Reference values of nuchal fold thickness in an Iranian population sample

Kimia Kazemi; Atoosa Adibi; Silva Hovsepian

doi:10.4103/jrms.JRMS_357_18

Previous article Browse articles Next article

ORIGINAL ARTICLE

J Res Med Sci 2018, 23:94

Reference values of nuchal fold thickness in an Iranian population sample

Kimia Kazemi¹, Atoosa Adibi¹, Silva Hovsepian²
¹ Department of Radiology, Isfahan University of Medical Sciences, Isfahan, Iran
² Emam Hossein Children's Hospital, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

Date of Submission	12-May-2018
Date of Decision	13-Jun-2018
Date of Acceptance	25-Jul-2018
Date of Web Publication	26-Oct-2018

Correspondence Address:
Prof. Atoosa Adibi
Student of Medicine, Isfahan University of Medical Sciences, Isfahan
Iran

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/jrms.JRMS_357_18

Abstract

Background: Considering that ethnicity and gestational age (GA) could affect the value of nuchal fold thickness (NFT) in mid-trimester, we aimed to determine the reference intervals of NFT values for each gestational week from 16 to 24 weeks of pregnancy among a group of Iranian pregnant women. Materials and Methods: In this cross-sectional study, medical files of pregnant women who underwent fetal anomaly scanning at 16–24 weeks of gestation were reviewed and the following data were extracted: GA, value of NFT, value of nuchal translucency (NT) in their previous ultrasound study, if available, and head circumference (HC). The 5^th, 25^th, 50^th, 75^th, and 95^th percentiles of NFT for each gestational week were determined. The association between NFT and HC, GA, and NT were also determined. Results: Medical files of 882 pregnant women were studied. The expected 95^th percentile value of NFT between 16^th and 24^th weeks of gestation ranged from 4 mm to 5.9 mm. The mean (standard deviation) of NFT increased with GA from 2.67 (0.90) mm at 16^th weeks to 4.69 (0.71) mm at 24^th weeks. There was a significant positive association between NFT and GA (β = 1.11, p < 0.001), HC (β = 0.21, p < 0.001), and NT (β = 0.351, p < 0.001). Conclusion: The findings of this study revealed that before the 20^th week of gestation, the appropriate cutoff value of NFT is 5 mm, and for 21^st to 24^th weeks, the proper cutoff is 6 mm. However, for providing more conclusive results, further studies with larger sample size and considering the impact of other influencing variables are recommended.

Keywords: Nuchal fold, pregnancy trimester, prenatal diagnosis, second, ultrasonography

How to cite this article:
Kazemi K, Adibi A, Hovsepian S. Reference values of nuchal fold thickness in an Iranian population sample. J Res Med Sci 2018;23:94

How to cite this URL:
Kazemi K, Adibi A, Hovsepian S. Reference values of nuchal fold thickness in an Iranian population sample. J Res Med Sci [serial online] 2018 [cited 2018 Dec 13];23:94. Available from: http://www.jmsjournal.net/text.asp?2018/23/1/94/244283

Introduction

Ultrasonic measurements have become a standard practice in prenatal screening for chromosomal abnormalities worldwide.^[1] Different ultrasonographic markers have been introduced and evaluated in this field for the first and second trimesters. One of the most important markers of the second trimester with appropriate sensitivity and specificity is nuchal fold thickness (NFT) which was first introduced in 1985 by Benacerraf et al.^{[2],[3],[4],[5]} According to the findings of different studies, the sensitivity and false positive rate for the marker were 75% (average of 34%) and 0.5% (ranging from 0% to 3%), respectively.^[5],[6],[7]

The association of NFT with an increased risk of fetal aneuploidy has been reported previously.^[8]

The results of a meta-analysis on the utility of different second-trimester markers for Down syndrome indicated that increased NFT is associated with increased risk of the syndrome with a likelihood ratio of 19.18.^[9]

In addition, the performance of NFT in the prediction of some fetal aneuploidies including trisomies 21, 18, and 13 during early second trimester has been reported in previous studies.^[10],[11]

Evidence indicated that the value of NFT could be influenced by some maternal, fetal, and technical factors such as gestational age (GA), fetal gender, presence or absence of nuchal cord, fetal presentation, cephalic index, and imaging technique.^{[12],[13],[14],[15]}

Although several studies showed that an NFT of ≥6 mm is the accepted cutoff for the detection of trisomy 21, some studies recommended that for improving the outcome of prenatal screening and increasing the sensitivity of the test, it is better to decrease the cutoff of NFT to 5 mm.^{[16],[17],[18]} However, there are still controversies in this field. Some studies suggest that proving population-based cutoffs for each gestational week would be a more accurate screening tool for chromosomal abnormalities than using the NFT ≥6 mm cutoff for all GAs.^[19]

Given that ethnicity and GA could affect the value of NFT in mid-trimester and providing proper screening cutoffs level would be useful in better diagnosis of fetal aneuploidies, we aimed to determine the reference intervals of NFT values for each gestational week from 16 to 24 weeks of pregnancy among a group of Iranian pregnant women.

Materials and Methods

This study was conducted as a cross-sectional study, during a 5-year period (2011–2016). All pregnant women who underwent fetal anomaly scanning at 16–24 weeks' gestation in a private ultrasonography center in Isfahan, Iran, were included.

The protocol of the study was approved by the Institutional Review Board and the Regional Ethics Committee of Isfahan University of Medical Sciences with a research project number of 395703.

The records of pregnant women with the following ultrasonographic findings were not included: any fetal abnormalities, multiple pregnancies, fetal hydrops, or intrauterine fetal demise.

The records of pregnant women with incomplete or missing data were excluded from the study.

Medical files of the selected women were reviewed and the following data were extracted: GA, value of NFT, head circumference (HC), and value of nuchal translucency (NT) in their previous first-trimester ultrasound if available.

The 5^th, 25^th, 50^th, 75^th, and 95^th percentiles of NFT for each gestational week were determined. The association between NFT and HC, NT, and GA were also determined.

Ultrasonographic measurements

All ultrasonographic measurements were performed by an expert radiologist (AA) during 16–24^th weeks of gestation.

Methods of NT measurement were described in detail in previous research.^[20] It was measured based on the recommended criteria by the Fetal Medicine Foundation.^[21]

Fetal NFT measurements were performed by transabdominal ultrasonography using GE Voluson 730 Pro, Expert (GE Healthcare, Milwaukee, WI) with a multifrequency: 3.5–5 MHz curvilinear transducer. NFT measurement was performed according to the previously described standard protocol.^[22],[23]

A transcerebellar plane of the fetal head displaying the cavum septum pellucidum, atria of the lateral ventricles, cerebral peduncles, and cerebellar hemispheres was visualized. NFT was measured by placing the calipers from the outer edge of the occipital bone to the outer edge of the overlying skin.

NFT was measured at least two times and the images were reviewed to select the most appropriate image and increase the accuracy of NFT measurement. The maximum value of NFT was considered as the final record of the marker.

Statistical analysis

Recorded quantitative data were reported as mean (standard deviation) analyzed using SPSS ver. 21 software (SPSS Inc., Chicago, IL, USA). Different percentiles of thickness including 5^th, 25^th, 50^th, 75^th, and 95^th percentile in different gestational weeks (16–24^th weeks) were computed. Repeated measures ANOVA was used for comparing the mean values of NFT over the time. The association between NFT and HC, NT, and GA was determined using simple regression, and the results were reported as a regression coefficient along with 95% confidence interval (95% CI) for the coefficient.

Results

In this study, medical files of 882 pregnant women were selected and studied. The 5^th, 25^th, 50^th, 75^th, and 95^th percentile values of NFT according to GA are presented in [Table 1]. Post hoc test indicated that the mean of NFT was not different between 16^th and 17^th weeks, 19^th and 20^th weeks, 21^st and 22^nd weeks, 21^st and 23^rd weeks, 22^nd and 23^rd weeks, 22^nd and 24^th weeks, and 23^rd and 24^th weeks.

Table 1: The mean (standard deviation) and expected 5^th, 25^th, 50^th, 75^th, and 95^th percentile values of nuchal fold thickness (mm) in each gestational week

Click here to view

The mean NFT value in each gestational week along with the 5^th and 95^th percentiles is shown in [Figure 1].

Figure 1: The mean nuchal fold thickness (mm) value in each gestational week along with the 5^th and 95^th percentiles

Click here to view

Simple linear regression analysis indicated that there was a significant positive association between NFT and GA (β = 1.11, P < 0.001, 95% CI: 0.968–1.254) and HC (β = 0.21, P < 0.001, 95% CI: 0.18–0.23).

In 380 cases, both NT and NFT were measured. There was a positive association between NFT and NT (β = 0.351, P < 0.001, 95% CI: 0.085–0.617).

Discussion

In this study, we determined the normal reference interval of NFT among a sample of Iranian pregnant women during 16–24 weeks of gestation. Our findings indicated that the mean NFT level increased by GA ranging from 2.67 to 4.69. The 95^th percentile value of NFT in the 16–20^th weeks of gestation was ≤5 and after that had an increasing trend, but still was <6.

As mentioned, the most accepted NFT cutoff for predicting Down syndrome is 6 mm. Some studies suggested that decreasing the cutoff to 5 mm would increase the sensitivity of the marker for the detection of chromosomal abnormalities. In accordance with increasing sensitivity, the approach would also increase the rate of false positivity which is not favorable for an appropriate screening test. So that, some studies recommended to use population-based cutoff for each gestational week in this field.^{[16],[17],[18],[19]}

Goynumer et al. in Turkey have determined the cutoff values of NFT based on GW among 2313 singleton pregnancies between 15^th and 24^th GW. They found a positive correlation between GA and NFT. According to their results, the 95^th percentile values of NFT during 15–24^th GW were as follows: 4.7, 4.77, 5.0, 5.5, 5.76, 5.9, 6.0, 6.1, 6.5, and 6.8 mm. They concluded that using the single cutoff of 6 mm would not be appropriate for the evaluation of chromosomal abnormalities during the 2^nd trimester of pregnancy and have a false positive rate of 1.8%–37%. Moreover, they recommended to determine the NFT cutoff values for each GW by population-based percentiles.^[19]

Manotaya et al. for the first time in Thailand have determined the nomogram of NFT in Thai pregnant women during 14–17 weeks of pregnancy. They showed that the mean value of NFT increased steadily by increasing GA from 2.59 mm to 4.12 mm.^[24]

In another recent study, in Brazil, the normal reference interval of NFT among 2559 normal singleton pregnancies between 18 and 24 weeks of pregnancy was determined and the association between NFT and GA was evaluated. They indicated that the mean fetal NFT ranged from 3.98 mm to 4.83 mm during the studied GA and showed a significant correlation between NFT and GA.^[25]

Singh and Biswas in Singapore have reported the GA-specific NFT values between 16 and 24 weeks of gestation. Similar to all mentioned studies, they also reported an increasing mean value for NFT from 16^th to 24^th weeks of gestation (3.13–5.08 mm). They reported that the 95^th percentile value of NFT at 24^th weeks was <6 mm and considered the threshold of 6 mm for NFT for GA of 20–24 weeks.^[26]

The results of our study regarding the association between NFT and GA were similar to the above-mentioned studies. The mean range of NFT in our population was not similar to the studies which could be explained by the role of ethnicity. Considering that the 95^th percentile of NFT measurements from 16 to 20 weeks were ≤5 mm and after that were <6 mm, it seems that for GA of 16–20 weeks, the threshold would be decreased to 5 mm.

For more accurate conclusion in this field and preventing overestimation of NFT, inappropriate invasive testing and putting a pregnancy at the risk of miscarriage using biochemical screening factors and planning a prospective study for evaluation of the sensitivity and rate of false positivity would be helpful.

NT is the only sonographic screening marker for trisomy 21, with reported 80% sensitivity and 5% false positive rate.^[27],[28] Some previous studies have evaluated the association between NT and NFT. Although it is suggested that the pathophysiology of both ultrasonographic markers is similar, studies in this field did not find any correlation between them.^{[29],[30],[31]} In this study, we found a significant association between NF and NT, which indicated that the markers could not be used as independent factors for the detection of fetal aneuploidy.

Three studies did not find any correlation between the markers and concluded that they may be used as independent markers for screening of chromosomal abnormalities.^{[29],[30],[31]}

Maymon et al. showed a small correlation between NT and NF, but they also recommended to use the markers independently for evaluation of Down syndrome risk.^[30]

Salomon et al. also did not report a significant association between NT measured at 11–14 weeks of gestation and NFT at 20–24 weeks of gestation. They concluded that the markers provide an independent contribution in prenatal screening of trisomy 21.^[31]

Miguelez et al. have reported a significant correlation between NT and NFT. They indicated that in cases with increased NT in the first trimester, the frequency of cases with NFT values more than 97.5^th percentile is higher than those with normal NT level. They concluded that using the findings, we could provide a multivariate risk model using both markers for better screening of fetal aneuploidy.^[32] Our findings in this field could also be useful for constructing mentioned multivariate risk model including both first- and second-trimester ultrasonographic markers.

The limitations of our study were small sample size and the retrospective design of the study. In addition, it is recommended to evaluate the influence of other variables such as fetal gender, presentation, cephalic index, and the presence or absence of nuchal cord on NFT values for obtaining more accurate results.

The strength of the current study was that it was the first study among Iranian pregnant women in this field.

Conclusion

The findings of this study demonstrated that before the 20^th week of gestation, the appropriate cutoff value of NFT is >5 mm and for 21–24^th weeks the proper cutoff is >6 mm. However, for providing more conclusive results, further studies with larger sample size and considering the impact of other influencing variables are recommended.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	ACOG Committee on Practice Bulletins. ACOG practice bulletin no 77: Screening for fetal chromosomal abnormalities. Obstet Gynecol 2007;109:217-27.
2.	Rao R, Platt LD. Ultrasound screening: Status of markers and efficacy of screening for structural abnormalities. Semin Perinatol 2016;40:67-78.
3.	Benacerraf BR, Barss VA, Laboda LA. A sonographic sign for the detection in the second trimester of the fetus with down's syndrome. Am J Obstet Gynecol 1985;151:1078-9.
4.	Bromley B, Shipp TD, Lyons J, Groszmann Y, Navathe RS, Benacerraf BR, et al. What is the importance of second-trimester “soft markers” for trisomy 21 after an 11- to 14-week aneuploidy screening scan? J Ultrasound Med 2014;33:1747-52.
5.	Benacerraf BR, Frigoletto FD Jr. Laboda LA. Sonographic diagnosis of down syndrome in the second trimester. Am J Obstet Gynecol 1985;153:49-52.
6.	Vergani P, Locatelli A, Piccoli MG, Ceruti P, Mariani E, Pezzullo JC, et al. Best second trimester sonographic markers for the detection of trisomy 21. J Ultrasound Med 1999;18:469-73.
7.	DeVore GR. Trisomy 21: 91% detection rate using second-trimester ultrasound markers. Ultrasound Obstet Gynecol 2000;16:133-41.
8.	Nyberg DA, Souter VL, El-Bastawissi A, Young S, Luthhardt F, Luthy DA, et al. Isolated sonographic markers for detection of fetal down syndrome in the second trimester of pregnancy. J Ultrasound Med 2001;20:1053-63.
9.	Agathokleous M, Chaveeva P, Poon LC, Kosinski P, Nicolaides KH. Meta-analysis of second-trimester markers for trisomy 21. Ultrasound Obstet Gynecol 2013;41:247-61.
10.	Geipel A, Willruth A, Vieten J, Gembruch U, Berg C. Nuchal fold thickness, nasal bone absence or hypoplasia, ductus venosus reversed flow and tricuspid valve regurgitation in screening for trisomies 21, 18 and 13 in the early second trimester. Ultrasound Obstet Gynecol 2010;35:535-9.
11.	Chitayat D, Langlois S, Douglas Wilson R, SOGC Genetics Committee, CCMG Prenatal Diagnosis Committee. Prenatal screening for fetal aneuploidy in singleton pregnancies. J Obstet Gynaecol Can 2011;33:736-50.
12.	Lee PR, Won HS, Chung JY, Shin HJ, Kim A. The variables affecting nuchal skin-fold thickness in mid-trimester. Prenat Diagn 2003;23:60-4.
13.	Ozkavukcu E, Haliloglu N. Does fetal gender affect nuchal skin-fold thickness? Prenat Diagn 2012;32:494-5.
14.	Özkavukcu E, Haliloğlu N. The effect of nuchal cord on nuchal fold thickness measured in the second trimester. Eur J Radiol 2012;81:e123-5.
15.	de Freitas Lda S, de Bello Barros FS, Negrini R, de Silva Bussamra LC, Júnior EA, Piato S, et al. Comparison of fetal nuchal fold thickness measurements by two- and three-dimensional ultrasonography (3DXI multislice view). Obstet Gynecol Int 2012;2012:837307.
16.	Crane JP, Gray DL. Sonographically measured nuchal skinfold thickness as a screening tool for down syndrome: Results of a prospective clinical trial. Obstet Gynecol 1991;77:533-6.
17.	Perrella R, Duerinckx AJ, Grant EG, Tessler F, Tabsh K, Crandall BF, et al. Second-trimester sonographic diagnosis of down syndrome: Role of femur-length shortening and nuchal-fold thickening. AJR Am J Roentgenol 1988;151:981-5.
18.	De Vore GR, Alfi O. The association between an abnormal nuchal skin fold, trisomy 21, and ultrasound abnormalities identified during the second trimester of pregnancy. Ultrasound Obstet Gynecol 1993;3:387-94.
19.	Goynumer G, Arisoy R, Turkmen O, Yayla M. Fetal nuchal skin-fold thickness during the 2^nd trimester of pregnancy. J Obstet Gynaecol 2015;35:111-4.
20.	Sharifzadeh M, Adibi A, Kazemi K, Hovsepian S. Normal reference range of fetal nuchal translucency thickness in pregnant women in the first trimester, one center study. J Res Med Sci 2015;20:969-73. [PUBMED] [Full text]
21.	Kagan KO, Avgidou K, Molina FS, Gajewska K, Nicolaides KH. Relation between increased fetal nuchal translucency thickness and chromosomal defects. Obstet Gynecol 2006;107:6-10.
22.	Benacerraf BR, Gelman R, Frigoletto FD Jr. Sonographic identification of second-trimester fetuses with down's syndrome. N Engl J Med 1987;317:1371-6.
23.	Benacerraf BR, Frigoletto FD Jr. Soft tissue nuchal fold in the second-trimester fetus: Standards for normal measurements compared with those in down syndrome. Am J Obstet Gynecol 1987;157:1146-9.
24.	Manotaya S, Tanawattanacharoen S, Uerpairojkit B, Tannirandorn Y, Charoenvidhya D. Nomogram of nuchal fold thickness of Thai fetuses. J Med Assoc Thai 1998;81:297-300.
25.	Júnior EA, Martins WP, Pires CR, Santana EF, Filho SZ. Fetal nuchal fold thickness measurement between 18 and 24 weeks of pregnancy: Reference intervals for a Brazilian population. J Matern Fetal Neonatal Med 2015;28:234-6.
26.	Singh C, Biswas A. Impact of gestational age on nuchal fold thickness in the second trimester. J Ultrasound Med 2014;33:687-90.
27.	Cuckle HS, Benn PA. Multi-Marker maternal serum screening for chromosomal abnormalities. In: Milunsky A, Milunsky JM, editors. Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment. 6^th ed. Oxford: Wiley-Blackwell; 2010. p. 771-818.
28.	Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O. Multicenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies: Results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 2005;25:221-6.
29.	Pandya PP, Snijders RJ, Johnson S, Nicolaides KH. Natural history of trisomy 21 fetuses with increased nuchal translucency thickness. Ultrasound Obstet Gynecol 1995;5:381-3.
30.	Maymon R, Zimerman AL, Weinraub Z, Herman A, Cuckle H. Correlation between nuchal translucency and nuchal skinfold measurements in down syndrome and unaffected fetuses. Ultrasound Obstet Gynecol 2008;32:501-5.
31.	Salomon LJ, Bernard JP, Taupin P, Benard C, Ville Y. Relationship between nuchal translucency at 11-14 weeks and nuchal fold at 20-24 weeks of gestation. Ultrasound Obstet Gynecol 2001;18:636-7.
32.	Miguelez J, De Lourdes Brizot M, Liao AW, De Carvalho MH, Zugaib M. Second-trimester soft markers: Relation to first-trimester nuchal translucency in unaffected pregnancies. Ultrasound Obstet Gynecol 2012;39:274-8.