Intrauterine death in singleton pregnancies with trisomy 21, 18, 13 and monosomy X

Óbito fetal em gestações únicas com diagnóstico de trissomias dos cromossomos 21, 18, 13 e monossomia do X

Summary

A retrospective study from November 2004 to May 2012, conducted at the Obstetric Clinic of Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HC-FMUSP), which included 92 singleton pregnancies with prenatal diagnosis of trisomy of chromosome 21 (T21), 18, 13 (T13/18) and monosomy X (45X), with diagnosis performed until the 26th week of pregnancy. The aim of the study was to describe the frequency and to investigate predictors of spontaneous fetal death (FD). Diagnosis (T21, n=36; T13/18, n=25; 45X, n=31) was made at a mean gestational age of 18.3±3.7 weeks, through chorionic villus biopsy (n=22,24%), amniocentesis (n=66, 72%) and cordocentesis (n=4, 4%). Major malformations were present in 45 (49%); with hydrops in 32 (35%) fetuses, more frequently in 45X [n=24/31, 77% vs. T21 (n=6/36, 17%) and T13/18 (n=2/25, 8%), p<0.001]. Specialized fetal echocardiography was performed in 60% (55/92). Of these, 60% (33/55) showed changes in heart morphology and/or function. Fetuses with T13/18 had a higher incidence of cardiac anomalies [60 vs. 25% (T21) and 29% (45X), p= 0.01]. FD occurred in 55 (60%) gestations, being more frequent in 45X [n=26/31, 84% vs. T21 (n=13/36, 36%) and T13/18 (n=16/25, 64%), p<0.01]. Stepwise analysis showed a correlation between hydrops and death in fetuses with T21 (LR= 4.29; 95CI=1.9-8.0, p<0.0001). In fetuses with 45X, the presence of echocardiographic abnormalities was associated with lower risk of FD (LR= 0.56; 95CI=0.27- 0.85, p=0.005). No predictive factors were identified in the T13/18 group. Intra- uterine lethality of aneuploid fetuses is high. Occurrence of hydrops increases risk of FD in pregnancies with T21. In pregnancies with 45X, the occurrence of echocardiographic changes reduces this risk.

Keywords:
Aneuploidy; trisomy; monosomy; fetal death; forecasting; prenatal diagnosis

Resumo

Estudo retrospectivo, de novembro de 2004 a maio de 2012, na Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, incluindo 92 gestações únicas com diagnóstico pré-natal de trissomia dos cromossomos 21 (T21), 18, 13 (T13/18) e monossomia do X (45X), realizado até a 26a semana, com o objetivo de descrever a frequência e investigar preditores do óbito fetal espontâneo (OF). O diagnóstico (T21: n=36; T13/T18: n=25; 45X: n=31) foi realizado em idade gestacional média de 18,3±3,7 semanas, por biópsia de vilo corial (n=22; 24%), amniocentese (n=66; 72%) e cordocentese (n=4; 4%). Malformação major presente em 45 (49%) fetos e hidropisia em 32 (35%), mais frequente no grupo 45X [n=24/31, 77% vs. T21 (n=6/36, 17%) e T13/18 (n=2/25, 8%); p<0,001]. Ecocardiografia fetal especializada foi realizada em 60% (55/92). Destes, 60% (33/55) tinham alterações na morfologia e/ou na função cardíaca. Fetos com T13/18 apresentaram incidência maior de anomalias cardíacas [60 vs. 25% (T21) e 29% (45X); p=0,01]. Ocorrência de OF em 55 (60%) gestações e mais frequente no grupo 45X [n=26/31, 84% vs. T21 (n=13/36, 36%) e T13/18 (n=16/25, 64%); p<0,01]. Análise stepwise demonstrou associação entre hidropisia e óbito em fetos com T21 (LR=4,29; IC95%=1,9-8,0; p<0,0001). Em fetos com 45X, a presença de alterações ecocardiográficas esteve associada com menor risco de OF (LR=0,56; IC95%=0,27-0,85; p=0,005). Não foram identificados fatores preditores no grupo T13/18. A letalidade intrauterina de fetos aneuploides é elevada. A presença de hidropisia aumenta o risco de OF em gestações com T21. Em gestações com 45X, a ocorrência de alterações ecocardiográficas reduz esse risco.

Palavras-chave:
aneuploidia; trissomia; monossomia; morte fetal; previsões; diagnóstico pré-natal

Introduction

Prenatal diagnosis of fetal chromosomal abnormalities is a major theme in modern perinatology. The prevalence of chromosomal abnormalities in clinically recognized abortion is about 50%.¹ Aneuploid fetuses accounts for 6% of stillbirths and 11% of neonatal deaths.² Aneuploidies that are compatible with life but bring considerable morbidity occur in 0.65% of live births.^1,3 Trisomies 21 (T21), 18 and 13 (T13/18) and x-chromosome monosomy (45X) are the most frequent aneuploidies in newborns.^4-6 Nowadays, tracking programs and prenatal diagnosis of such abnormalities are quite widespread.¹

Conventional prenatal screening is conducted based on parameters such as maternal age (MA), and the study of ultrasound and biochemical markers. For pregnant women categorized as high risk, the assessment of fetal karyotype is offered through invasive procedures such as chorionic villus sampling (CVS) and amniocentesis (AMNIO), which carry a small but known risk of fetal loss.⁷

After demonstration of the presence of free fetal nucleic acids (DNA) in maternal plasma in 1997 by Lo et al., a range of possibilities was presented for noninvasive prenatal diagnosis of various fetal diseases, including aneuploidies.⁸ The great advantage of using non-invasive techniques is reducing the number of invasive procedures, and consequently loss of normal fetuses.^8,9 Recently, several studies have validated a technology known as mass genomic sequencing, quantifying millions of DNA fragments in biological samples and providing results within days with high accuracy to detect T13/18 and T21 in early gestational age (less than 10 weeks).^4,10-12 Others have demonstrated a detection rate of over 98% with a false positive rate of less than 0.5%.^13-20 Thus, non-invasive prenatal testing (NIPT) seems to be the most effective screening method in women at high risk²¹ and is already available at private laboratories in Brazil for tracking autosomal and sexual aneuploidies.

In many countries, the termination of pregnancies relating to aneuploid fetuses is allowed. In these cases, about 60-90% of parents choose to terminate the pregnancy after receiving the diagnosis of the abnormality.^22-24 In Brazil, the current legislation does not provide permission for termination of a pregnancy in cases of chromosomal abnormalities, and this practice is typified in the country's Criminal Code. There are favorable judicial decisions for termination in the case of anomalies incompatible with life.²⁵

It is also known that many of these fetuses die in the womb due to spontaneous mortality, which is high for aneuploidies.²⁶ Few studies describe the natural evolution of cases with abnormal karyotype, as such pregnancies are often terminated in countries where it is permitted.^25-29

So, in Brazil, many parents experience the anguish of knowing that the fetus is carrying a chromosomal abnormality, which is often associated with high intrauterine or neonatal mortality rates, with the only choice being to follow the natural course.

At the Obstetrics Clinic in the Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HC-FMUSP), screening by measuring nuchal translucency (NT) has been offered since 1995 to all pregnant women who start prenatal care in the service or who are referred for their first trimester ultrasound. As a center of reference, the Fetal Medicine Division also receives many cases with recommendations for invasive prenatal diagnosis, referred due to the high risk of chromosomal abnormalities after ultrasound screening in the first and second trimester at other services. After diagnosis, these fetuses are monitored until the end of pregnancy.

Methods

This was a retrospective study of singleton pregnancies with prenatal diagnosis of T21, T13/18 and 45X, monitored by the Fetal Medicine Division of the HC-FMUSP Obstetrics Clinic. The research project was approved by the Ethics Committee for Research Project Analysis at the HC-FMUSP on 5/31/2011. Singleton pregnancies with prenatal diagnosis of chromosome 21 (T21), 18, 13 (T13/18) trisomy and X monosomy (45X) performed until the 26^(th) week of gestation were included, whose parents had not sought court approved termination, and with a known outcome. Cases were identified by consulting the record books of invasive procedures for diagnosis of fetal karyotype at the Fetal Medicine Division of the HC-FMUSP Obstetrics Clinic. For each identified case, epidemiological maternal, gestational and perinatal data was collected from the electronic search of the computerized reports system in obstetrics and gynecology (SILOG) and hospital records. Patients whose final outcome occurred in other hospitals were contacted by telephone to obtain the relevant information.

The data were analyzed using the statistical software Minitab 16 (version 16.2.4, United States). The results were described according to the mean, standard deviation and absolute and relative frequencies. The comparisons between groups were conducted using the Kruskal-Wallis test and chi-square or Fisher's exact tests, if appropriate. Multivariate stepwise analysis was used to investigate the significant predictors of fetal death (FD) and included MA, parity, multiparity (two or more previous births), previous occurrence of abortions, gestational age at diagnosis, karyotype group, presence of major malformation (MF), presence of echocardiographic changes, fetal sex, and presence of fetal hydrops. The level of statistical significance was set at 0.05. For the significant variables in the multivariate regression, likelihood ratio (LR) and confidence interval were calculated, with a confidence interval (CI) of 95%.

Results

181 singleton pregnancies were identified with prenatal diagnosis of chromosome 21, 18, 13 trisomy or X chromosome monosomy. 97 (53.6%) of these pregnant women underwent fetal karyotype studies at a gestational age of less than 26 weeks and had known pregnancy outcomes, with five cases terminated after court order. Thus, the final sample of this study included 92 pregnancies (T21 n=36, T18 n=15, T13 n=10; 45X n=31).

MA ranged from 14 to 46 years, with a mean age of 32.7±8.7, and 48% (44 of 92) aged more than 35 years. Pregnant women with fetuses carrying 45X had a mean age of 26.2±7.5 years, significantly lower than those in the trisomy 21 (37.8±5.4, p<0.001) and trisomy 13/18 (33.4±8.9, p<0.001, Table 1) groups. Gestational age at the time of the diagnostic procedure ranged from 11.9 to 26.9 weeks, with an average of 18.3±3.7 weeks. Sixty-seven (72.8%) fetuses were female, and 25 (27.2%) male. Among fetuses with trisomy 21 and 13/18, 44% (16/36) and 80% (20/25) were female, respectively. All fetuses with the 45X karyotype were female.

TABLE 1
Maternal epidemiological, gestational, clinical and perinatal characteristics in 92 pregnancies with prenatal diagnosis of trisomies 21, 18 and 13 and X monosomy at the HC-FMUSP, from May 2004 to November 2012

		All	T21	T13/18	45X	p*
n		92	36	25	31
Maternal age in years, mean±SD		32.7±8.7	37.8±5.4	33.4±8.9	26.2±7.5	<0,001 45X<T21; 45X<T13/18
Primigravida, n (%)		43 (47)	12 (33)	12 (48)	19 (61)	0.07
Multigravida, n (%)		27 (29)	11 (31)	10 (40)	6 (19)	0.24
Previous abortion, n (%)		3 (3)	1 (3)	1 (4)	1 (3)	0.97
Gestational age in weeks, mean±SD		18.3±3.7	17.9±4	19.7±3.5	17.6±3.2	0.08
Procedure, n (%)
	Chorionic villus sampling	22 (24)	11 (31)	6 (24)	5 (16)	0.28
	Amniocentesis	66 (72)	25 (70)	18 (72)	23 (74)
	Cordocentesis	4 (4)	-	1 (4)	3 (10)
Major malformation n (%)
	None	47 (51)	24 (67)	9 (36)	14 (45)	0.045** T21<T18
	1	31 (34)	12 (33)	3 (12)	16 (52)
	2	6 (6)	-	5 (20)	1 (3)
	≥ 3	8 (9)	-	8 (32)	-
Echocardiographic abnormality, n (%)		33 (36)	9 (25)	15 (60)	9 (29)	0.01 T13/18>T21; T13/18>45X
Hydrops, n (%)		32 (35)	6 (17)	2 (8)	24 (77)	<0,001 45X>T21; 45X>t13/18
Male fetus, n (%)		25 (27)	20 (56)	5 (20)	-	<0,001 45X<T21; 45X<T13/18
Intrauterine death, n (%)		55 (60)	13 (36)	16 (64)	26 (84)	<0,01 45X>T21; 45X>T13/18

• ^*
  Kruskal Wallis or chi-squared tests. SD: Standard deviation, N: Number of cases, P: Level of statistical significance
• ^**
  Comparison between the frequencies of at least one major malformation

Twenty-four percent (22 of 92) underwent chorionic villus sampling, 72% (66 of 92) amniocentesis, and 4% (4 of 92) underwent cordocentesis. The T21, T13/18 and 45X subgroups did not differ regarding the distribution of the types of invasive procedures. The main indications for the fetal karyotype study were the presence of major MF in 49% (45 of 92) of cases, the presence of ultrasound markers in 38% (35 of 92) of cases and the presence of fetal hydrops in 35% (32 of 92) of cases.

Forty-nine percent (45 of 92) showed MF of the fetus, 34% (31 of 92) had only one MF, 6% (6 of 92) had two MF and 9% (8 of 92) had 3 or more MF. The frequency of at least one major MF in the T21 group was significantly lower than the T13/18 groups: T21 (12/36) vs. T13/18 (16/25) vs. 45X (17/31); p=0.045, Table 1.

Fifty-five pregnant women underwent specialized fetal echocardiography and 33 (60%) of these showed changes in heart morphology and/or function. The most common cardiac abnormality was ventricular septal defect (VSD), which corresponded to 39% of diagnoses. Fetuses with trisomy 13/18 had a significantly higher incidence of cardiac abnormalities (60 vs. 25% (T21) and 29% (45X), p=0.01). Hydrops was identified in 32 (35%) fetuses, and its occurrence was significantly higher in fetuses with Turner syndrome (24/31, 77%, p<0.001) compared to the T21 (6/36, 17%) and T13/18 (2/25, 8%) fetuses. FD occurred in 55 (60%, 95CI: 49-70) fetuses, and this outcome was significantly more frequent in the 45X group (n=26/31, 84%, 95CI: 66-95%) compared to the T21 group (n=13/36, 36%, 95CI: 21-54%, p<0.0001). The rate of FD in the T13/18 group was 64% (n=16/25, 95CI: 43-82%).

In the stepwise logistical regression analysis for prediction of FD in pregnancies with trisomy 21, the presence of hydrops was the variable that correlated significantly with the occurrence of FD (p<0.0001; LR = 4.29; 95CI = 1.9 to 8.0), in fetuses with trisomy 13/18 predictive variables of FD were not identified. For the 45X group, the presence of echocardiographic abnormalities was associated with a lower risk of FD (p=0.005; LR = 0.56; 95CI = 0.27-0.85, Table 2).

TABLE 2
Stepwise logistic regression for prediction of fetal death in 36 pregnancies with prenatal diagnosis of trisomy 21, and 31 pregnancies with prenatal diagnosis of X monosomy – HC-FMUSP from 2004 to 2012

	Coefficient	Standard error	p*	LR	95CI
Trisomy 21
Constant	0.23	0.07	0.003
Fetal hydrops	0.77	0.18	<0,001	4.29	1.87- 7.99
Monosomy X
Constant	0.96	0.07	<0,001
Echocardiographic abnormalities	-0.40	0.13	0.005	0.56	0.27- 0.85

• ^*
  Level of significance of 0.05; LR: Likelihood ratio, CI: Confidence interval

Discussion

Chromosomal abnormalities are incurable congenital abnormalities. Those that are the subject of this study are the most frequent in live births, and so have the greatest impact at the social, economic and family levels. The incidence of trisomies increases with MA.^30-36 Due to socio-cultural changes of the last century, such as the introduction of family planning and the inclusion of women in the labor market, women have started getting pregnant later and later and so the prevalence of trisomies has increased in recent decades.^26,37-40

This study was based on data obtained from tracking of aneuploid fetuses identified after fetal karyotype studies, indicated by the presence of morphological changes in ultrasound examinations in the first and/or second trimester. Only in 1% (1 of 92) of cases the karyotype study was indicated due to advanced MA. Historically, MA equal to 35 years or older was the first indication for fetal karyotype studies, but with the development of ultrasound and biochemical screening programs, advanced MA alone is used less and less to recommend karyotype studies.^1,35,41,42

In 2012, Kohatsu et al.⁴³ in a retrospective study at the HC-FMUSP Obstetrics Clinic described the indications for conducting 713 invasive procedures for studying fetal karyotype and the presence of fetal morphological changes, indicating 69.8% of the procedures. In this series, 99% of the cases had an ultrasound abnormality as an indication for karyotype studies, where the main indications were 49% MF (45 of 92), 38% (35 of 92) ultrasound markers from the first and second trimester and 35% (32 of 92) fetal hydrops. This difference is justified by the fact that, in this study, all fetuses had aneuploidy, while in the study by Kohatsu et al., only 25% (187 of 713) of the fetuses were aneuploid.

Most studies that monitor the natural evolution of fetuses with prenatal diagnosis of chromosomal abnormalities use data from fetuses identified after the biochemical and/or ultrasound screening of the first and/or second trimester or sequentially.^29,44-47 In Brazil, there is a public policy of screening for aneuploidy, therefore, cases with ultrasound changes in the morphological examination from the first and second trimester are referred to tertiary care centers, such as the HC-FMUSP, a situation similar to that described by Yamanaka et al.⁴⁴ in a study published in Japan in 2006. In 2013, Loane et al.,³⁸ in a study using data from the European Surveillance of Congenital Anomalies (Eurocat), reported that 58% of cases with prenatal diagnosis of T21 are identified in the ultrasound screening at the first trimester, and 16% after combined screening (biochemical and ultrasound). Cultural, social and legal differences between countries justify the differences in the recommendations for invasive procedure for fetal karyotype studies.

In this series of cases, the average MA was 32.7±8.7 years. The majority of observational studies between 1970 and 1990, such as that by Hook et al.,³⁴ in 1983, have a higher average MA (39.1±6.2 years), which is justified by the fact that fetal karyotype studies were, at that time, recommended for a MA greater than or equal to 35 years. In this study, the average MA for the 45X group was 26.2±7.5 years, significantly lower than in the T21 and T13/18 groups (p<0.001). The MA for cases with 45X was similar to that in the study by Iyer et al.,⁴⁹ namely 27.9 years. The prevalence of 45X does not increase with MA,^50,51 which justifies the lower average MA in this group.

In this study, 49% (45 of 92) had ultrasound findings suggesting major MF in the diagnosis procedure. In the literature, this proportion is similar, between 43%⁵² and 51%.⁵³ If considered separately by karyotype, in this sample, the T13/18 group showed a higher frequency of MA: 64% (16 of 25). In the medical literature, the frequency of structural abnormalities in fetuses with T13/18 is high, and is found in 80 to 100%.^{26,32,47,54-56} In this study, of the 9 fetuses with prenatal diagnosis of T13/18 that showed no MF at the time of the karyotype studies, 6 underwent karyotype studies using CVS in the first trimester, showing an increased NT as an indication.

The association between cardiac MF and chromosomal abnormality is well known, and the medical literature indicates that cardiac abnormalities are present in about 50% of fetuses with T21, 90% of fetuses with T18 and 40% of those with 45X.⁴¹ In this study, fifty-five pregnant women underwent specialized fetal echocardiography and 33 (60%) showed changes in heart morphology and/or function. The most common cardiac anomaly was VSD, which corresponded to 39% of abnormal diagnoses, similar to the study by Lopes et al.,⁵⁷ in 2003, in which they report that out of 275 fetuses with increased NT, 24 (8.7%) had abnormal karyotype and cardiac structural abnormalities, the most frequent being the VSD, present in 38% (9 of 24). In this study, fetuses with trisomy 13/18 had a significantly higher incidence of cardiac anomalies: 60 versus 25% (T21) and 29% (45X). If we considered only the fetuses with T13/18 who underwent echocardiography, structural abnormalities can be found in 83% (15 of 18), similar to the 90% described in the literature for these anomalies.^41,58

This study's intrauterine fatality rate was 60% (55 of 92) for fetuses with prenatal diagnosis of trisomies 21, 18, 13 and X monosomy from 2004 to 2012 at the HC-FMUSP. Schupp et al.,⁵⁹ in 2000, in a study conducted at the HC-FMUSP, reported a rate of FD of 4.48% in 11,733 births, occurring between 1993 and 1998. The fatality rate for fetuses with chromosomal abnormalities was, therefore, 14.7 times higher than in the general population within the HC-FMUSP. Saldanha et al.,² in 2009, describing the gestational outcome of 35 fetuses with chromosomal abnormalities and increased NT, also reported FD in 60% (12 in 20), considering the karyotypes of T13/18, T21 and 45X only. In a study by Hook et al.,³⁴ in 1983, spontaneous intrauterine mortality for fetuses with the same abnormalities included in this series is 48%, a possible explanation for this lower rate is that in that study the main indication for karyotype investigation was advanced MA, while in this study it was the presence of morphological changes.

For fetuses with T21, intrauterine mortality was 36% (13 of 36) which is consistent with the findings of Hook et al.⁴⁸ in 1995, in a study of 168 cases of fetuses diagnosed with T21 after AMNIO, where parents chose to continue the pregnancy, and whose intrauterine fatality rate was 35%. In studies comparing prevalence, the mortality rate for T21 ranges between 12 and 24% from AMNIO to birth and 30-54% from CVS to birth.^31,60-65 In this study, there was no difference in the mortality rate among T21 cases diagnosed after the CVS or after AMNIO, given that 36% (4 of 11) cases diagnosed after CVS and 36% (9 of 25) cases diagnosed after AMNIO evolved to FD.

In the group including T13 and T18 karyotypes, the intrauterine fatality rate was 64% (16 of 25). In the literature, observational studies report mortality rates from 32 to 100% for T18 and from 21 to 67% for T13.^{26,29,45-47,66-70}

For the Turner syndrome, there is a variable phenotypic expression, varying greatly in the prognosis, from a more subtle, form whose diagnosis is postnatal and causes short stature, infertility and higher frequency of aortic coarctation, up to more serious forms, with morphological abnormalities that allow prenatal diagnosis and evolve with high intrauterine mortality.^30,71-74 The main ultrasound findings described in the literature are cystic hygroma and fetal hydrops, which in this sample were present in 55% (17 of 31) and 77% (24 of 31) of fetuses with the 45X karyotype. In this series, intrauterine mortality was 84% (26 of 31), while in the medical literature this rate ranges from 20 to 82%.^{34,45,49,50,75,76}

In this study, it was used multivariate stepwise logistical analysis to evaluate which findings could predict the death of aneuploid fetuses. For fetuses with T21, the presence of hydrops was the variable that correlated significantly with the occurrence of stillbirths (LR= 4.29; 95CI= 1.9-8.0). The association between fetal hydrops and chromosomal abnormalities is well known,^77-80 as well as the high mortality of this condition which reaches 90%,⁷⁹ although there are no specific studies in the literature demonstrating fetal hydrops as a mortality predictor for fetuses with T21.

Savva et al.,⁶⁷ in 2006, evaluated 5,177 cases with prenatal diagnosis of T21, reporting that the risk of FD correlates with the increase in MA for fetuses diagnosed after CVS (p=0.04), with a mortality rate of 35% for these fetuses (CI: 14-50) at age 35 and 55% (CI: 17-30) at 45 years. This study did not find the same association for fetuses diagnosed after AMNIO. MA was not a predictor of death for fetuses with T21, as well as in the study by Hook et al.,³⁴ in 1983, where the authors compare the mean MA among live births and FD, and report no significant difference in the mean MA among cases where fetuses with prenatal diagnosis of chromosomal abnormalities survive those who die in the womb.

In 1995, Hook et al.⁴⁵ published a case series with 168 cases of fetuses with prenatal diagnosis of T21, with gestational age at diagnosis from 12 to 38 weeks, and reported that the mortality rate is related to gestational age at diagnosis, ranging from 50% in the group diagnosed between 15 and 17 weeks, up to 20% in the group diagnosed at over 27 weeks. In this study, the gestational age at diagnosis did not correlate with FD for fetuses with T21.

TABLE 3
Studies on intrauterine mortality of fetuses with chromosomal abnormalities

Author	Year	Method*	Period**	Intrauterine death, % (n)
				T13	T18	T21	X0
Hook34	1983	direct	AMNIO	50 (4)	67 (21)	33 (52)	82 (11)
Hook et al.45	1989	direct	AMNIO	33 (3)	68 (15)	27 (37)	50 (4)
Hook et al.48	1995	direct	AMNIO	-	-	35 (168)	-
Halliday et al.61	1995	indirect	CVS	-	-	31 (NR)	-
			AMNIO	-	-	18 (NR)	-
Macintosh et al.62	1995	indirect	CVS	-	-	54 (71)	-
Snijders et al.50	1995	indirect	CVS	83 (NR)	86 (NR)	47 (NR)	76 (NR)
			AMNIO	71 (NR)	74 (NR)	31 (NR)	52 (NR)
Gravholt et al.75	1996	direct	CVS	–	–	–	40 (5)
			AMNIO	–	–	–	25 (8)
Bray e Wright60	1998	indirect	CVS	–	–	39 (NR)	–
			AMNIO	–	–	12 (NR)	–
Snijders et al.63	1999	indirect	CVS	–	–	30 (NR)	–
			AMNIO	–	–	21 (NR)	–
Morris et al.64	1999	indirect	CVS	–	–	31 (NR)	–
			AMNIO	–	–	24 (NR)	–
Cuckle65	1999	indirect	CVS	–	–	45-46 (NR)	–
			AMNIO	–	–	22-24 (NR)	–
Surerus et al.76	2003	direct	CVS	–	–	-	75 (8)
Won et al.29	2005	direct	AMNIO	–	32 (106)	10 (392)	–
Alberman et al.70	2012	direct	AMNIO	21(NR)	36 (NR)	7 (NR)	–
Yamanaka et al.44	2006	direct	AMNIO	-	45 (58)	–	–
Morris e Savva66	2008	direct		47 (19)	70 (80)	–	–
Crider et al.32	2008	direct		50 (20)	63 (57)	–	–
Irving et al.26	2011	direct		29 (7)	100 (32)	–	–
Lakovschek et al.46	2011	direct		67 (3)	87 (15)	–	–
Burke et al.47	2013	direct		–	61 (23)	–	–
Iyer et al.49	2012	direct	AMNIO/BVC	–	–	–	40 (20)

• AMNIO: Amniocentesis, CVS: Chorionic villus sampling, N: Number of cases with the anomaly, NR: Not reported
• ^*
  Method used: Direct monitoring of pregnancies or indirect by comparing prevalence
• ^**
  Start period of monitoring (after CVS or amniocentesis up to term)

For fetuses with trisomy 18/13, applying the stepwise logistical regression analysis, predictors of FD were not identifyed. Morris et al.⁶⁶ published a case series in 2008, including 80 fetuses with prenatal diagnosis of T18 and, in the study, intrauterine mortality of male fetuses was higher at 79% (95CI: 65-90%) than deaths in females, at 67% (95CI: 52-81%). Other studies also suggest a higher mortality to male fetuses with T18^6,45,81 but find no correlation between death and fetal sex for T13.^6,66 In this study, only 20% (5 of 25) of fetuses in the T18/13 group were male and the T13 and T18 karyotypes were evaluated together. This is a possible explanation for not having identified the male sex as a predictor of death in this group.

For the 45X group, the presence of echocardiographic abnormalities was associated with a lower risk of FT (LR = 0.56; 95CI = 0.27-0.85). This is explained by the fact that of the 31 fetuses with the 45X karyotype included in this study, only 12 underwent the echocardiography requested, with 4 of the 5 that were born alive undertaking the exam, and only 8 of the 26 that died having an echocardiographic assessment. Therefore, 69% of fetuses that died in this group did not have their cardiac anatomy evaluated. In the medical literature, several studies have correlated the presence of fetal hydrops with poor prognosis in fetuses with 45X.^77,82,83 Using the stepwise analysis, we did not find a correlation between the presence of hydrops and increased risk of death, although it was present in 85% (22 of 26) of fetuses with 45X that died.

It is known that chromosomal abnormalities occur with increased frequency of structural defects and have high intrauterine mortality. In many countries termination of pregnancy is understood as the sole treatment for aneuploidy, especially for lethal forms. However, the legal aspects for terminating pregnancy vary widely from country to country, from permission without any specific reason to permission only to safeguard the mother's life.

In Brazil, the interruption of pregnancy can only be performed in cases of rape, to safeguard the mother's life or, more recently, when faced with the diagnosis of anencephaly. In cases of anomalies incompatible with life, as in trisomies 13 and 18 there are court decisions favoring termination, but only after a court order.

According to Gadow et al.,²⁴ in 2006, in a study conducted in Argentina - a country where termination of pregnancy after the diagnosis of chromosomal abnormality is not legally permitted - with 372 couples during counseling prior to the invasive procedure for fetal karyotyping, 68% of couples thought about terminating the pregnancy despite the practice being illegal and the mother being exposed to unsafe methods of abortion. In the same study, 87% of couples reported that the main reason for wishing to have access to a prenatal diagnosis is to receive accurate information about the health of the fetus, regardless of the possibility of termination.

In Brazil, many couples want to know the fetal karyotype to prepare for the birth. When there is a diagnosis of any chromosomal abnormality, they want to know about the prognosis of the pregnancy, the chance of the child being born alive, the presence of any fetal structural abnormalities whose treatment would be surgical, if the child will have any physical and/or mental disability and the severity of such, etc.

This study was conducted with the intention of improving the care provided to such couples. Hopefully, the findings here presented can contribute to future legal debates around the law that addresses the desire of parents for the right to decide on the fate of a pregnancy with a fetus with a chromosomal abnormality.

Conclusion

Spontaneous FD occurs in 36, 64 and 85% of pregnancies with prenatal diagnosis of trisomy 21, 18, 13 and X monosomy, respectively. The presence of hydrops increases the risk of fetal death in pregnancies with trisomy 21. The incidence of echocardiographic abnormalities reduces this risk in pregnancies with monosomy X.

• Study conducted at Department of Obstetrics and Gynecology, Faculdade de Medicina, Universidade de São Paulo, Hospital de Clínicas de São Paulo, São Paulo, SP, Brazil

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Publication Dates

• Publication in this collection
  Mar-Apr 2016

History

• Received
  23 June 2014
• Accepted
  25 June 2014