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Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21
IJG-08624; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21 Sarah N. Bernstein a,⁎, Devereux N. Saller b, Janet M. Catov b,c, Timothy P. Canavan b a b c
Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA Department of Obstetrics, Gynecology and Reproductive Science, Magee-Women's Hospital of the University of Pittsburgh, Pittsburgh, PA, USA Magee-Women's Research Institute, Pittsburgh, PA, USA
a r t i c l e
i n f o
Article history: Received 15 July 2015 Received in revised form 17 September 2015 Accepted 11 February 2016 Keywords: Down syndrome Fetal growth curves Trisomy 21 Ultrasonography
a b s t r a c t Objective: To construct growth curves specific for fetuses with trisomy 21 (T21) and to compare them with the reference-based standard. Methods: A retrospective cohort study was conducted of ultrasonography examinations from women with singleton pregnancies with a confirmed diagnosis of T21 who sought care at an academic tertiary-care center in the USA between January 1, 2003, and December 31, 2013. Growth curves were constructed using linear regression and compared with the Hadlock standard. Results: The study included 425 ultrasonography examinations from 235 women. The head circumference and femur length were smaller than the reference standards at all gestational ages (head circumference: P = 0.017; femur length: P b 0.001). The abdominal circumference was larger than the reference standard from 29 weeks onward (P b 0.001). The biparietal diameter was smaller in the second trimester and in the late third trimester (P b 0.001). The overall estimated fetal weight was not different from the reference standard. Conclusion: The T21-specific growth curves indicate anthropometric differences between T21 fetuses and the general population. Once validated, such individual growth curves could allow for more accurate prenatal assessment and management of fetuses affected by T21. © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Trisomy 21 (T21) is one of the most common chromosomal abnormalities among live-born neonates: approximately 6000 affected newborns are delivered annually in the USA, resulting in a prevalence of 14 per 10 000 births [1]. Advances in medical care have led to longer life expectancies and improved quality of life for affected individuals. Additionally, the capabilities for screening and prenatal diagnosis of T21 have greatly improved, most recently with the implementation of noninvasive prenatal testing using cell-free fetal DNA. Following genetic counseling, many women with a prenatal diagnosis of T21 choose to continue their pregnancies [2]. However, there is a very limited body of literature on the natural history and appropriate prenatal management of these pregnancies. It is widely accepted that the growth pattern of children with T21 differs considerably from that of euploid children after birth. Postnatally, they are of shorter stature, are heavier, and have smaller head circumferences [3,4]. Additionally, a shortened femur and humerus have been recognized as sonographic markers for T21 [5]. Nevertheless, there is a lack of published, longitudinal studies of growth in fetuses with T21.
Fetuses with T21 are thought to be at increased risk for adverse neonatal outcomes including stillbirth [6], although the underlying pathophysiology remains poorly understood. For this reason, many of these fetuses, especially those thought to be growth-restricted, could be subject to extensive prenatal surveillance, without empirical evidence of benefit. The application of standard growth curves to fetuses with T21 could inappropriately suggest growth restriction. The resultant prenatal testing carries a considerable cost and burden, and could affect decisions regarding the timing of delivery. Additionally, many fetuses affected by T21 have major morphological malformations including congenital heart defects that could require neonatal intervention. Iatrogenic premature delivery could therefore result in additional neonatal morbidity. We hypothesized that fetal biometry differs in the T21 population compared with standard reference curves. The implementation of modified growth curves—once validated—would decrease interventions, decrease patient anxiety, and more accurately target specific fetuses for interventions in this unique population. The primary aim of the present study was to develop such curves for future implementation.
2. Materials and methods ⁎ Corresponding author at: 8 Lamartine Terrace, Boston, MA 02130, USA. Tel.: +1 646 468 0742, +1 617 724 2640; fax: +1 617 726 4267. E-mail address: [email protected] (S.N. Bernstein).
The present study was a retrospective cohort study of all singleton pregnancies with a prenatal or postnatal laboratory diagnosis of T21 for which growth ultrasonography (with biometry) was performed at
http://dx.doi.org/10.1016/j.ijgo.2015.09.034 0020-7292/© 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Bernstein SN, et al, Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.034
2
S.N. Bernstein et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
least once between 14 and 41 weeks of pregnancy at Magee-Women's Hospital (MWH) of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA, between January 1, 2003, and December 31, 2013. The study was approved by the University of Pittsburgh Institutional Review Board, which also granted an exemption from informed consent because of the retrospective nature of the data. The genetic diagnosis was abstracted from the Pittsburgh Cytogenetics Laboratory database. These data were matched with biometric and demographic data from the MWH ultrasonography database. Additional maternal and neonatal data for women who delivered at MWH were derived from the Magee Obstetric Maternal and Infant database. Growth ultrasonography was performed on a Philips iU22 (Philips Healthcare, Andover, MA, USA) ultrasonography system using a C5-1 transabdominal probe, and involved measurement of the biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). All ultrasonography studies were interpreted by board-certified Maternal-Fetal Medicine specialists in a dedicated obstetric and gynecologic ultrasonography practice. The fetal age was determined by either a crown–rump length measurement in the first trimester or an ultrasonography examination in the first or second trimester that confirmed a known, normal last menstrual period. With the former method, the fetal age was changed to the age determined from the crown–rump length if the menstrual age was outside the range of error on the basis of the estimates of Hadlock et al. [7]. With the second method, the ultrasonography age was used if the composite age—obtained using the BPD, HC, AC, and FL in the regression formula of Hadlock et al. [7]—was more than 7% different from the menstrual age. Fetal growth restriction was defined as a fetal weight that was less than the 10th percentile. The number of biometric examinations varied from one to six, the average being two. Growth models for the HC, BPD, AC, FL, and estimated fetal weight were generated using generalized least-squares regression. All examinations were used in the model; however, to control for the effect of multiple examinations for individual participants, panels were established on the basis of the gestational age at the time of the examination. Growth curves with 95% confidence intervals were generated from the regression models. Each individual curve was then compared with a reference-based standard developed by Hadlock [8]. P b 0.05 was considered statistically significant. The statistical analysis was performed using Stata version 13 (StataCorp, College Station, TX, USA). 3. Results The study included 425 ultrasonography examinations from 235 women, 103 of whom delivered at MWH. Most women were white (Table 1). Three-quarters of the women received a prenatal T21 diagnosis, at the time of the first growth ultrasonography. Heart disease was suspected in 50 (21.3%) fetuses. Of the women who delivered at MWH, 16 (15.5%) had gestational or pregestational diabetes and 14 (13.6%) had a hypertensive disorder during pregnancy. Smoking was not common (Table 1). Approximately one-fifth of women who delivered at MWH did so before 37 weeks (Table 2). The cesarean delivery rate was 35.0%. Approximately two-fifths of the neonates born at MWH were admitted to the neonatal intensive care unit, with a mean duration of stay of 5.3 days (Table 3). The HC values of the T21 fetuses were smaller than the reference standards at all gestational ages (P = 0.017) (Fig. 1). The FL curve for the T21 fetuses was similar in shape to that of the reference standard with shorter measurements at all gestational ages (P b 0.001) (Fig. 2). The AC of the T21 fetuses was larger than the reference standard from 29 weeks onward (P b 0.001) (Fig. 3). The BPD was smaller in T21 fetuses during the second trimester and again during the late third trimester (P b 0.001) (Fig. 4). The overall estimated fetal weight calculated from these components was not different from the reference standard (P = 0.09) (Fig. 5).
Table 1 Demographics and clinical characteristics (n = 235).a Characteristic
Value
Age, y Ethnic origin (n = 233) White Black Latina Asian Educationb Not college educated Completed college or higher Unclassified Body mass indexc Height, m Pre-pregnancy weight, kg Parity (n = 194) Primiparous Multiparous Medical comorbidities b Hypertensive disorder d Diabetes e Tobacco use (n = 81) b Time of diagnosis Prenatal Postnatal No. of growth ultrasonography examinations Prenatal anomaly detection Congenital heart disease Non-congenital heart disease Ultrasonography-diagnosed fetal growth restriction
33.7 ± 6.7 205 (88.0) 22 (9.4) 2 (0.9) 4 (1.7) 42 (40.8) 40 (38.8) 21 (20.4) 26.3 ± 7.0 1.7 ± 0.1 71.6 ± 20.1 56 (28.9) 138 (71.1) 14 (13.6) 16 (15.5) 10 (12.3) 175 (74.4) 60 (25.5) 1.8 ± 1.1 39 (16.6) 11 (4.7) 15 (6.4)
a
Values are given as mean ± SD or number (percentage). Data only available for women who delivered at Magee-Women's Hospital (n = 103). c Calculated as weight in kilograms divided by the square of height in meters. d Includes women with chronic and gestational hypertension and those with pre-eclampsia. e Includes women with gestational and pregestational diabetes. b
When the prenatally and postnatally diagnosed cohorts were compared separately, there was no difference in any of the models (data not shown). Curves for the growth-restricted cohort (n = 15) were generated and compared with the T21-specific curves. The diagnosis of fetal growth restriction was not changed when these fetuses were plotted on the T21-specific curves (data not shown).
4. Discussion As hypothesized, the present data indicate that fetal biometry of the T21 population differs from standard reference curves. Each biometric component commonly used to estimate fetal size was significantly different from the reference standard. Although the overall estimated fetal weight in the T21 population did not differ significantly from the reference standard, the effect in individual cases could be substantial. Using a general population-based standard in the T21 population could therefore result in inaccurate centile estimates for growth throughout pregnancy. In a population at increased risk for neonatal Table 2 Delivery outcomes (n = 103).a Characteristic
Value
Pregnancy duration at delivery, wk Preterm/term delivery, wk b 37 ≥ 37 Mode of delivery Vaginal Cesarean
37.5 ± 2.6
a
22 (21.4) 81 (78.6) 67 (65.0) 36 (35.0)
Values are given as mean ± SD or number (percentage).
Please cite this article as: Bernstein SN, et al, Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.034
S.N. Bernstein et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
3
Table 3 Neonatal outcomes (n = 103).a Characteristic Apgar score Minute 1 Minute 5 Birth weight, g Neonatal intensive care unit Admissions Duration of stay, d Unknown Stillbirth a
Value 7.54 ± 1.9 8.4 ± 1.6 2873.8 ± 679.5 39 (37.9) 5.3 ± 9.7 32 (31.1) 2 (1.9)
Values are given as mean ± SD or number (percentage).
morbidity and mortality, it is critically important to obtain precise estimates of fetal size to inform prenatal management. This is exemplified by the MWH subcohort, in which nearly onequarter of the fetuses were delivered preterm and 35.0% were delivered via cesarean delivery. This far exceeded the overall cesarean delivery rate of 27.9% at MWH during the study years (unpublished data). Additionally, 16.6% of the entire study cohort had a prenatally diagnosed congenital heart defect. These numbers could be so high because the study center is a perinatal referral center and is therefore an appropriate location for the delivery of neonates anticipated to require immediate intervention or surgery. Although details of individual deliveries were not available for analysis, it is reasonable to surmise that a more accurate estimation of fetal weight could have allowed clinicians the opportunity to better individualize the mode and timing of delivery, thus improving neonatal outcomes. A short FL is a validated sonographic marker for T21 [1] and FL is one of the four components used in estimating fetal size using the Hadlock equation. It is therefore suboptimal to apply the same standards used for the general population to the T21 fetus. The lack of T21-specific growth curves could result in fetuses being misclassified and clinically mismanaged. The mechanism underlying growth differences in the T21 population is not well understood and could be related to inherent differences in cellular hypertrophy. The assumption has always been that T21 fetuses classified as small for gestational age are at increased risk for stillbirth, but this assumption is based on the premise that this smallness is pathologic and not physiological. This assumption was called into question by a study [9] that showed that cytogenetically abnormal fetuses have normal umbilical artery Doppler velocimetry. Notably, in the present study cohort, despite differences in all the biometric components, the diagnosis of fetal growth restriction would not have changed if our T21-specific curves had been used in the 15 fetuses labeled as such. Of
Fig. 1. Head circumference growth in trisomy 21 compared with the Hadlock model [8]. Abbreviation: HC, head circumference; GA, gestational age; CI, confidence interval.
Fig. 2. Femur length growth in trisomy 21 compared with the Hadlock model [8]. Abbreviation: FL, femur length; GA, gestational age; CI, confidence interval.
the two stillbirths, one was deemed growth-restricted by both the standard and the T21-specific curves and the other was deemed normally grown by both curves. This could have been attributable to the small numbers in this subgroup and requires further investigation. The strength of the present study is the investigation of in-utero growth in a fairly large number of T21 fetuses. The data were obtained at a center that serves as one of the few perinatal referral centers in the region. Additionally, it houses the largest cytogenetics laboratory in the region. Therefore, it is unlikely that a significant number of T21 fetuses were not ascertained during the period in question. Additionally, the ultrasonography unit at MWH is overseen by maternal–fetal medicine specialists in a practice dedicated to obstetric and gynecologic ultrasonography only. The present study was, however, limited by the retrospective nature of the data, which were obtained from multiple sources. Biometric data were available for the vast majority of the prenatally and postnatally diagnosed individuals; however, some did undergo growth ultrasonography at other centers. Demographic data were only partly available for the entire cohort because many of the participants delivered at other institutions. Furthermore, for the purposes of evaluating fetal growth restriction and neonatal outcomes, a larger sample size would have been more informative. Finally, because the present dataset is limited to patients with continuing pregnancies, it might not represent all diagnosed T21 fetuses.
Fig. 3. Abdominal circumference growth in trisomy 21 compared with the Hadlock model [8]. Abbreviation: AC, abdominal circumference; GA, gestational age; CI, confidence interval.
Please cite this article as: Bernstein SN, et al, Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.034
4
S.N. Bernstein et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
In the context of women delaying childbearing and improvements in prenatal diagnosis and screening, the diagnosis of fetal T21 could be increasingly common. Because many patients will continue their pregnancies, the prevalence of ongoing fetal T21 pregnancies might be expected to increase as well. An appreciation of the unique prenatal growth patterns of this population will allow for the development of individualized standards, and will subsequently allow counseling and management to be optimized. Once validated, T21-specific fetal growth curves have the potential to greatly improve the prenatal management of individuals in this unique population. Conflict of interest The authors have no conflicts of interest. References
Fig. 4. Biparietal diameter growth in trisomy 21 compared with the Hadlock model [8]. Abbreviation: BPD, biparietal diameter growth; GA, gestational age; CI, confidence interval.
[1] Presson AP, Partyka G, Jensen KM, Devine OJ, Rasmussen SA, McCabe LL, et al. Current estimate of Down Syndrome population prevalence in the United States. J Pediatr 2013;163(4):1163–8. [2] Natoli JL, Ackerman DL, McDermott S, Edwards JG. Prenatal diagnosis of Down syndrome: a systematic review of termination rates (1995-2011). Prenat Diagn 2012; 32(2):142–53. [3] Myrelid A, Gustafsson J, Ollars B, Anneren G. Growth charts for Down's syndrome from birth to 18 years of age. Arch Dis Child 2002;87(2):97–103. [4] Cronk C, Crocker AC, Pueschel SM, Shea AM, Zackai E, Pickens G, et al. Growth charts for children with Down syndrome: 1 month to 18 years of age. Pediatrics 1988;81(1): 102–10. [5] Nyberg DA, Resta RG, Luthy DA, Hickok DE, Williams MA. Humerus and femur length shortening in the detection of Down's syndrome. Am J Obstet Gynecol 1993;168(2): 534–8. [6] Hook EB, Mutton DE, Ide R, Alberman E, Bobrow M. The natural history of Down syndrome conceptuses diagnosed prenatally that are not electively terminated. Am J Hum Genet 1995;57(4):875–81. [7] Hadlock FP, Shah YP, Kanon DJ, Lindsey JV. Fetal crown-rump length: reevaluation of relation to menstrual age (5–18 weeks) with high-resolution real-time US. Radiology 1992;182(2):501–5. [8] Hadlock FP. Sonographic estimation of fetal age and weight. Radiol Clin North Am 1990;28(1):39–50. [9] Snijders RJ, Sherrod C, Gosden CM, Nicolaides KH. Fetal growth retardation: associated malformations and chromosomal abnormalities. Am J Obstet Gynecol 1993; 168(2):547–55.
Fig. 5. Estimated fetal weight for trisomy 21 compared with the Hadlock model [8]. Abbreviation: EFW, estimated fetal weight; GA, gestational age; CI, confidence interval.
Please cite this article as: Bernstein SN, et al, Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.034
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21 Sarah N. Bernstein a,⁎, Devereux N. Saller b, Janet M. Catov b,c, Timothy P. Canavan b a b c
Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA Department of Obstetrics, Gynecology and Reproductive Science, Magee-Women's Hospital of the University of Pittsburgh, Pittsburgh, PA, USA Magee-Women's Research Institute, Pittsburgh, PA, USA
a r t i c l e
i n f o
Article history: Received 15 July 2015 Received in revised form 17 September 2015 Accepted 11 February 2016 Keywords: Down syndrome Fetal growth curves Trisomy 21 Ultrasonography
a b s t r a c t Objective: To construct growth curves specific for fetuses with trisomy 21 (T21) and to compare them with the reference-based standard. Methods: A retrospective cohort study was conducted of ultrasonography examinations from women with singleton pregnancies with a confirmed diagnosis of T21 who sought care at an academic tertiary-care center in the USA between January 1, 2003, and December 31, 2013. Growth curves were constructed using linear regression and compared with the Hadlock standard. Results: The study included 425 ultrasonography examinations from 235 women. The head circumference and femur length were smaller than the reference standards at all gestational ages (head circumference: P = 0.017; femur length: P b 0.001). The abdominal circumference was larger than the reference standard from 29 weeks onward (P b 0.001). The biparietal diameter was smaller in the second trimester and in the late third trimester (P b 0.001). The overall estimated fetal weight was not different from the reference standard. Conclusion: The T21-specific growth curves indicate anthropometric differences between T21 fetuses and the general population. Once validated, such individual growth curves could allow for more accurate prenatal assessment and management of fetuses affected by T21. © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Trisomy 21 (T21) is one of the most common chromosomal abnormalities among live-born neonates: approximately 6000 affected newborns are delivered annually in the USA, resulting in a prevalence of 14 per 10 000 births [1]. Advances in medical care have led to longer life expectancies and improved quality of life for affected individuals. Additionally, the capabilities for screening and prenatal diagnosis of T21 have greatly improved, most recently with the implementation of noninvasive prenatal testing using cell-free fetal DNA. Following genetic counseling, many women with a prenatal diagnosis of T21 choose to continue their pregnancies [2]. However, there is a very limited body of literature on the natural history and appropriate prenatal management of these pregnancies. It is widely accepted that the growth pattern of children with T21 differs considerably from that of euploid children after birth. Postnatally, they are of shorter stature, are heavier, and have smaller head circumferences [3,4]. Additionally, a shortened femur and humerus have been recognized as sonographic markers for T21 [5]. Nevertheless, there is a lack of published, longitudinal studies of growth in fetuses with T21.
Fetuses with T21 are thought to be at increased risk for adverse neonatal outcomes including stillbirth [6], although the underlying pathophysiology remains poorly understood. For this reason, many of these fetuses, especially those thought to be growth-restricted, could be subject to extensive prenatal surveillance, without empirical evidence of benefit. The application of standard growth curves to fetuses with T21 could inappropriately suggest growth restriction. The resultant prenatal testing carries a considerable cost and burden, and could affect decisions regarding the timing of delivery. Additionally, many fetuses affected by T21 have major morphological malformations including congenital heart defects that could require neonatal intervention. Iatrogenic premature delivery could therefore result in additional neonatal morbidity. We hypothesized that fetal biometry differs in the T21 population compared with standard reference curves. The implementation of modified growth curves—once validated—would decrease interventions, decrease patient anxiety, and more accurately target specific fetuses for interventions in this unique population. The primary aim of the present study was to develop such curves for future implementation.
2. Materials and methods ⁎ Corresponding author at: 8 Lamartine Terrace, Boston, MA 02130, USA. Tel.: +1 646 468 0742, +1 617 724 2640; fax: +1 617 726 4267. E-mail address: [email protected] (S.N. Bernstein).
The present study was a retrospective cohort study of all singleton pregnancies with a prenatal or postnatal laboratory diagnosis of T21 for which growth ultrasonography (with biometry) was performed at
http://dx.doi.org/10.1016/j.ijgo.2015.09.034 0020-7292/© 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Bernstein SN, et al, Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.034
2
S.N. Bernstein et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
least once between 14 and 41 weeks of pregnancy at Magee-Women's Hospital (MWH) of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA, between January 1, 2003, and December 31, 2013. The study was approved by the University of Pittsburgh Institutional Review Board, which also granted an exemption from informed consent because of the retrospective nature of the data. The genetic diagnosis was abstracted from the Pittsburgh Cytogenetics Laboratory database. These data were matched with biometric and demographic data from the MWH ultrasonography database. Additional maternal and neonatal data for women who delivered at MWH were derived from the Magee Obstetric Maternal and Infant database. Growth ultrasonography was performed on a Philips iU22 (Philips Healthcare, Andover, MA, USA) ultrasonography system using a C5-1 transabdominal probe, and involved measurement of the biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). All ultrasonography studies were interpreted by board-certified Maternal-Fetal Medicine specialists in a dedicated obstetric and gynecologic ultrasonography practice. The fetal age was determined by either a crown–rump length measurement in the first trimester or an ultrasonography examination in the first or second trimester that confirmed a known, normal last menstrual period. With the former method, the fetal age was changed to the age determined from the crown–rump length if the menstrual age was outside the range of error on the basis of the estimates of Hadlock et al. [7]. With the second method, the ultrasonography age was used if the composite age—obtained using the BPD, HC, AC, and FL in the regression formula of Hadlock et al. [7]—was more than 7% different from the menstrual age. Fetal growth restriction was defined as a fetal weight that was less than the 10th percentile. The number of biometric examinations varied from one to six, the average being two. Growth models for the HC, BPD, AC, FL, and estimated fetal weight were generated using generalized least-squares regression. All examinations were used in the model; however, to control for the effect of multiple examinations for individual participants, panels were established on the basis of the gestational age at the time of the examination. Growth curves with 95% confidence intervals were generated from the regression models. Each individual curve was then compared with a reference-based standard developed by Hadlock [8]. P b 0.05 was considered statistically significant. The statistical analysis was performed using Stata version 13 (StataCorp, College Station, TX, USA). 3. Results The study included 425 ultrasonography examinations from 235 women, 103 of whom delivered at MWH. Most women were white (Table 1). Three-quarters of the women received a prenatal T21 diagnosis, at the time of the first growth ultrasonography. Heart disease was suspected in 50 (21.3%) fetuses. Of the women who delivered at MWH, 16 (15.5%) had gestational or pregestational diabetes and 14 (13.6%) had a hypertensive disorder during pregnancy. Smoking was not common (Table 1). Approximately one-fifth of women who delivered at MWH did so before 37 weeks (Table 2). The cesarean delivery rate was 35.0%. Approximately two-fifths of the neonates born at MWH were admitted to the neonatal intensive care unit, with a mean duration of stay of 5.3 days (Table 3). The HC values of the T21 fetuses were smaller than the reference standards at all gestational ages (P = 0.017) (Fig. 1). The FL curve for the T21 fetuses was similar in shape to that of the reference standard with shorter measurements at all gestational ages (P b 0.001) (Fig. 2). The AC of the T21 fetuses was larger than the reference standard from 29 weeks onward (P b 0.001) (Fig. 3). The BPD was smaller in T21 fetuses during the second trimester and again during the late third trimester (P b 0.001) (Fig. 4). The overall estimated fetal weight calculated from these components was not different from the reference standard (P = 0.09) (Fig. 5).
Table 1 Demographics and clinical characteristics (n = 235).a Characteristic
Value
Age, y Ethnic origin (n = 233) White Black Latina Asian Educationb Not college educated Completed college or higher Unclassified Body mass indexc Height, m Pre-pregnancy weight, kg Parity (n = 194) Primiparous Multiparous Medical comorbidities b Hypertensive disorder d Diabetes e Tobacco use (n = 81) b Time of diagnosis Prenatal Postnatal No. of growth ultrasonography examinations Prenatal anomaly detection Congenital heart disease Non-congenital heart disease Ultrasonography-diagnosed fetal growth restriction
33.7 ± 6.7 205 (88.0) 22 (9.4) 2 (0.9) 4 (1.7) 42 (40.8) 40 (38.8) 21 (20.4) 26.3 ± 7.0 1.7 ± 0.1 71.6 ± 20.1 56 (28.9) 138 (71.1) 14 (13.6) 16 (15.5) 10 (12.3) 175 (74.4) 60 (25.5) 1.8 ± 1.1 39 (16.6) 11 (4.7) 15 (6.4)
a
Values are given as mean ± SD or number (percentage). Data only available for women who delivered at Magee-Women's Hospital (n = 103). c Calculated as weight in kilograms divided by the square of height in meters. d Includes women with chronic and gestational hypertension and those with pre-eclampsia. e Includes women with gestational and pregestational diabetes. b
When the prenatally and postnatally diagnosed cohorts were compared separately, there was no difference in any of the models (data not shown). Curves for the growth-restricted cohort (n = 15) were generated and compared with the T21-specific curves. The diagnosis of fetal growth restriction was not changed when these fetuses were plotted on the T21-specific curves (data not shown).
4. Discussion As hypothesized, the present data indicate that fetal biometry of the T21 population differs from standard reference curves. Each biometric component commonly used to estimate fetal size was significantly different from the reference standard. Although the overall estimated fetal weight in the T21 population did not differ significantly from the reference standard, the effect in individual cases could be substantial. Using a general population-based standard in the T21 population could therefore result in inaccurate centile estimates for growth throughout pregnancy. In a population at increased risk for neonatal Table 2 Delivery outcomes (n = 103).a Characteristic
Value
Pregnancy duration at delivery, wk Preterm/term delivery, wk b 37 ≥ 37 Mode of delivery Vaginal Cesarean
37.5 ± 2.6
a
22 (21.4) 81 (78.6) 67 (65.0) 36 (35.0)
Values are given as mean ± SD or number (percentage).
Please cite this article as: Bernstein SN, et al, Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.034
S.N. Bernstein et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
3
Table 3 Neonatal outcomes (n = 103).a Characteristic Apgar score Minute 1 Minute 5 Birth weight, g Neonatal intensive care unit Admissions Duration of stay, d Unknown Stillbirth a
Value 7.54 ± 1.9 8.4 ± 1.6 2873.8 ± 679.5 39 (37.9) 5.3 ± 9.7 32 (31.1) 2 (1.9)
Values are given as mean ± SD or number (percentage).
morbidity and mortality, it is critically important to obtain precise estimates of fetal size to inform prenatal management. This is exemplified by the MWH subcohort, in which nearly onequarter of the fetuses were delivered preterm and 35.0% were delivered via cesarean delivery. This far exceeded the overall cesarean delivery rate of 27.9% at MWH during the study years (unpublished data). Additionally, 16.6% of the entire study cohort had a prenatally diagnosed congenital heart defect. These numbers could be so high because the study center is a perinatal referral center and is therefore an appropriate location for the delivery of neonates anticipated to require immediate intervention or surgery. Although details of individual deliveries were not available for analysis, it is reasonable to surmise that a more accurate estimation of fetal weight could have allowed clinicians the opportunity to better individualize the mode and timing of delivery, thus improving neonatal outcomes. A short FL is a validated sonographic marker for T21 [1] and FL is one of the four components used in estimating fetal size using the Hadlock equation. It is therefore suboptimal to apply the same standards used for the general population to the T21 fetus. The lack of T21-specific growth curves could result in fetuses being misclassified and clinically mismanaged. The mechanism underlying growth differences in the T21 population is not well understood and could be related to inherent differences in cellular hypertrophy. The assumption has always been that T21 fetuses classified as small for gestational age are at increased risk for stillbirth, but this assumption is based on the premise that this smallness is pathologic and not physiological. This assumption was called into question by a study [9] that showed that cytogenetically abnormal fetuses have normal umbilical artery Doppler velocimetry. Notably, in the present study cohort, despite differences in all the biometric components, the diagnosis of fetal growth restriction would not have changed if our T21-specific curves had been used in the 15 fetuses labeled as such. Of
Fig. 1. Head circumference growth in trisomy 21 compared with the Hadlock model [8]. Abbreviation: HC, head circumference; GA, gestational age; CI, confidence interval.
Fig. 2. Femur length growth in trisomy 21 compared with the Hadlock model [8]. Abbreviation: FL, femur length; GA, gestational age; CI, confidence interval.
the two stillbirths, one was deemed growth-restricted by both the standard and the T21-specific curves and the other was deemed normally grown by both curves. This could have been attributable to the small numbers in this subgroup and requires further investigation. The strength of the present study is the investigation of in-utero growth in a fairly large number of T21 fetuses. The data were obtained at a center that serves as one of the few perinatal referral centers in the region. Additionally, it houses the largest cytogenetics laboratory in the region. Therefore, it is unlikely that a significant number of T21 fetuses were not ascertained during the period in question. Additionally, the ultrasonography unit at MWH is overseen by maternal–fetal medicine specialists in a practice dedicated to obstetric and gynecologic ultrasonography only. The present study was, however, limited by the retrospective nature of the data, which were obtained from multiple sources. Biometric data were available for the vast majority of the prenatally and postnatally diagnosed individuals; however, some did undergo growth ultrasonography at other centers. Demographic data were only partly available for the entire cohort because many of the participants delivered at other institutions. Furthermore, for the purposes of evaluating fetal growth restriction and neonatal outcomes, a larger sample size would have been more informative. Finally, because the present dataset is limited to patients with continuing pregnancies, it might not represent all diagnosed T21 fetuses.
Fig. 3. Abdominal circumference growth in trisomy 21 compared with the Hadlock model [8]. Abbreviation: AC, abdominal circumference; GA, gestational age; CI, confidence interval.
Please cite this article as: Bernstein SN, et al, Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.034
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In the context of women delaying childbearing and improvements in prenatal diagnosis and screening, the diagnosis of fetal T21 could be increasingly common. Because many patients will continue their pregnancies, the prevalence of ongoing fetal T21 pregnancies might be expected to increase as well. An appreciation of the unique prenatal growth patterns of this population will allow for the development of individualized standards, and will subsequently allow counseling and management to be optimized. Once validated, T21-specific fetal growth curves have the potential to greatly improve the prenatal management of individuals in this unique population. Conflict of interest The authors have no conflicts of interest. References
Fig. 4. Biparietal diameter growth in trisomy 21 compared with the Hadlock model [8]. Abbreviation: BPD, biparietal diameter growth; GA, gestational age; CI, confidence interval.
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Fig. 5. Estimated fetal weight for trisomy 21 compared with the Hadlock model [8]. Abbreviation: EFW, estimated fetal weight; GA, gestational age; CI, confidence interval.
Please cite this article as: Bernstein SN, et al, Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.034