organ system cardiac anomalies
were most frequent (n 11, 65%) (Table 2). None of the cases with isolated
ventricular septal defects required surgical intervention in the immediate postnatal period. Limited visualization of 1
organ systems occurred in 13 cases
(4.4%) at the second-trimester anatomy
scan.
Of pregnancies, 95% ended in live
birth and 70% of these were at term. Two
fetal demises occurred: 1 in the context
of severe preeclampsia and 1 due to fetal
growth restriction, however autopsy
data were not available to identify the
precise cause. Of 5 elective terminations,
2 were for major fetal anomalies, 1 was
for previable preterm premature rupture
of membranes, 1 was for a fetus with trisomy 21, and 1 was for an anomalous
fetus with a high suspicion of trisomy 21
with unsuccessful karyotype culture
(case 7) (Table 1). There were no other
documented cases of aneuploidy.
Baseline characteristics between pregnancies with and without anomalies

American Journal of Obstetrics & Gynecology MAY 2013

were similar, except women with an

anomalous fetus had higher first-trimester HbA1c. These pregnancies were also
delivered at earlier gestational age and
less likely to result in live birth. Neonates
with anomalies had lower birthweight
and were more likely to require neonatal
intensive care unit admission (Table 3).
For pregnancies ending in live birth,
all anomalies were confirmed postnatally and additional anomalies were diagnosed in 2 cases. In 1 fetus with a complex cardiac defect hypospadias was
diagnosed neonatally (case 4). In another fetus with second-trimester ultrasound evidence of liver calcifications,
pulmonary stenosis was diagnosed postnatally (case 16).
Of the 17 fetuses with anomalies, 1 had
NT 95th centile, 2 had reversed DV awave, and 13 had HbA1c 7%. Neither
NT 95th centile nor reversed DV
a-wave alone was predictive for anomalies. Detection rates for NT, DV Doppler,
HbA1c, and various combinations are
shown in Table 4. ROC curve analysis
did not identify better predictive cutoffs
for the NT thickness or the DV pulsatility
index. For the HbA1c, ROC curve analysis identified a value 8.35% as the optimal first-trimester screening cutoff for
prediction of all anomalies (75% sensitivity; 76% specificity; area under the
curve, 0.724; 95% confidence interval,
0.571 0.878) (Figure).
Since 6 of the 7 major defects occurred
in women with HbA1c 7%, we analyzed this subset of patients. Increased
NT alone performed similarly in identifying major and cardiovascular anomalies. Absent or reversed DV a-wave was
not predictive.
Having either an increased NT or
HbA1c 8.35% was predictive for both
the presence of any anomaly or major
anomalies and cardiovascular or vascular anomalies. Evaluating the first-trimester NT and DV screen performance
in patients with HbA1c 8.35%, the addition of NT significantly stratified the
risk for anomalies (Table 4). Logistic regression identified the HbA1c level that
was the best predictor for the presence of
anomalies (Nagelkerke r2, 0.15; P
.001) while the NT thickness and DV awave were not found to be independent

Obstetrics

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TABLE 4

Predictive value of first-trimester screening parameters to detect fetal anomalies

Parameter

n/n

Sensitivity, %

Specificity, %

PPV, %

NPV, %

FPR, %

LR

Area under
curve (95% CI)

NT 95th centile or DV reversed

a-wave

.......................................................................................................................................................................................................................................................................................................................................................................

Any anomaly

3/17

17.6

96.4

23.1

95

3.6

4.9

0.55 (0.400.71)

Major anomaly

2/7

28.6

96.2

15.4

98.2

3.8

7.5

0.57 (0.320.83)

.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

HbA1c 7%

.......................................................................................................................................................................................................................................................................................................................................................................

Any anomaly

13/16

81.3

50.6

9.6

49.8

4.4

97.7

49.4

1.6

0.66 (0.540.78)

50.2

0.75 (0.630.87)

.......................................................................................................................................................................................................................................................................................................................................................................

Major anomaly

6/6

100

100

................................................................................................................................................................................................................................................................................................................................................................................

HbA1c 8.35% or NT 95th centile

.......................................................................................................................................................................................................................................................................................................................................................................

Any anomaly

12/17

70.6

77.4

16.2

97.7

22.6

3.1

0.74 (0.610.87)

Major anomaly

5/7

71.4

75.7

6.8

99.1

24.3

2.9

0.77 (0.600.95)

CV anomaly

8/11

72.7

76.4

10.8

98.6

23.6

3.1

0.72 (0.570.88)

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

HbA1c 8.35% or NT 95th centile

or DV reversed a-wave

.......................................................................................................................................................................................................................................................................................................................................................................

Any anomaly

13/17

76.5

73.6

15.1

98.1

26.4

2.9

0.73 (0.60.86)

Major anomaly

6/7

85.7

72

99.5

28

3.1

0.76 (0.590.94)

CV anomaly

8/11

72.7

72.3

9.3

98.6

27.7

2.6

0.71 (0.560.87)

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

Table demonstrates capability of each parameter or combination of parameters to predict fetal anomalies.
CI, confidence interval; CV, cardiovascular; DV, ductus venosus; FPR, false positive rate; HbA1c, glycosylated hemoglobin; LR, likelihood ratio; NPV, negative predictive value; NT, nuchal translucency;
PPV, positive predictive value.
Miller. First-trimester screening for fetal anomalies in women with pregestational diabetes. Am J Obstet Gynecol 2013.

predictors (P .058 and P .073,

respectively).

C OMMENT
Women with pregestational diabetes are
at significant risk for fetal anomalies due
to the effects of hyperglycemia on the developing embryo.25 The spectrum of fetal anomalies and their relationships to
poor glycemic control opens possibilities
for first-trimester screening by measurement of NT thickness and Doppler of
the DV. Therefore, we prospectively
evaluated the performance of the NT
screening, DV Doppler, and hemoglobin A1c levels to predict fetal anomalies in women with pregestational diabetes mellitus.
In this study population of urban
women with an increased prevalence of
obesity, we observed a preponderance of
cardiac and central nervous system malformations that was probably related to
glycemic control rather than the duration and maternal end-organ effects of
diabetes mellitus.26 About 17% of all
anomalies and approximately 30% of

major anomalies were found in fetuses

with either NT thickness 95th percentile or an abnormal DV a-wave. However, first-trimester screening alone is ineffective and only sequential utilization
of the second-trimester examinations
enabled us to diagnose nearly all fetal
anomalies prenatally. The first-trimester
screen and the second-trimester fetal
echocardiogram were the main contributors to the prenatal diagnosis of major
anomalies, while the second-trimester
anatomy survey was important for detection of minor anomalies. Because of
the risk for anomalies is primarily determined by the HbA1c value, efficiency of
first-trimester prediction of anomalies
by NT is only effective in women with a
value 8.3%.
To our knowledge this is the first prospective first-trimester screening study
in women with pregestational diabetes.
The frequency of anomalies, particularly
of the cardiac and nervous systems, in
our study population is higher than the
anticipated background rate27 but consistent with the spectrum found in preg-

nancies complicated by diabetes or maternal obesity.2,28-30 The escalation of

anomaly frequency from 9.5% for
HbA1c 7% to 20.7% for HbA1c 10%
is equally characteristic, documenting
the effect of poor periconceptional glycemic control on embryogenesis. Increased NT thickness has been found in
association with cardiac defects and central nervous system abnormalities such
as encephalocele.4,31-34 Absent or reversed flow of the DV a-wave has been
associated with an increased risk for cardiac anomalies and adverse outcome in
patients with normal and increased NT
thickness.13,14,35-39 Given the high rate
and spectrum of anomalies in our population we expected a higher prediction
rate integrating HbA1c, NT measurement, and DV Doppler. Although, the
prediction was statistically significant
our results indicate that at most 70% of
anomalies can be predicted in patients at
highest risk with HbA1c 8.3% using
NT screening alone.
In our population, the majority of cardiac defects involved the ventricular sep-

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FIGURE

ROC curves demonstrating relationship between first-trimester screening parameters and fetal anomalies

ROC curves demonstrating curves identify A, HbA1c 8.35% as best cutoff for predicting fetal anomalies in first trimester, relationship of combined
first-trimester screening parameters to identify B, any, C, major, and D, cardiovascular anomalies.
AUC, area under curve; CI, confidence interval; DV, ductus venosus; HbA1c, hemoglobin A1c; NT, nuchal translucency; ROC, receiver operating characteristic.
Miller. First-trimester screening for fetal anomalies in women with pregestational diabetes. Am J Obstet Gynecol 2013.

tum. The proposed basis for the relationship between cardiac defects and an
increased NT or reversed DV a-wave lies
in the hemodynamic disturbance leading to increased central venous pressures. Only one of the fetuses in this series where a tetralogy of Fallot was
associated with a large atrioventricular
canal defect had NT of 2.6 mm. Accordingly, our study suggests that the spectrum of fetal cardiac anomalies observed
in pregnancies of diabetic women is not
associated with an increased NT or DV
a-wave reversal. In the case of the occipital encephalocele the defect was clearly
visible and did not produce an abnormal
385.e6

NT but was associated with a reversed

DV a-wave. In the other patient with a
reversed DV a-wave stillbirth occurred
in the absence of a major fetal anomaly.
This suggests that the relationship between abnormal DV a-wave is too nonspecific to be clinically useful for the
screening for fetal anomalies. Evaluation
of additional markers for cardiac anomalies, such as tricuspid regurgitation into
the first-trimester assessment may increase detection of anomalies in this
population, but this requires further
study.
Although the technique for the NT
and DV measurement was standardized

American Journal of Obstetrics & Gynecology MAY 2013

and under quality control, a detailed

first-trimester anatomic survey with defined criteria aimed at characterization
of suspected anomalies was not part of
our study protocol. Accordingly, we are
unable to ascertain if a detailed first-trimester anatomy sonogram would have
identified a greater proportion of anomalies in the first trimester. The target
population poses a challenge to prenatal
diagnosis since the prevalence and degree of obesity impairs ultrasound visualization of fetal structures. Souka et al40
reported that a maternal body mass index 30 kg/m2 is a hindrance to complete the first-trimester examination. In

Obstetrics

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that series, only 8.2% of the patients were
obese and a complete evaluation was
possible in only 27.6% of them. Given
the 69% rate of obesity in our study this
would translate into an unsuccessful examination in almost 20% of diabetic
women. Despite the diagnostic challenges secondary to maternal obesity, every major anomaly was identified prenatally in our study. Neonates had a
standard pediatric examination rather
than a targeted search for additional
anomalies so it is conceivable that additional anomalies were present but not
clinically detected in the population.
However, this diagnostic accuracy,
which was significantly higher than reported for general prenatal diagnostic
sonography,41 was not accomplished
early in pregnancy and most likely would
not be reproducible in a setting where
follow-up at a specialist center is not
available beyond the second trimester.
Given the limited precision of combined HbA1c, NT, and DV Doppler to
delineate fetal anomalies, detailed firsttrimester anatomic survey deserves prospective evaluation in women with
pregestational diabetes. Studies on firsttrimester anatomic survey usually demonstrate the requirement for follow-up
evaluation in the midtrimester and beyond.8,42,43 In a study of 536 women, Yagel et al44 showed that anomalies can be
misdiagnosed or remain unidentified if
only an early scan is used. In addition,
anomalies, particularly of the central
nervous system, may be difficult to diagnose in the first trimester because this
system is still undergoing development.45 However, a significant advantage of the first-trimester anatomic
survey in women with pregestational diabetes with obesity is the availability of
transabdominal and transvaginal examination approaches. Using transvaginal
sonography, improved diagnostic accuracy has already been documented for
unscreened populations and women at
risk for fetal cardiac defects.46-48 Our results indicate that women with HbA1c
8.3%, increased NT, or reversed DV awave would be an appropriate target for
a study on first-trimester detailed anatomy utilizing transabdominal or trans-

vaginal routes guided by imaging quality

criteria.
The prospective design and large sample size of our study provides important
insight into the importance of serial evaluation for women at increased risk of fetal anomalies. The large number of
anomalies and proportion of women
with poorly controlled diabetes verifies
that we studied our target population. A
standardized first-trimester evaluation
protocol and complete ultrasound data
also ensured that the screening tests were
performed according to quality criteria.
Our patients had a high follow-up rate
and most delivered at our institutions so
the outcome data were obtained directly
rather than from outside providers.
Our study protocol did not allow us to
evaluate the true capacity of a first-trimester targeted anatomic survey as this
was not performed in a systematic way.
Another potential confounder that was
not evaluated was the unblinding of the
follow-up examiners to the findings of
the first-trimester examination results,
which could have positively skewed the
diagnostic accuracy. As guidelines for
detailed first-trimester anatomy assessment are developed, this is anticipated to
be a powerful tool that requires further
study. Additional first-trimester predictors for cardiac anomalies such as tricuspid regurgitation and cardiac axis as well
as more detailed evaluation of the posterior fossa for central nervous system
anomalies are important for investigation in this population.
Our study indicates that first-trimester screening with HbA1c, NT, and DV
Doppler can significantly stratify risks
for fetal anomalies in women with pregestational diabetes. Following this early
risk triage, high diagnostic accuracy can
be achieved during follow-up sonograms. It remains to be determined if a
targeted first-trimester anatomic survey
in women identified to be at highest risk
can parallel this diagnostic accuracy with
the advantage of a choice of scanning
routes and the benefit of early diagnosis.
The high prevalence of anomalies in the
presence of a high HbA1c and maternal
obesity stresses the importance of preconceptional counseling and lifestyle
f
modification.

Research

ACKNOWLEDGMENTS
We acknowledge Oza Bela for database management; Donna Ortiz, RDMS, and Annette
Slater, RDMS, for quality control of ultrasound
images; and Alfred Abuhamad, MD, for review
and critical discussion. All are affiliated with
Eastern Virginia Medical School.

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