Prevalence of Fetal Structural Anomalies and Genetic Testing in Fetuses With Increased Nuchal Translucency: A Single-Center Cohort Study and Systematic Review With Meta-Analysis Comparing Latin America and Other Regions

Abstract

Background:

Chromosomal microarray analysis (CMA) is the recommended genetic test for fetuses with increased nuchal translucency (NT); however, its use in Latin America remains limited. The objective of this study was to determine the prevalence of genetic testing in fetuses with increased NT in Panama and across Latin America.

Methods:

We conducted a retrospective cohort study of 1512 women who underwent first-trimester screening in Panama, along with a systematic review and meta-analysis of studies reporting genetic testing in Latin America. A comprehensive literature search was conducted across MEDLINE (via PubMed), Epistemonikos, LILACS, BRISA, SciELO, and Google Scholar, covering studies from inception to June 2023 was updated to December 2023. The extracted data included population, setting, timing, and genetic testing methods. The Joanna Briggs Tool was used to assess the risk of bias. Pooled prevalence estimates were calculated using random-effects models.

Results:

Among 1236 fetuses in the Panamanian cohort, 77 (6.23%) had NT ≥95th percentile. The systematic review included 11 studies encompassing 842 fetuses diagnosed with increased NT. The overall proportion of fetuses undergoing invasive testing was 0.31 (95% confidence interval [CI]: 0.28–0.33). Anomalies were found in 63% of cases with increased NT. CMA was not reported in any of the studies.

Conclusions:

Most patients in Latin America do not undergo invasive testing, and conventional karyotyping remains the most frequently performed method. To date, no studies have reported the use of CMA in this context. Therefore, the findings of this study highlight significant gaps in access to genetic testing, emphasizing the need for strategic initiatives to improve test availability and build capacity for implementing microarray analysis in the region.

Registration:

The study has been registered on https://www.crd.york.ac.uk/prospero/ (registration number: CRD42023398899; registration link: https://www.crd.york.ac.uk/PROSPERO/view/CRD42023398899).

Graphical abstract

Keywords

prenatal screening / nuchal translucency / chromosomal microarray analysis / genetic testing / Latin America / fetal anomalies / prenatal diagnosis

1. Introduction

Nuchal translucency (NT), a first-trimester sonographic marker characterized by a subcutaneous accumulation of fluid behind the fetal neck [1, 2, 3, 4], has been studied for over three decades. Increased fetal NT is associated with chromosomal abnormalities, congenital heart defects, and structural anomalies. Defined by the 95th and the 99th percentiles, NT \ge3 mm increases the risk of severe malformations by 15-fold, while NT \ge3.5 mm raises it by 40-fold [4, 5]. Increased NT has also been linked to microdeletion syndromes and single-gene disorders.

1.1 Genetic Testing and International Guidelines

Despite standardized NT measurements, international guidelines for managing increased NT vary. For instance, the Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends genetic counseling, chromosomal microarray analysis (CMA), and a detailed second-trimester ultrasound for NT >3.5 mm [6]. The American College of Obstetricians and Gynecologists (ACOG) advises similar measures, including fetal echocardiography, for NT >3.0 mm or above the 99th percentile [7]. In countries with universal healthcare, CMA is routinely offered for NT >99th percentile. Additionally, cell-free DNA testing is offered as an alternative for patients who do not consent to invasive procedures [8, 9].

1.2 Challenges in Latin America

In Latin America, only one national prenatal screening program has been established [10, 11, 12]. However, significant barriers to accessing this program include a lack of genetic counselors, limited reimbursement policies, and inadequate medical genetics training. Moreover, the absence of national guidelines for prenatal genetic diagnosis has led to limited data on the availability and use of genetic and genomic testing for high-risk subgroups, such as fetuses with increased NT.

1.3 Objectives

This study aimed to determine the prevalence of fetal structural anomalies in pregnancies with increased NT and the proportion of women who underwent invasive prenatal diagnosis due to increased NT in Latin America and other countries.

2. Materials and Methods

2.1 Panamanian Cohort

This retrospective study selected women who underwent sonographic examination at the Hospital Punta Pacifica, Panama (November 2005–September 2018). Informed consent was obtained from all participants. Singleton and multiple pregnancies were included in the sample, with the maternal and fetal data collected using questionnaires and ultrasound assessments. NT measurements, recorded as the highest of three values, were considered to have increased if they were above the 95th percentile using established reference ranges [13]. Patients with a Down syndrome risk >1/250 were offered counseling and diagnostic tests (chorionic villus sampling or amniocentesis) using rapid FISH or quantitative fluorescence polymerase chain reaction (QF-PCR). Since 2014, noninvasive prenatal tests (i.e., Harmony, Nova Screen, Verify, and Panorama) have become available. Birth outcomes, including live births and adverse events (e.g., intrauterine death, miscarriage, or chromosomal anomalies), were retrieved from clinical records. The study followed ethical guidelines (RESEGIS 2397) and received IRB exemption (CBI-21-104).

2.2 Statistical Analysis

Quantitative variables were tested for normality using the Shapiro-Wilk test. Moreover, normally distributed variables were compared using the t-test (mean \pm SD), whereas non-normally distributed variables were compared using the Mann-Whitney U test (median, interquartile range [IQR]). Qualitative variables were analyzed using the chi-square or Fisher’s exact test, and significance was set at p 0.05. Further, data were analyzed using STATA version 14.1 (College Station, TX, USA) and R version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria).

2.3 Systematic Review

This systematic review followed the PRISMA guidelines [14] (Supplementary Table 1) and was registered on https://www.crd.york.ac.uk/prospero/ (registration number: CRD42023398899; registration link: https://www.crd.york.ac.uk/PROSPERO/view/CRD42023398899). Searches were conducted using databases such as MEDLINE (via PubMed), Epistemonikos, LILACS, BRISA, SciELO, and Google Scholar, without date restrictions, focusing on Spanish and Portuguese studies related to increased NT, genetic anomalies, and Latin America. The initial search (June 2023) was updated to December 2023.

Retrospective and prospective cohort studies on pregnant patients in Latin America were included in the review, whereas case series (four cases) and pediatric studies without maternal data were excluded. Notably, the data were extracted using a pre-piloted Google Forms sheet by two independent reviewers, covering study details, sample size, inclusion criteria, diagnostic methods, and genetic findings. References were cross-checked, and discrepancies were resolved by consensus. Methodological quality was assessed using the Joanna Briggs Institute checklist for prevalence studies.

2.4 Data Synthesis and Statistical Analysis

Statistical analyses were performed using R version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria), while a meta-analysis of proportions was conducted using the “meta” and “metafor” packages. A random-effects model was applied using the restricted maximum likelihood (REML) estimator to account for between-study variability.

Heterogeneity was assessed using the \tau², \chi² (Cochran’s Q), and I² statistics. The results are presented as forest plots [15, 16]. For outcomes with low heterogeneity, a fixed-effects model was reported for comparison, and funnel plots and Egger regression tests were used to assess potential publication bias. Further, to ensure robustness, pooled estimates and heterogeneity metrics were independently confirmed using Stata version 14.1 (StataCorp, College Station, TX, USA) with the metaprop command. All results were presented with 95% confidence intervals (CIs), and significance was determined using a two-tailed p-value threshold of 0.05.

3. Results

3.1 Panamanian Cohort

A total of 1512 obstetric ultrasound examinations (of 1652 fetuses) were performed. After excluding patients who were lost to follow-up, pregnant at the time of data extraction, or had incomplete information, 1236 fetuses were included in the final analysis. The mean maternal age of the participants was 31.9 \pm 5.2 years, the mean gestational age at the time of the scan was 13 weeks, and the median NT measurement was 1.76 mm (interquartile range: 0.90–9.80 mm). In 77 fetuses (6.23%), the NT measurement was equal to or above the 95th percentile, while 140 fetuses (13.4%) had an NT measurement equal to or above the 90th percentile (Fig. 1).

As regards pregnancy outcomes, 998 fetuses (96.1%) resulted in live births, while 40 fetuses (3.9%) had a composite adverse perinatal outcome. Additional findings included abnormal nasal bone in 11 fetuses (0.9%), abnormal ductus venosus flow in 10 fetuses (0.8%), and abnormal tricuspid flow in nine fetuses (0.7%). The characteristics of the study population are presented in Supplementary Table 2.

3.2 Fetuses With Increased NT

In 77 fetuses (6.23%), 58 had live birth without anomalies (75.3%): 25 had adverse outcomes (32.5%). 4 termination of pregnancy (TOP), one stillbirth and two neonatal death lacked karyotype results. Structural abnormalities were noted in adverse outcomes, which are detailed in Table 1.

Invasive diagnostic procedures such as chorionic villous sampling (CVS) or amniocentesis were performed in 20 cases (23.5%), while two cases (2.3%) underwent cell-free DNA (cfDNA) testing, both leading to healthy live births. Among the TOP cases, one had trisomy 21, one stillbirth was linked to severe oligohydramnios, and two neonatal deaths involved complex congenital heart defects, including a complete atrioventricular canal and double outlet right ventricle with anomalous pulmonary venous connection.

3.3 Fetuses With Normal NT

Adverse outcomes occurred in 24 fetuses with normal NT (2.5 mm). Six (25%) patients had MC, including two monochorionic and one dichorionic twin pregnancies. Two of these MC were due to cervical incompetence; one followed intra-amniotic infection after cerclage, while the other occurred post-amniocentesis complications. The cause was unknown in 13 cases (54%). Additionally, two stillbirths were recorded: one in an obese patient with hypertension and preeclampsia and another in a patient with low body mass index (BMI) and chronic anemia in Supplementary Table 3.

3.4 Systematic Review

The present systematic literature search identified 306 citations related to increased NT, genetic testing, and chromosomal anomalies in Latin America. After removing duplicates, 39 full-text studies were assessed, of which 11 met the inclusion criteria Fig. 2 (Ref. [14]). Collectively, these 11 studies included 842 fetuses with increased NT. Among them, nine studies applied the fetal medicine foundation (FMF) guidelines and NT measurements to evaluate the risk of Down syndrome and other aneuploidies [11, 17, 18, 19, 20, 21, 22, 23, 24]. One study used maternal age as the sole screening criterion [25], while another employed the “Fetal Test” software for risk assessment [22].

The main characteristics of the studies included in the systematic review are presented in Table 2 (Ref. [11, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]).

3.5 Geographical Distribution of Studies

Four studies were conducted in Brazil and Mexico at academic university hospitals [17, 18, 19, 20]. Three studies from Cuba were conducted in provincial centers affiliated with the National Center of Medical Genetics at the Medical University of Havana [7, 21, 25]. The studies carried out in Peru, Chile, and Colombia were conducted in various settings, including in vitro fertilization clinics [22, 26], private genetic laboratories [23], and private clinics [24]. Invasive testing options included CVS and amniocentesis, although 36.6% of the patients did not undergo karyotype analysis.

3.6 Methodological Quality of Studies

The methodological quality assessment using the Joanna Briggs Institute (JBI) checklist revealed variability in study quality (Table 3, Ref. [11, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26]).

Three studies were classified as having a low risk of bias, one had a moderate risk, and seven exhibited a high risk of bias. Common limitations of high-risk studies include inadequate sample sizes, unclear sampling methods, and a lack of response rate reporting. Conversely, low-risk studies demonstrated robust study designs, appropriate statistical analyses, and comprehensive reporting of study settings and participants.

3.7 Prevalence of Increased NT

Fig. 3 illustrates the pooled proportion of fetuses with increased NT identified across the four studies. The overall proportion of increased NT cases was found to be 0.03 (95% CI: 0.03–0.04). Individual study estimates ranged from 0.02 (95% CI: 0.02–0.03) in Vázquez in 2008 to 0.04 (95% CI: 0.03–0.04) in Saldanha in 2009 [18, 23].

There was evidence of substantial statistical heterogeneity (I² = 87.40%) and statistically significant Cochran’s Q test (p 0.001). Egger’s test for funnel plot asymmetry was also conducted, resulting in z value in 0.33 and a p-value of 0.7374. This indicates no significant evidence of publication bias (p > 0.05). The expected effect size as the standard error approached zero was estimated to be 0.0306, with a 95% CI of 0.0105 to 0.0506. This finding suggests that the underlying effect size is likely unaffected by publication bias (Supplementary Fig. 1).

3.8 Prevalence of Invasive Testing

Fig. 4 presents a forest plot of the proportion of fetuses undergoing invasive testing. The pooled proportion of invasive testing was 0.31 (95% CI: 0.28–0.33), with individual study estimates ranging from 0.29 to 0.39. Heterogeneity was moderate (I² = 36.65%), with a non-significant Q-test (p = 0.11), indicating that the variability across studies was not statistically significant.

3.9 Prevalence of Fetal Anomalies

A meta-analysis was conducted to determine the proportion of anomalies in cases with increased NT. The pooled estimate under the common-effect model indicated that 0.63 (95% CI: 0.59–0.68) of cases with increased NT were associated with anomalies. Similarly, the random-effects model yielded a proportion of 0.63 (95% CI: 0.52–0.73), albeit with a wider CI due to study variability (Fig. 5).

3.10 Risk of Cardiac Anomalies in Fetuses With Increased NT

The pooled proportion of cardiac anomalies was estimated to be 0.42 (95% CI: 0.1–0.73). The proportion of cardiac anomalies varied across studies, with Saldanha et al. (2009) [18] reporting 2.4%, Vieira et al. (2013) [19] reporting 7.0%, and the Panamanian cohort reporting 0.36%. The random effects model was used to account for heterogeneity, yielding a conservative estimate.

3.11 Comparison With Other Regions

A total of 1512 pregnancies (1236 fetuses) from the Panamanian cohort and 842 fetuses from 11 Latin American studies were analyzed. The prevalence of NT \ge95th percentile varied across regions, ranging from 3.6% to 62% in Latin America, 4%–6% in Europe, and higher in selected Asian studies. Congenital heart defects (CHD) were the most frequent structural anomalies in all regions, with rates between 10.4% and 20%, followed by cystic hygroma and hydrops fetalis (Table 4, Ref. [28]).

The aneuploidy detection rate was 33% among MC with karyotyping in Panama and varied from 10.5% to 62% across Latin America. In contrast, North American and European studies reported aneuploidy rates of 34.35%–51.3% in fetuses with NT \ge3.5 mm. Turner syndrome, trisomy 21, and trisomy 18 are the most commonly identified aneuploidies.

The invasive testing uptake was significantly lower in Latin America (31%) than in North America and Europe (close to 100%). Notably, CMA has not been reported in any Latin American study, despite it being the recommended genetic test in developed countries. Pregnancy termination rates were lowest in Latin America (7.1%–7.8%), in contrast to 46.9% in Canada and 66.1% in Turkey, likely reflecting legal and cultural differences in prenatal decision-making.

4. Discussion

4.1 Principal Findings

This study highlights the low uptake of invasive genetic testing for fetuses with increased NT in the context of Latin America, despite its importance in detecting chromosomal and structural abnormalities. In the Panamanian cohort, only 23.5% underwent invasive testing, while a systematic review of 842 fetuses across 11 Latin American studies found a rate of 0.31 (95% CI: 0.28–0.33). These figures contrast sharply with those of North America and Europe, where nearly all high-risk pregnancies receive invasive testing [1, 2, 3].

Congenital heart defects (10.4%) and cystic hygroma with hydrops fetalis (13%) were found to be the most frequent fetal abnormalities in our cohort, aligning with global data showing structural anomalies in 30–50% of fetuses with increased NT [4, 5, 6]. However, unlike North America and Europe, where Turner syndrome is the most commonly reported chromosomal abnormality in increased NT cases (26.5%), no cases were reported in our review. This discrepancy likely reflects the low karyotyping and molecular testing rates in Latin America, thereby leading to potential underdiagnosis [7, 8, 9].

4.2 Comparison With International Data

The absence of CMA data in this review highlights the significant gap between Latin America and developed countries. While the ACOG and SOGC recommend CMA as the first-line diagnostic tool for fetuses with increased NT due to its ability to detect submicroscopic chromosomal imbalances [7], none of the included Latin American studies reported CMA use, which suggests limited accessibility.

Besides, invasive testing rates also vary widely. While Latin America reports a 31% invasive testing rate, nearly 100% of patients with NT >3.5 mm undergo invasive procedures in Canada and Europe, reflecting differences in healthcare policies, patient preferences, and access to genetic services [3, 9, 10]. Pregnancy termination rates also differ, with Latin America reporting it at a rate of 7.1–7.8%, compared to 47.8% in Canada. This is likely influenced by legal and cultural factors [29, 30, 31, 32, 33].

4.3 Clinical Implications

Our findings emphasize the urgent need for expanded access to genetic testing and counseling in Latin America [34, 35, 36, 37, 38]. Although cfDNA testing is a viable noninvasive alternative, it fails to detect 2–10% of chromosomal aberrations, making it inadequate as a standalone test for high-risk cases [39, 40, 41]. Additionally, the absence of molecular testing in Latin America limits the identification of RASopathies and other monogenic disorders, which are increasingly recognized as contributors to increased NT in fetuses with normal karyotypes [42, 43, 44, 45]. Exome sequencing is increasingly recommended for cases when both CMA and karyotype are normal because identifies pathogenic variants in up to 10% of these cases [46]. Exome sequencing remains largely inaccessible in Latin America.

4.4 Strengths and Limitations

This study has several strengths. For instance, we conducted a systematic review of Latin American studies, incorporating data from multiple national and regional databases to ensure a comprehensive representation of prenatal diagnostic trends in the region. Additionally, our Panamanian cohort provides direct insights into local screening practices and their alignment with global recommendations.

However, the limitations of this study must also be acknowledged. First, the lack of large, multicenter, or population-based studies in Latin America restricts the generalizability of our findings. Second, no CMA or molecular testing data were available for either the Panamanian cohort or the systematic review, limiting the ability to detect submicroscopic chromosomal imbalances and monogenic disorders. Finally, differences in healthcare infrastructure, socioeconomic factors, and legal frameworks across Latin American countries may contribute to variability in prenatal diagnostic practices, requiring further investigation.

5. Conclusions

This study highlights the disparities in prenatal genetic testing for increased NT in Latin America, where only 31% of high-risk pregnancies undergo invasive testing, and no reported cases include CMA analysis. These findings contrast sharply with those of developed regions, where universal access to invasive and molecular genetic testing is standard practice. Therefore, efforts to improve genetic counseling, expand CMA availability, and standardize prenatal screening guidelines are urgently required to ensure that patients receive equitable access to prenatal diagnostics. Hence, addressing barriers such as the lack of genetic specialists, limited reimbursement, and legal restrictions on pregnancy termination will be essential to align Latin American prenatal care practices with international standards. Future research should focus on evaluating patient and provider perspectives regarding genetic testing uptake, assessing healthcare disparities, and conducting cost-effectiveness studies to support the implementation of CMA and expanded genetic testing programs in Latin America.

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Funding

Secretaría Nacional de Ciencia, Tecnología e Innovación, and Sistema Nacional de Investigación(136-2022)