Acessibilidade / Reportar erro

Behavior of the Genetic Markers at Screening during the First Trimester of Pregnancy in Euploid Fetuses

Comportamento dos marcadores genéticos na triagem durante o primeiro trimestre de gravidez em fetos euploides

Abstract

Objective

This study aims to describe the behavior of chromosomopathy screenings in euploid fetuses.

Methods

This is a prospective descriptive study with 566 patients at 11 to 14 weeks of gestation. The associations between ultrasound scans and serological variables were studied. For the quantitative variables we used the Spearman test; for the qualitative with quantitative variables the of Mann-Whitney U-test; and for qualitative variables, the X2 test was applied. Significance was set at p ≤ 0.05.

Results

We have found that gestational age has correlation with ductus venosus, nuchal translucency, free fraction of β subunit of human chorionic gonadotropin, pregnancy-associated plasma protein-A and placental growth factor; there is also a correlation between history of miscarriages and nasal bone. Furthermore, we correlated body mass index with nuchal translucency, free fraction of β subunit of human chorionic gonadotropin, and pregnancy-associated plasma protein-A. Maternal age was associated with free fraction of β subunit of human chorionic gonadotropin and pregnancy-associated plasma protein-A.

Conclusion

Our study demonstrates for the first time the behavior of the biochemical and ultrasonographic markers of chromosomopathy screenings during the first trimester in euploid fetuses in Colombia. Our information is consistent with international reference values. Moreover, we have shown the correlation of different variables with maternal characteristics to determine the variables that could help with development of a screening process during the first trimester with high detection rates.

Keywords
genetic markers; screening; ultrasonography; chromosomal abnormality; pregnancy

Resumo

Objetivo

Este estudo tem como objetivo descrever o comportamento do rastreamento de cromossomopatias em fetos euploides.

Métodos

Trata-se de um estudo prospectivo descritivo com 566 pacientes, entre 11 e 14 semanas de gestação. A associação entre a ultrassonografia e as variáveis sorológicas foi estudada. Para as variáveis quantitativas foi utilizado o teste de Spearman; para as qualitativas com variáveis quantitativas foi utilizado o teste U de Mann-Whitney e para as variáveis qualitativas foi aplicado o teste X2. A significância foi fixada em p ≤ 0,05.

Resultados

Constatou-se que a idade gestacional tem correlação com o ducto venoso, translucência nucal, fração livre da subunidade β da gonadotrofina coriônica humana, proteína plasmática A associada à gravidez e fator de crescimento placentário; há também correlação entre a história de abortos e o osso nasal. Além disso, correlacionamos o índice de massa corporal com translucência nucal, fração livre da subunidade β da gonadotrofina coriônica humana e proteína plasmática A associada à gravidez. A idade materna foi relacionada com fração livre da subunidade β da gonadotrofina coriônica humana e proteína plasmática A associada à gravidez.

Conclusão

Nosso estudo demonstra pela primeira vez o comportamento dos marcadores bioquímicos e ultrassonográficos de triagem de cromossomas durante o primeiro trimestre em fetos euploides na Colômbia. Nossa informação é consistente com a referência de valores internacionais. Além disso, mostram-se as relações das diferentes variáveis com as características maternas para determinar as variáveis capazes de ajudar no desenvolvimento de um processo de rastreamento durante o primeiro trimestre com alta taxa de detecção.

Palavras-chave
marcadores genéticos; triagem; ultrassonografia; anormalidade cromossômica; gravidez

Introduction

The chromosomopathies are an important cause of perinatal deaths and child disability. It has been described that approximately 7.9 million children had some type of congenital malformation.11 Christianson A, Howson CP, Modell B. March of Dimes global report on birth defects: the hidden toll of dying and disabled children [Internet]. White Plains: March of Dimes Birth Defects Foundation;. 2006 [cited 2021 Aug 12]. Available from: https://www.marchofdimes.org/materials/global-report-on-birth-defects-the-hidden-toll-of-dying-and-disabled-children-executive-summary.pdf
https://www.marchofdimes.org/materials/g...
Additionally, they are responsible for approximately 270.000 deaths of newborns in the first 28 days.22 Restrepo Cano GA. [Prenatal diagnosis of congenital anormalies; an absent policy in Colombia]. Rev Fac Med (Caracas) 2016; 24 (01) 102-110 DOI: 10.18359/rmed.2764. Spanish.
https://doi.org/10.18359/rmed.2764...
Therefore, the importance of early diagnosis is the early detection of any anatomical and functional alterations that can suggest a genetic abnormality,33 Wright D, Syngelaki A, Bradbury I, Akolekar R, Nicolaides KH. First-trimester screening for trisomies 21, 18 and 13 by ultrasound and biochemical testing. Fetal Diagn Ther 2014; 35 (02) 118-126 DOI: 10.1159/000357430.
https://doi.org/10.1159/000357430...
to provide adequate counseling to parents and offer diagnostic methods that could define the course of the pregnancy and the fetus' prognosis.

Diverse methods have been introduced for diagnosing chromosomal abnormalities. Invasive methods such as chorionic villus biopsy and amniotic fluid sample for doing karyotype have been done for ages and are well known for their accuracy. Nevertheless, there is an estimated risk of pregnancy loss associated with these procedures, between 0.5 and 1.5%, during all three trimesters.44 Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson genetics in medicine. Chicago: Saunders; 2007,55 Parga Soler MN, Martínez Machuca S, Martín Idoeta O, Sánchez-Pastor Ruiz M. Diagnóstico prenatal y cribado de cromosomopatías. [Prenatal diagnosis and chromosomal abnormalities screening]. Med Fam Ginecol Obstet. 2001; 11 (10) 590-598 Spanish. Therefore, other methods, like the cell-free DNA analysis in maternal blood are used with a detection rate (DR) of 99% for trisomy 21, 96% for fetal trisomy 18, and 91% for trisomy 13, which are the most frequent chromosomal abnormalities.66 Santorum M, Wright D, Syngelaki A, Karagioti N, Nicolaides KH. Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound Obstet Gynecol 2017; 49 (06) 714-720 DOI: 10.1002/uog.17283.
https://doi.org/10.1002/uog.17283...
The biggest limitation of these methods are their high cost, which prevents their use as a primary assessment tool for the entire population.77 Kagan KO, Wright D, Nicolaides KH. First-trimester contingent screening for trisomies 21, 18 and 13 by fetal nuchal translucency and ductus venosus flow and maternal blood cell-free DNA testing. Ultrasound Obstet Gynecol 2015; 45 (01) 42-47 DOI: 10.1002/uog.14691.
https://doi.org/10.1002/uog.14691...

The combined screening at 11 to 14 weeks of gestation has appeared as a tool for effective early detection of fetal trisomies and is accessible for all patients.66 Santorum M, Wright D, Syngelaki A, Karagioti N, Nicolaides KH. Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound Obstet Gynecol 2017; 49 (06) 714-720 DOI: 10.1002/uog.17283.
https://doi.org/10.1002/uog.17283...
,88 Franco C. [Evaluation of the nasal bone, ductus venosus and tricuspid regurgitation for the screening of Down Syndrome. Its Utility in intermediate risks] [thesis].. Madrid: Universidad Autónoma de Madrid;; 2013. . Spanish. This screening includes maternal characteristics, fetal nuchal translucency thickness (NT), fetal heart rate, maternal free fraction of β subunit of human chorionic gonadotropin (free β-HCG), and pregnancy-associated plasma protein-A (PAPP-A), with DRs for trisomy 21 (91%), 18 (97%), and 13 (94%). Additionally, the DR can be improved, and the false positive rate can decrease by including other markers, such as as nasal bone, ductus venosus, tricuspid valve, and placental growth factor (PlGF).33 Wright D, Syngelaki A, Bradbury I, Akolekar R, Nicolaides KH. First-trimester screening for trisomies 21, 18 and 13 by ultrasound and biochemical testing. Fetal Diagn Ther 2014; 35 (02) 118-126 DOI: 10.1159/000357430.
https://doi.org/10.1159/000357430...
,66 Santorum M, Wright D, Syngelaki A, Karagioti N, Nicolaides KH. Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound Obstet Gynecol 2017; 49 (06) 714-720 DOI: 10.1002/uog.17283.
https://doi.org/10.1002/uog.17283...

7 Kagan KO, Wright D, Nicolaides KH. First-trimester contingent screening for trisomies 21, 18 and 13 by fetal nuchal translucency and ductus venosus flow and maternal blood cell-free DNA testing. Ultrasound Obstet Gynecol 2015; 45 (01) 42-47 DOI: 10.1002/uog.14691.
https://doi.org/10.1002/uog.14691...

8 Franco C. [Evaluation of the nasal bone, ductus venosus and tricuspid regurgitation for the screening of Down Syndrome. Its Utility in intermediate risks] [thesis].. Madrid: Universidad Autónoma de Madrid;; 2013. . Spanish.

9 Nicolaides KH. Turning the pyramid of prenatal care. Fetal Diagn Ther 2011; 29 (03) 183-196 DOI: 10.1159/000324320.
https://doi.org/10.1159/000324320...
-1010 Veduta A, Vayna AM, Duta S. et al. The first trimester combined test for aneuploidies - a single center experience. J Matern Fetal Neonatal Med 2018; 31 (16) 2091-2096 DOI: 10.1080/14767058.2017.1336220.
https://doi.org/10.1080/14767058.2017.13...
With further benefits of early prediction of other complications such as preeclampsia, intrauterine growth restriction (IUGR), and other anatomical malformations.66 Santorum M, Wright D, Syngelaki A, Karagioti N, Nicolaides KH. Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound Obstet Gynecol 2017; 49 (06) 714-720 DOI: 10.1002/uog.17283.
https://doi.org/10.1002/uog.17283...
,99 Nicolaides KH. Turning the pyramid of prenatal care. Fetal Diagn Ther 2011; 29 (03) 183-196 DOI: 10.1159/000324320.
https://doi.org/10.1159/000324320...

In Colombia, congenital malformations affect 2 to 3% of newborns and are the main cause of mortality for infants under one-year-old.22 Restrepo Cano GA. [Prenatal diagnosis of congenital anormalies; an absent policy in Colombia]. Rev Fac Med (Caracas) 2016; 24 (01) 102-110 DOI: 10.18359/rmed.2764. Spanish.
https://doi.org/10.18359/rmed.2764...
Moreover, only 21.5% of chromosomal abnormalities are diagnosed early and opportunely,22 Restrepo Cano GA. [Prenatal diagnosis of congenital anormalies; an absent policy in Colombia]. Rev Fac Med (Caracas) 2016; 24 (01) 102-110 DOI: 10.18359/rmed.2764. Spanish.
https://doi.org/10.18359/rmed.2764...
with the rest being diagnosed postnatally. The Ministry of Health's guidelines only recommend the measurement of the NT at 11 to 13 + 6 weeks, and ultrasonography to detect abnormalities at 18 to 23 + 6 weeks.1111 Cancino E, León H, Otálora R, Pérez E, Sarmiento R, Yates A. [Guidelines of prenatal control and risk factors] [Internet]. Bogotá: Secretaría Distrital de Salud de Bogotá/ASBOG; [s.d.] [cited 2021 Aug 12]. Spanish. Available from: http://www.saludcapital.gov.co/DDS/Publicaciones/GUIA%201.%20%20CONTROL%20PRENATAL%20Y%20FACTORES%20DE%20RIESGO.pdf
http://www.saludcapital.gov.co/DDS/Publi...

12 Ministerio de Salud y Protección Social - Colciencias.. [Guideline of clinical practice. Detection of congenital anomalies in newborns] [Internet]. Colombia: Minsalud; 2013 [cited 2021 Jun 10]. (Guide no. 3). Spanish. Available from: https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/INEC/IETS/GPC_Ptes_AC.pdf
https://www.minsalud.gov.co/sites/rid/Li...
-1313 Ministerio de Salud y Protección Social - Colciencias.. [Clinical practice guide ministry of health for prevention, early detection and treatment of complications of pregnancy, childbirth and the puerperium] [Internet]. Colombia: MinSalud; 2013 [cited 2021 Jun 10]. Spanish. Available from: https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/INEC/IETS/Gu%C3%ADa.completa.Embarazo.Parto.2013.pdf
https://www.minsalud.gov.co/sites/rid/Li...
Therefore, it is important to implement a better method to identify women at risk and increase the detection rates for the sake of appropriate evaluations and on-time interventions, as described by the assessment of the combined screening at first trimester for chromosomopathies.

This has not been previously studied in Colombia, and it is necessary to have references of the screening in our population. For that reason, the aim of this study is to describe, for the first time, the behavior of chromosomopathy screening in euploid fetuses at Bogotá, Colombia.

Methods

A prospective descriptive study was performed through the analysis of pregnant women over 14-years-old, in the first trimester, between 11 and 14 weeks of gestation, who underwent prenatal care in Bogotá, Colombia. This study evaluated 566 pregnant women, between 2014 and 2018, at the Ecodiagnóstico El Bosque SAS Diagnostic Unit Centre, Clínica El Bosque and Subred Integrada de Servicios de Salud Sur Occidente ESE – Unidad de Servicios de Salud Occidente de Kennedy. Women at risk of abortion and who had not completed the screening were excluded from the study.

In the first prenatal control, we collected data regarding race, socioeconomical level, mother's age, single or multiple pregnancy, personal and familiar background, mean blood pressure, cardiac heart rate, weight, height, and body mass index (BMI).

As part of the screening for chromosomopathies, the following biochemical markers were measured: PAPP-A, free β-HCG and PlGF; we analyzed the ultrasonographic findings regarding theNT, absence or hypoplasia of the nasal bone, ductus venosus, and tricuspid insufficiency. These ultrasonographic data were obtained and evaluated by a certified professional. The biochemical markers were taken the same day that the ultrasound scan was performed, and they were processed by using DELFIA XPRESS (PerkimElmer Inc., Waltham, MA, USA). Data from the medical records were typed and validated by two of the researchers in a Microsoft Excel 2019 (Microsoft Corp. Redmond, Washington, USA) database (El Bosque University License).

For the analytical study of the data it was used the Statistical Package for Social Sciences (IBM Corp., Armonk, NY, USA) software, version 22.0 (Universidad El Bosque License), in which the ultrasound scan and serological variables were compared with five maternal variables—gestational age, maternal age, family history of malformations, history of abortions, and BMI—to identify the possible association between variables. For quantitative variables, averages and standard deviation were calculated. Frequencies and percentages were determined for qualitative variables.

To establish association or not between quantitative variables, a normality test was applied. For the comparison between the quantitative variables, it was used the test of Spearman, for the qualitative with quantitative variable it was used the test U of Mann Whitney and for the comparison between qualitative and qualitative variables, the test X 2 was applied. Significance was set at p ≤ 0.05.

This project has the approval of the Ethical Committee of the Universidad El Bosque. The ethical principles for human research from the Helsinki Declaration1414 Asociación Médica Mundial (AMM).. [Declaration of Helsinki. Ethical principles for medical research in humans] [Internet]. 2017 [cited 2021 Jun 10]. Spanish. Available from: https://www.wma.net/es/policies-post/declaracion-de-helsinki-de-la-amm-principios-eticos-para-las-investigaciones-medicas-en-seres-humanos/
https://www.wma.net/es/policies-post/dec...
and the Colombian Resolution 8430 of 19931515 Ministerio de Salud. [Resolution number 8430 of 1993] [Internet]. Bogotá: MinSalud;; 1993 [cited 2021 Jul 20]. Spanish. Available from: https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/DE/DIJ/RESOLUCION-8430-DE-1993.PDF
https://www.minsalud.gov.co/sites/rid/Li...
were considered in the development of this study, which is an investigation with minimal risk.

Written informed consent was obtained from the pregnant women who participated in this study, which allowed the group to use patients' information, while their privacy was respected throughout the study.

A selection bias was present because the patients in this study correspond to a specific population that can't represent all the population of Bogotá. However, the bias was minimized by clearly describing our participants' characteristics and establishing that the results of this study are representative only for the population study.

Results

There were 566 mother patients and 572 fetuses evaluated (there were six twin pregnancies). The mean maternal age was 27 years (standard deviation, SD = 6.43). We found that 96.3% (n= 551) of the women were mixed race (mestizo), while the remaining 3.67% (n= 21) identified as either white or African-American. The medium and low socioeconomic levels grouped 96% (n= 579) of the study participants (Table 1). The most frequent pathological antecedents were obesity, 8.39% (n= 48), followed by hypothyroidism, 6.12% (n= 35) and hypertension, 2.45% (n= 14) (Table 1).

Table 1
Maternal characteristics of the patients

Within the population studied, 8.22% (n= 47) of the mothers had direct exposure to tobacco and only 0.87% (n= 5) had previous exposure to x-rays. Regarding the gynecologic and obstetric history, 63.96% (n= 362) of the maternal patients were multigravidas, while 25.27% (n= 143) were primigravidas. Furthermore, 37.8% (n= 214) had history of abortions; 24.2% (n= 137) had a history of one abortion, and 1.94% (n= 77) of two or more abortions. Compared with the biomarkers studied, it was found that PAPP-A had an average value of 3.19 mUl/ml (SD = 18.30). The average free β-HCG value was 36.43 mUl / ml (SD = 27.90). The mean value of PlGF concentration among the 554 participants with this information available was 31.26 pg / mL (SD = 18.30). Regarding ultrasound variables, the mean fetal heart rate of the 572 fetuses studied was 157.7 beats per minute (SD = 10.05). Regarding the cephalocaudal length, the average found was 66.35 mm (SD = 9.33). The NT had a mean of 1.60 mm (SD = 0.56). The ductus venosus presented an average pulsatility index (PI) of 0.98 (SD = 0.46) (Table 2). The nasal bone was present in 99.8% of the fetuses (n= 571) and the absence of this marker was found in only one fetus. Finally, tricuspid insufficiency did not occur in any if the patients of this study population. This is the first study of chromosomopathies developed in the Colombian population; therefore, it is important to determine what are the values obtained for each variable in a healthy population (Table 2).

Table 2
Biochemical and biophysical markers' average in the study population

To define the behavior and correlation of the variables, each variable was analyzed in relation with gestational age, background of abortions, family history of malformations, maternal age, and BMI, which were the most relevant characteristic found in these women, that are associated with the development of chromosomopathies (Table 3). Of the ultrasonographic variables (Table 3) in this study, we found that the ductus venosus had a statistical significative correlation with the gestational age (p= 0.0000) and history of miscarriages (p= 0.013). Additionally, we found a relation between the ductus venosus and BMI but it was not significant. It was not found any case of tricuspid insufficiency; therefore, it was not possible to analyze this variable. The NT had a direct significative correlation with the gestational age and BMI. It was not found other correlations. The absence or hypoplasia of the nasal bone was associated with the family history of malformations (X2 = 308,392; p= 0.000). In relation to the biochemicalmarkers (Table 3), it was found that free β-HCG had an inversely significative relation with the gestational age,maternal age, and BMI, and direct correlation with the history of malformations.

Table 3
Correlation of the screening variables

The PAPP-A had a significant direct correlation with the gestational age. A significant statistical inverse correlation of PAPP-A with maternal age and BMI was found. The last variable evaluated was the PlGF, which had a direct significative correlation with gestational age. No other correlations were found (Table 4).1616 Nicolaides KH. The 11–13 + 6 weeks scan. London: The Fetal Medicine Foundation;; 2004

17 Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10-14 weeks: the role of ductus venosus blood flow. Ultrasound Obstet Gynecol 1998; 12 (06) 380-384 DOI: 10.1046/j.1469-0705.1998.12060380.x.
https://doi.org/10.1046/j.1469-0705.1998...

18 Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening program for trisomy 21 at 10-14 weeks using fetal nuchal translucency, maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 1999; 13 (04) 231-237 DOI: 10.1046/j.1469-0705.1999.13040231.x.
https://doi.org/10.1046/j.1469-0705.1999...
-1919 Kasdaglis T, Aberdeen G, Turan O. et al. Placental growth factor in the first trimester: relationship with maternal factors and placental Doppler studies. Ultrasound Obstet Gynecol 2010; 35 (03) 280-285 DOI: 10.1002/uog.7548.
https://doi.org/10.1002/uog.7548...

Table 4
Biochemical and biophysical markers value study versus literature

Discussion

The identification of pregnancies with a high risk of developing fetuses with chromosomal abnormalities by non-invasive methods is still a big challenge. However, it facilitates early detection and prevents unnecessary invasive tests in low risk pregnancies.44 Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson genetics in medicine. Chicago: Saunders; 2007,2020 Yu B, Lu BY, Zhang B. et al. Overall evaluation of the clinical value of prenatal screening for fetal-free DNA in maternal blood. Medicine (Baltimore) 2017; 96 (27) e7114 DOI: 10.1097/MD.0000000000007114.
https://doi.org/10.1097/MD.0000000000007...
Therefore, the early screening for chromosomopathies is the proposed tool, with high detection rates which offer a complete biochemical and ultrasonographic evaluation of the pregnancy for determining the high risk on time.1010 Veduta A, Vayna AM, Duta S. et al. The first trimester combined test for aneuploidies - a single center experience. J Matern Fetal Neonatal Med 2018; 31 (16) 2091-2096 DOI: 10.1080/14767058.2017.1336220.
https://doi.org/10.1080/14767058.2017.13...
,2121 Sørensen S, Momsen G, Sundberg K, Friis-Hansen L, Jørgensen FS. First-trimester risk calculation for trisomy 13, 18, and 21: comparison of the screening efficiency between 2 locally developed programs and commercial software. Clin Chem 2011; 57 (07) 1023-1031 DOI: 10.1373/clinchem.2010.161299.
https://doi.org/10.1373/clinchem.2010.16...
,2222 Shiefa S, Amargandhi M, Bhupendra J, Moulali S, Kristine T. First trimester maternal serum screening using biochemical markers PAPP-A and free β-HCG for Down Syndrome, Patau Syndrome and Edward Syndrome. Indian J Clin Biochem 2013; 28 (01) 3-12 DOI: 10.1007/s12291-012-0269-9.
https://doi.org/10.1007/s12291-012-0269-...
The data collected is evaluated with the Nicolaides software, which allowed us to calculate the individual risk through a logarithmic method.1010 Veduta A, Vayna AM, Duta S. et al. The first trimester combined test for aneuploidies - a single center experience. J Matern Fetal Neonatal Med 2018; 31 (16) 2091-2096 DOI: 10.1080/14767058.2017.1336220.
https://doi.org/10.1080/14767058.2017.13...
,1616 Nicolaides KH. The 11–13 + 6 weeks scan. London: The Fetal Medicine Foundation;; 2004

This screening has been deeply described in countries like England, but it has not been studied in countries with lower economical resources such as Colombia, where invasive methods are expensive, nearly inaccessible, and rarely included in health insurance plans. Therefore, the repercussion of this study is high, as it describes for the first time the behavior of the different variables (ultrasonographic and biochemical) of the genetic screening in relation with maternal characteristics in a healthy group of pregnant women in Bogotá, Colombia, to determine the importance and correlation of each test.

The average results found for each variable are not far from what the literature describes, as shown in Table 4. The ductus venosus PI had a media of 0.98, which was described by Matias et al.1717 Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10-14 weeks: the role of ductus venosus blood flow. Ultrasound Obstet Gynecol 1998; 12 (06) 380-384 DOI: 10.1046/j.1469-0705.1998.12060380.x.
https://doi.org/10.1046/j.1469-0705.1998...
as 0.6 to 3.3, and by Kalayci et al.2323 Kalayci H, Yilmaz Baran Ş, Doğan Durdağ G. et al. Reference values of the ductus venosus pulsatility index for pregnant women between 11 and 13+6 weeks of gestation. J Matern Fetal Neonatal Med 2020; 33 (07) 1134-1139 DOI: 10.1080/14767058.2018.1517152.
https://doi.org/10.1080/14767058.2018.15...
as 0.73 to 1.22. The NT had an average value of 1.64 mm, which is between the normal values described by Nicolaides et al.2424 Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004; 191 (01) 45-67 DOI: 10.1016/j.ajog.2004.03.090.
https://doi.org/10.1016/j.ajog.2004.03.0...
of 1.2 to 2.7 mm. Regarding the biochemical markers, free β-HCG and PAPP-A had values of 36.43 mUI/ml and 3.19 mUI/ml, respectively, which were also between the values described for this two variables, of 28.05 to 36.88 mU/ml,2525 Cuckle HS, Spencer K, Nicolaides KH. Down syndrome screening marker levels in women with a previous aneuploidy pregnancy. Prenat Diagn 2005; 25 (01) 47-50 DOI: 10.1002/pd.1082.
https://doi.org/10.1002/pd.1082...
and 0.6 to 3.3 mUI/ml, respectively.1818 Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening program for trisomy 21 at 10-14 weeks using fetal nuchal translucency, maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 1999; 13 (04) 231-237 DOI: 10.1046/j.1469-0705.1999.13040231.x.
https://doi.org/10.1046/j.1469-0705.1999...
Finally, we evaluated the PlGF as being the newest variable included in the screening; it had a medium value of 31.26 pg/ml, which is also within the values described by Kasdaglis et al.,1919 Kasdaglis T, Aberdeen G, Turan O. et al. Placental growth factor in the first trimester: relationship with maternal factors and placental Doppler studies. Ultrasound Obstet Gynecol 2010; 35 (03) 280-285 DOI: 10.1002/uog.7548.
https://doi.org/10.1002/uog.7548...
of 1.01 to 176.1 pg/ml. This information means that the values found in this sample of pregnant women have similar normal values to the ones reported in other studies for healthy pregnancies. These data describe the distribution of the biophysical and biochemical markers for chromosomopathies in Colombian pregnant women during the first trimester of pregnancy.

Among the ultrasonographic variables, the ductus venosus (DV) showed an inverse relation with the gestational age, which means that the longer the pregnancy, the lower is the ductus venosus PI. Maiz et al.2626 Maiz N, Valencia C, Kagan KO, Wright D, Nicolaides KH. Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation. Ultrasound Obstet Gynecol 2009; 33 (05) 512-517 DOI: 10.1002/uog.6330.
https://doi.org/10.1002/uog.6330...
made a study to evaluate the ductus venosus, in which they found that the reverse wave prevalence is inversely associated with the CRL, which is useful for determining the gestational age. It is important to mention that 65% of the fetuses with trisomy 21 had this alteration, 55% of the fetuses with trisomy 13 and 18, and 75% of those with Turner syndrome.2626 Maiz N, Valencia C, Kagan KO, Wright D, Nicolaides KH. Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation. Ultrasound Obstet Gynecol 2009; 33 (05) 512-517 DOI: 10.1002/uog.6330.
https://doi.org/10.1002/uog.6330...
Additionally, the DV is a fundamental variable in the first trimester screening for chromosomopathies, as it has been demonstrated that the evaluation of the DV increased the sensitivity of the screening up to 92 to 96% and reduced the rate of false positive up to 2.4 to 2.6%.77 Kagan KO, Wright D, Nicolaides KH. First-trimester contingent screening for trisomies 21, 18 and 13 by fetal nuchal translucency and ductus venosus flow and maternal blood cell-free DNA testing. Ultrasound Obstet Gynecol 2015; 45 (01) 42-47 DOI: 10.1002/uog.14691.
https://doi.org/10.1002/uog.14691...
,2626 Maiz N, Valencia C, Kagan KO, Wright D, Nicolaides KH. Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation. Ultrasound Obstet Gynecol 2009; 33 (05) 512-517 DOI: 10.1002/uog.6330.
https://doi.org/10.1002/uog.6330...
,2727 Florjański J, Fuchs T, Zimmer M, Homola W, Pomorski M, Blok D. The role of ductus venosus Doppler flow in the diagnosis of chromosomal abnormalities during the first trimester of pregnancy. Adv Clin Exp Med 2013; 22 (03) 395-401

The absence or hypoplasia of the nasal bone in this study was significantly associated with family history of malformations, but it was only found in one patient. There were no further associations with the other variables. There are few studies which describe the role of the nasal bone and in the literature it has been described that it doesn't influence over the other variables of the screening. However, when it is used in combination with maternal age, NT, free β-HCG, and PAPP-A, it rises the DR of this screening up to 90%, with a false positive rate of 0.5%.2828 Cicero S, Bindra R, Rembouskos G, Spencer K, Nicolaides KH. Integrated ultrasound and biochemical screening for trisomy 21 using fetal nuchal translucency, absent fetal nasal bone, free beta-hCG and PAPP-A at 11 to 14 weeks. Prenat Diagn 2003; 23 (04) 306-310 DOI: 10.1002/pd.588.
https://doi.org/10.1002/pd.588...
Moreover, regardless of whether it is directly associated with the modification of other variables in the screening or not, its frequency of presentation is higher in the fetuses with trisomy 21 and other chromosomal abnormalities than in the fetuses with normal genetical studies such as karyotype.2929 Zoppi MA, Ibba RM, Axiana C, Floris M, Manca F, Monni G. Absence of fetal nasal bone and aneuploidies at first-trimester nuchal translucency screening in unselected pregnancies. Prenat Diagn 2003; 23 (06) 496-500 DOI: 10.1002/pd.628.
https://doi.org/10.1002/pd.628...

On the other hand, the NT is proportionally associated with gestational age and BMI. This association has been described in other study populations, studies from the United Kingdom described a statistically significant correlation between the measure of NT, maternal BMI, smoking status, and Afro-Caribbean ethnicity.3030 Díaz V, Guevara R, Brito J. Translucencia nucal fetal y ductus venosus como marcadores ecográficos de cromosomopatías. Invest Clin 2008; 49 (04) 523-532 Additionally, for a long time the increased NT thickness has been associated with risk of having a genetic alteration. Since 1998, studies have concluded that the screening including maternal age and NT could have a DR of trisomy 21 of 90%, and a false positive of 5%.3131 Theodoropoulos P, Lolis D, Papageorgiou C, Papaioannou S, Plachouras N, Makrydimas G. Evaluation of first-trimester screening by fetal nuchal translucency and maternal age. Prenat Diagn 1998; 18 (02) 133-137 Nowadays, it is considered an important risk factor, and the prevalence of aneuploidies, especially trisomy 21, is higher when NT is increased.33 Wright D, Syngelaki A, Bradbury I, Akolekar R, Nicolaides KH. First-trimester screening for trisomies 21, 18 and 13 by ultrasound and biochemical testing. Fetal Diagn Ther 2014; 35 (02) 118-126 DOI: 10.1159/000357430.
https://doi.org/10.1159/000357430...
However, the measurement of the NT is also associated with the gestational age and fetal CRL, and its important to determine the distribution values for the population to have a fixed cut-off point according to the gestational age. A study that was done in Taiwan demonstrates the positive correlation between NT and CRL.3232 Jou HJ, Wu SC, Li TC, Hsu HC, Tzeng CY, Hsieh FJ. Relationship between fetal nuchal translucency and crown-rump length in an Asian population. Ultrasound Obstet Gynecol 2001; 17 (02) 111-114 DOI: 10.1046/j.1469-0705.2001.00332.x.
https://doi.org/10.1046/j.1469-0705.2001...

Of the biochemical markers, free β-HCG and PAPP-A are well now for the genetic screening during the first trimester. In this study, we found a direct relation of free β-HCG with gestational age, maternal age, and maternal BMI, while PAPP-A was inversely associated with maternal age and maternal BMI, and directly related to gestational age. A similar result for PAPP-A was obtained in Australia, where it was found an inverse relation between maternal BMI and the values of free β-HCG and PAPP-A.3333 Khambalia AZ, Roberts CL, Morris J, Tasevski V, Nassar N. Maternal body weight and first trimester screening for chromosomal anomalies. Aust N Z J Obstet Gynaecol 2014; 54 (05) 490-492 DOI: 10.1111/ajo.12231.
https://doi.org/10.1111/ajo.12231...
Spencer et al.1818 Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening program for trisomy 21 at 10-14 weeks using fetal nuchal translucency, maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 1999; 13 (04) 231-237 DOI: 10.1046/j.1469-0705.1999.13040231.x.
https://doi.org/10.1046/j.1469-0705.1999...
also found a direct relation between PAPP-A and gestational age. Moreover, the presence of trisomy 21 has been associated with lower levels of PAPP-A and higher levels of free β-HCG. Regarding trisomy 18 and 13, we found lower levels of PAPP-A and free β-HCG.33 Wright D, Syngelaki A, Bradbury I, Akolekar R, Nicolaides KH. First-trimester screening for trisomies 21, 18 and 13 by ultrasound and biochemical testing. Fetal Diagn Ther 2014; 35 (02) 118-126 DOI: 10.1159/000357430.
https://doi.org/10.1159/000357430...
These biochemical markers are included in the first trimester screening and are useful for obtaining a DR of 90%, 97%, and 92% for trisomy 21, 18, and 13, respectively, with a false positive rate of 3.1% if PAPP-A and free β-HCG are adjusted to gestational age, maternal weight, ethnicity, and smoking habits, among others.66 Santorum M, Wright D, Syngelaki A, Karagioti N, Nicolaides KH. Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound Obstet Gynecol 2017; 49 (06) 714-720 DOI: 10.1002/uog.17283.
https://doi.org/10.1002/uog.17283...

Finally, chromosomopathy studies began analyzing PlGF along with the other variables; studies from the United Kingdom describe that PlGF has a statistically significant direct relation with the gestational age, and inverse relation with the maternal BMI.3434 Zaragoza E, Akolekar R, Poon LC, Pepes S, Nicolaides KH. Maternal serum placental growth factor at 11-13 weeks in chromosomally abnormal pregnancies. Ultrasound Obstet Gynecol 2009; 33 (04) 382-386 DOI: 10.1002/uog.6331.
https://doi.org/10.1002/uog.6331...
Similarly, Sifakis et al.3535 Sifakis S, Akolekar R, Kappou D, Mantas N, Nicolaides KH. Maternal serum IGF-I, IGFBP-1 and IGFBP-3 at 11-13 weeks in trisomy 21 and trisomy 18 pregnancies. Eur J Obstet Gynecol Reprod Biol 2011; 157 (02) 166-168 DOI: 10.1016/j.ejogrb.2011.03.029.
https://doi.org/10.1016/j.ejogrb.2011.03...
has described that the P1GF values increased with the gestational age. In this study, we also found a statistically significant positive relation between gestational age and PlGF.

Conclusion

There is no available information about the behavior of the tests used in the screening for chromosomopathies in the Colombian population. Therefore, this study could be useful for understanding the correlations of the different variables with maternal characteristics, to determine the most helpful variables for developing the first trimester screening in this population. Moreover, this article provides information on the distribution of the biochemical and ultrasonographic markers in euploid fetuses, which could be the first approach to reference values in Colombian pregnant women, agreeing with the international values of reference. We suggest that the studies in this domain should continue to develop the best way to asses an early diagnosis of chromosomopathies, with the aim of doing appropriate, timely interventions and defining the course of the pregnancy and fetus's prognosis.

Funding/Acknowledgments

This study was conducted with the support of the El Bosque Research Group of Maternal Fetal Medicine and Gynecology, Ecodiagnóstico El Bosque S. A. S (PMMFGEB-011), and Universidad El Bosque (PCI-2013-472).

References

  • 1
    Christianson A, Howson CP, Modell B. March of Dimes global report on birth defects: the hidden toll of dying and disabled children [Internet]. White Plains: March of Dimes Birth Defects Foundation;. 2006 [cited 2021 Aug 12]. Available from: https://www.marchofdimes.org/materials/global-report-on-birth-defects-the-hidden-toll-of-dying-and-disabled-children-executive-summary.pdf
    » https://www.marchofdimes.org/materials/global-report-on-birth-defects-the-hidden-toll-of-dying-and-disabled-children-executive-summary.pdf
  • 2
    Restrepo Cano GA. [Prenatal diagnosis of congenital anormalies; an absent policy in Colombia]. Rev Fac Med (Caracas) 2016; 24 (01) 102-110 DOI: 10.18359/rmed.2764. Spanish.
    » https://doi.org/10.18359/rmed.2764
  • 3
    Wright D, Syngelaki A, Bradbury I, Akolekar R, Nicolaides KH. First-trimester screening for trisomies 21, 18 and 13 by ultrasound and biochemical testing. Fetal Diagn Ther 2014; 35 (02) 118-126 DOI: 10.1159/000357430.
    » https://doi.org/10.1159/000357430
  • 4
    Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson genetics in medicine. Chicago: Saunders; 2007
  • 5
    Parga Soler MN, Martínez Machuca S, Martín Idoeta O, Sánchez-Pastor Ruiz M. Diagnóstico prenatal y cribado de cromosomopatías. [Prenatal diagnosis and chromosomal abnormalities screening]. Med Fam Ginecol Obstet. 2001; 11 (10) 590-598 Spanish.
  • 6
    Santorum M, Wright D, Syngelaki A, Karagioti N, Nicolaides KH. Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound Obstet Gynecol 2017; 49 (06) 714-720 DOI: 10.1002/uog.17283.
    » https://doi.org/10.1002/uog.17283
  • 7
    Kagan KO, Wright D, Nicolaides KH. First-trimester contingent screening for trisomies 21, 18 and 13 by fetal nuchal translucency and ductus venosus flow and maternal blood cell-free DNA testing. Ultrasound Obstet Gynecol 2015; 45 (01) 42-47 DOI: 10.1002/uog.14691.
    » https://doi.org/10.1002/uog.14691
  • 8
    Franco C. [Evaluation of the nasal bone, ductus venosus and tricuspid regurgitation for the screening of Down Syndrome. Its Utility in intermediate risks] [thesis].. Madrid: Universidad Autónoma de Madrid;; 2013. . Spanish.
  • 9
    Nicolaides KH. Turning the pyramid of prenatal care. Fetal Diagn Ther 2011; 29 (03) 183-196 DOI: 10.1159/000324320.
    » https://doi.org/10.1159/000324320
  • 10
    Veduta A, Vayna AM, Duta S. et al. The first trimester combined test for aneuploidies - a single center experience. J Matern Fetal Neonatal Med 2018; 31 (16) 2091-2096 DOI: 10.1080/14767058.2017.1336220.
    » https://doi.org/10.1080/14767058.2017.1336220
  • 11
    Cancino E, León H, Otálora R, Pérez E, Sarmiento R, Yates A. [Guidelines of prenatal control and risk factors] [Internet]. Bogotá: Secretaría Distrital de Salud de Bogotá/ASBOG; [s.d.] [cited 2021 Aug 12]. Spanish. Available from: http://www.saludcapital.gov.co/DDS/Publicaciones/GUIA%201.%20%20CONTROL%20PRENATAL%20Y%20FACTORES%20DE%20RIESGO.pdf
    » http://www.saludcapital.gov.co/DDS/Publicaciones/GUIA%201.%20%20CONTROL%20PRENATAL%20Y%20FACTORES%20DE%20RIESGO.pdf
  • 12
    Ministerio de Salud y Protección Social - Colciencias.. [Guideline of clinical practice. Detection of congenital anomalies in newborns] [Internet]. Colombia: Minsalud; 2013 [cited 2021 Jun 10]. (Guide no. 3). Spanish. Available from: https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/INEC/IETS/GPC_Ptes_AC.pdf
    » https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/INEC/IETS/GPC_Ptes_AC.pdf
  • 13
    Ministerio de Salud y Protección Social - Colciencias.. [Clinical practice guide ministry of health for prevention, early detection and treatment of complications of pregnancy, childbirth and the puerperium] [Internet]. Colombia: MinSalud; 2013 [cited 2021 Jun 10]. Spanish. Available from: https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/INEC/IETS/Gu%C3%ADa.completa.Embarazo.Parto.2013.pdf
    » https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/INEC/IETS/Gu%C3%ADa.completa.Embarazo.Parto.2013.pdf
  • 14
    Asociación Médica Mundial (AMM).. [Declaration of Helsinki. Ethical principles for medical research in humans] [Internet]. 2017 [cited 2021 Jun 10]. Spanish. Available from: https://www.wma.net/es/policies-post/declaracion-de-helsinki-de-la-amm-principios-eticos-para-las-investigaciones-medicas-en-seres-humanos/
    » https://www.wma.net/es/policies-post/declaracion-de-helsinki-de-la-amm-principios-eticos-para-las-investigaciones-medicas-en-seres-humanos/
  • 15
    Ministerio de Salud. [Resolution number 8430 of 1993] [Internet]. Bogotá: MinSalud;; 1993 [cited 2021 Jul 20]. Spanish. Available from: https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/DE/DIJ/RESOLUCION-8430-DE-1993.PDF
    » https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/DE/DIJ/RESOLUCION-8430-DE-1993.PDF
  • 16
    Nicolaides KH. The 11–13 + 6 weeks scan. London: The Fetal Medicine Foundation;; 2004
  • 17
    Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10-14 weeks: the role of ductus venosus blood flow. Ultrasound Obstet Gynecol 1998; 12 (06) 380-384 DOI: 10.1046/j.1469-0705.1998.12060380.x.
    » https://doi.org/10.1046/j.1469-0705.1998.12060380.x
  • 18
    Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening program for trisomy 21 at 10-14 weeks using fetal nuchal translucency, maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 1999; 13 (04) 231-237 DOI: 10.1046/j.1469-0705.1999.13040231.x.
    » https://doi.org/10.1046/j.1469-0705.1999.13040231.x
  • 19
    Kasdaglis T, Aberdeen G, Turan O. et al. Placental growth factor in the first trimester: relationship with maternal factors and placental Doppler studies. Ultrasound Obstet Gynecol 2010; 35 (03) 280-285 DOI: 10.1002/uog.7548.
    » https://doi.org/10.1002/uog.7548
  • 20
    Yu B, Lu BY, Zhang B. et al. Overall evaluation of the clinical value of prenatal screening for fetal-free DNA in maternal blood. Medicine (Baltimore) 2017; 96 (27) e7114 DOI: 10.1097/MD.0000000000007114.
    » https://doi.org/10.1097/MD.0000000000007114
  • 21
    Sørensen S, Momsen G, Sundberg K, Friis-Hansen L, Jørgensen FS. First-trimester risk calculation for trisomy 13, 18, and 21: comparison of the screening efficiency between 2 locally developed programs and commercial software. Clin Chem 2011; 57 (07) 1023-1031 DOI: 10.1373/clinchem.2010.161299.
    » https://doi.org/10.1373/clinchem.2010.161299
  • 22
    Shiefa S, Amargandhi M, Bhupendra J, Moulali S, Kristine T. First trimester maternal serum screening using biochemical markers PAPP-A and free β-HCG for Down Syndrome, Patau Syndrome and Edward Syndrome. Indian J Clin Biochem 2013; 28 (01) 3-12 DOI: 10.1007/s12291-012-0269-9.
    » https://doi.org/10.1007/s12291-012-0269-9
  • 23
    Kalayci H, Yilmaz Baran Ş, Doğan Durdağ G. et al. Reference values of the ductus venosus pulsatility index for pregnant women between 11 and 13+6 weeks of gestation. J Matern Fetal Neonatal Med 2020; 33 (07) 1134-1139 DOI: 10.1080/14767058.2018.1517152.
    » https://doi.org/10.1080/14767058.2018.1517152
  • 24
    Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004; 191 (01) 45-67 DOI: 10.1016/j.ajog.2004.03.090.
    » https://doi.org/10.1016/j.ajog.2004.03.090
  • 25
    Cuckle HS, Spencer K, Nicolaides KH. Down syndrome screening marker levels in women with a previous aneuploidy pregnancy. Prenat Diagn 2005; 25 (01) 47-50 DOI: 10.1002/pd.1082.
    » https://doi.org/10.1002/pd.1082
  • 26
    Maiz N, Valencia C, Kagan KO, Wright D, Nicolaides KH. Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation. Ultrasound Obstet Gynecol 2009; 33 (05) 512-517 DOI: 10.1002/uog.6330.
    » https://doi.org/10.1002/uog.6330
  • 27
    Florjański J, Fuchs T, Zimmer M, Homola W, Pomorski M, Blok D. The role of ductus venosus Doppler flow in the diagnosis of chromosomal abnormalities during the first trimester of pregnancy. Adv Clin Exp Med 2013; 22 (03) 395-401
  • 28
    Cicero S, Bindra R, Rembouskos G, Spencer K, Nicolaides KH. Integrated ultrasound and biochemical screening for trisomy 21 using fetal nuchal translucency, absent fetal nasal bone, free beta-hCG and PAPP-A at 11 to 14 weeks. Prenat Diagn 2003; 23 (04) 306-310 DOI: 10.1002/pd.588.
    » https://doi.org/10.1002/pd.588
  • 29
    Zoppi MA, Ibba RM, Axiana C, Floris M, Manca F, Monni G. Absence of fetal nasal bone and aneuploidies at first-trimester nuchal translucency screening in unselected pregnancies. Prenat Diagn 2003; 23 (06) 496-500 DOI: 10.1002/pd.628.
    » https://doi.org/10.1002/pd.628
  • 30
    Díaz V, Guevara R, Brito J. Translucencia nucal fetal y ductus venosus como marcadores ecográficos de cromosomopatías. Invest Clin 2008; 49 (04) 523-532
  • 31
    Theodoropoulos P, Lolis D, Papageorgiou C, Papaioannou S, Plachouras N, Makrydimas G. Evaluation of first-trimester screening by fetal nuchal translucency and maternal age. Prenat Diagn 1998; 18 (02) 133-137
  • 32
    Jou HJ, Wu SC, Li TC, Hsu HC, Tzeng CY, Hsieh FJ. Relationship between fetal nuchal translucency and crown-rump length in an Asian population. Ultrasound Obstet Gynecol 2001; 17 (02) 111-114 DOI: 10.1046/j.1469-0705.2001.00332.x.
    » https://doi.org/10.1046/j.1469-0705.2001.00332.x
  • 33
    Khambalia AZ, Roberts CL, Morris J, Tasevski V, Nassar N. Maternal body weight and first trimester screening for chromosomal anomalies. Aust N Z J Obstet Gynaecol 2014; 54 (05) 490-492 DOI: 10.1111/ajo.12231.
    » https://doi.org/10.1111/ajo.12231
  • 34
    Zaragoza E, Akolekar R, Poon LC, Pepes S, Nicolaides KH. Maternal serum placental growth factor at 11-13 weeks in chromosomally abnormal pregnancies. Ultrasound Obstet Gynecol 2009; 33 (04) 382-386 DOI: 10.1002/uog.6331.
    » https://doi.org/10.1002/uog.6331
  • 35
    Sifakis S, Akolekar R, Kappou D, Mantas N, Nicolaides KH. Maternal serum IGF-I, IGFBP-1 and IGFBP-3 at 11-13 weeks in trisomy 21 and trisomy 18 pregnancies. Eur J Obstet Gynecol Reprod Biol 2011; 157 (02) 166-168 DOI: 10.1016/j.ejogrb.2011.03.029.
    » https://doi.org/10.1016/j.ejogrb.2011.03.029

Publication Dates

  • Publication in this collection
    29 Aug 2022
  • Date of issue
    July 2022

History

  • Received
    11 Nov 2021
  • Accepted
    02 Feb 2022
  • Published
    01 June 2022
Federação Brasileira das Sociedades de Ginecologia e Obstetrícia Av. Brigadeiro Luís Antônio, 3421, sala 903 - Jardim Paulista, 01401-001 São Paulo SP - Brasil, Tel. (55 11) 5573-4919 - Rio de Janeiro - RJ - Brazil
E-mail: editorial.office@febrasgo.org.br