Human Reproduction, Vol. 14, No. 8, 2102-2105,
August 1999
© 1999 European Society of Human Reproduction and Embryology
The feasibility of nuchal translucency measurement in higher order multiple gestations achieved by assisted reproduction
Department of Obstetrics and Gynecology, Assaf Harofe Medical Center, Zerifin (affiliated with Sackler Faculty of Medicine, Tel Aviv), 70300 Israel
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Abstract |
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Nuchal translucency (NT) measurement for screening chromosomal abnormalities and detecting fetal anomalies is an effective ultrasonographic marker, originally developed for singleton pregnancies. This study sought to evaluate the feasibility of NT measurements in higher order multiple gestations. Pregnant patients who conceived following assisted reproduction and were carrying three or more fetuses were enrolled in the study. Each fetus was ultrasonographically assessed, a NT measurement was obtained, and the findings were used for counselling prior to any invasive procedure. In all, 24 pregnant patients, initially carrying 79 fetuses aged 10–14 weeks of gestation, were compared with 79 consecutively matched, singleton controls, naturally conceived, having similar crown–rump lengths (± 3 mm). NT measurements were feasible for both study and control fetuses, which exhibited similar NT measurements for 5th, 50th and 95th centiles. Also, mean NT thicknesses [measurements in mm or multiple of the medians (MOM)] were similar for both groups (1.41 ± 0.41 and 1.35 ± 0.39 mm respectively and 0.87 ± 0.23 and 0.83 ± 0.25 MOM respectively). Prenatally no chromosomal abnormalities were detected in either group, and, of those infants who had no karyotyping, no traits were observed that warranted chromosomal analysis. NT measurements are feasible in higher order multiple gestations. Since there is no other effective screening modality for these pregnancies, it seems reasonable to recommend NT measurement for antenatal screening services for higher order multiple gestations.
Key words: multiplicity of higher order gestations/nuchal translucency/ultrasound
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Introduction |
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It is well documented that ultrasound can identify and measure small fluid collections between the soft tissue covering the fetal spine and the overlying skin during the late first trimester (Szabo and Gallen, 1990
; Pandya et al., 1995a). The thickness of this hypoechoic ultrasonographic feature, defined as nuchal translucency (NT) has been reported in association with chromosomal abnormalities (Pandya et al., 1995a; Snijders et al., 1996), cardiac and other structural defects (Snijders et al., 1996; Reynders et al., 1997), as well as an increased risk of spontaneous abortion (Fukada et al., 1997; Reynders et al., 1997).
Since NT has evolved into a valuable marker for detecting the above-mentioned fetal abnormalities and complications, its importance is clear-cut with multiple pregnancies where biochemical screening is of limited value. Accordingly, it has been reported that in twin pregnancies, first trimester screening for chromosomal abnormalities is reliable and feasible (Pandya et al., 1995b). Furthermore, NT measurement may offer additional data about twin pathophysiology, such as underlying haemodynamic changes associated with early onset of twin–twin transfusion syndrome (Sebire et al., 1997).
The aim of the current study was to evaluate the feasibility of NT measurements in higher order multiple gestation, conceived by assisted reproduction, and to compare the measurements with those of a singleton gestation. We are unaware of any other similar report published in English.
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Materials and methods |
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The study was conducted in our ultrasound unit between January 1997 and May 1998. A total of 1100 patients was scanned and screened at 10–14 weeks of pregnancy by measuring the crown–rump length (CRL) and NT thickness according to a previously described protocol (Nicolaides et al., 1992
; Pandya et al., 1995a; Snijders et al., 1996). The size of each image was magnified until the fetus occupied at least 75% of the screen (Figure 1). The maximum NT thickness was achieved and recorded by measuring it in the midsagittal plane with calipers placed on the inner surface of the nuchal membrane. At least three measurements were obtained and the largest among them was used for counselling. Special care was taken to observe fetal movement, so that the fetal skin and amnion were adequately discriminated. Only fetuses with CRL between 38 and 84 mm were included. This corresponds with a gestational age of between 10 3/7 weeks and 17 weeks.
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The study group comprised 24 of these pregnant women, with three or more fetuses, who conceived following various forms of fertility treatment. They were scanned by one of the two sonographers (R.M., A.H.) with intra-observer repeatability coefficients of 0.34 and 0.28 mm respectively, and an interobserver repeatability coefficient of 0.36 mm (Herman et al., 1998a
). Individual sonographers and departmental measurements were subject to regular internal audit, to check standardization and distribution of measurement (Herman et al., 1998b). These values correspond to previous reports (Pandya et al., 1995c).
A curvilinear abdominal transducer (HDI 3000; Advanced Technology Laboratories, Seattle, WA, USA) was used without a time limitation to generate a satisfactory image and an accurate NT measurement of each fetus. Demographic data and ultrasound findings, including the number of fetuses, CRL, NT and any obvious fetal malformations, were recorded into a computer database (Snijders et al., 1996, 1998) at the time of scanning. The calculated risk of having a trisomy 21 newborn was based on maternal age and gestational age-related prevalence, multiplied by the likelihood ratio depending upon the deviation from normal in NT thickness for CRL (Snijders et al., 1996, 1998). Pregnancy outcome was obtained from the maternity units or from the patients themselves.
To examine a possible effect of multiplicity on NT thickness, the measurements of the study group were compared with those of spontaneous, singleton pregnancies. Thus, consecutive, singleton pregnancies were chosen as matched controls using similar CRL (±3 mm) as a criterion. The measurements were expressed as thickness in mm or as a multiple of medians (MOM). Since NT was log normally distributed the equation produced to calculate MOM of NT was based on the formula: Log10NT = –0.3599 + 0.0127 CRL – 0.000058 CRL2 as previously reported (Nicolaides et al., 1998). The analysis included comparison of 5th, 50th and 95th centiles between each case in the study group and its matched control. It also included comparisons of mean NT thickness between each pregnancy and the study and control groups, and the maximal difference of NT thickness within each pregnancy with the maximal difference between its matched control. Paired Student's t-test was used for comparing matched controls, comparing means between the groups, and P < 0.05 was considered as statistically significant. Values were expressed as mean ± SD.
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Results |
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This study included 24 patients with a high order of multiplicity with a total of 79 fetuses, who had conceived after using various ovulation induction drugs and/or in-vitro fertilization (IVF) technology. Thirteen women conceived following IVF with intracytoplasmic sperm injection, seven following IVF, and four following human menopausal gonadotrophin administration. The mean maternal age at conception was 29 ± 4 years. There was one patient who had septuplets, three who had quadruplets and 20 with triplets. Ten patients (six triplets, three quadruplets, and one septuplet) underwent fetal reduction to twins. In this group, three patients had aborted within four weeks following the reduction. The remaining 14 patients with triplets declined fetal reduction, and three of these aborted at mid-gestation. NT measurements were performed as part of the first trimester screening or before fetal reduction. Accordingly, one fetus, found to have increased NT of 3.7 mm, underwent feticide. Before the KCl injection, a minute amount of amniotic fluid was aspirated and a normal karyotype was found. In another case, an anencephalic fetus was diagnosed and was reduced as well. In only one case of a triplet pregnancy were monochorionic twins diagnosed using triangular placental tissue projections between the base of the intertwin membrane, known as the `epsilon sign' (Figure 1
; Sepulveda et al., 1996). The remaining third fetus was reduced. Of the study group of 24 patients, 18 completed uneventful pregnancies and deliveries, and there was one case of early neonatal death in this study group. Six patients aborted. In the current series, no abnormal karyotypes were detected prenatally and no traits were observed postnatally that warranted chromosomal analysis.
Table I shows that the study and control groups exhibited almost identical measurements for 5th and 95th centiles. Also, mean NT thickness expressed in mm or MOM were similar in both groups. While examining NT differences between wider and narrower thickness within each case of the study group and its corresponding control, it was found that the variation between siblings (study group) was smaller than that observed in non-siblings (control group) (0.43 ± 0.22 versus 0.72 ± 0.43 mm respectively). This difference was statistically significant (P < 0.01, paired Student's t-test).
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Discussion |
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Over the past decade, both maternal age and the use of various ovulation induction drugs and assisted reproductive technology have risen dramatically (Maymon et al., 1995
). This has led to an increasing number of multiple pregnancies at high risk of chromosomal defects, as well as other specific prenatal problems (Snijders et al., 1996). In such a highly selected population, it has been reported that whereas maternal serum screening in twin pregnancies exhibits similar false-positive rates as singletons, the detection rate is likely to be lower (Neveux et al., 1996). Additionally, while an affected co-twin may be indicated, identification of which one is difficult. To further complicate matters, there is evidence that maternal serum marker concentrations may be affected by various assisted reproduction techniques with on average higher concentrations of human chorionic gonadotrophin (HCG) and lower oestradiol concentrations, which additionally increases the false-positive rate for these pregnancies (Barkai et al., 1996; Frishman et al., 1997).
Another critical problem in a higher order multiple gestation is the fetal reduction which recently has been introduced into the prenatal treatment armamentarium. This procedure's aim is to decrease feto-maternal complications related to premature contractions and deliveries among multiple pregnancies (Maymon et al., 1995), as well as to offer an alternative other than terminating the entire pregnancy to those women carrying either a higher number of fetuses than desired or an affected co-twin (Maymon et al., 1995). Before feticide, a careful ultrasonographic assessment of the entire pregnancy is recommended to determine the actual number of living fetuses, their location, the placentation for monochorionic twins (Sepulveda et al., 1996), presence of any visible fetal anomalies, or any fetal discordancy (Dickey et al., 1992; Maymon et al., 1995), as well as slower fetal heart rate (Achiron et al., 1991). Those parameters may indicate an anomaly or poor prognosis for the survival of that fetus (Achiron et al., 1991; Dickey et al., 1992; Maymon et al., 1995). In this context, a new challenge has been raised by the same authors (Berkowitz et al., 1993), who reported that among 200 patients who underwent fetal reduction, six of the remaining fetuses had either anatomic (n = 4 cases) or chromosomal (n = 2 cases) abnormalities. Based on this, it seems important to offer pre-procedure, non-invasive genetic testing and a careful scanning, especially for those patients with a significantly increased risk of karyotypic abnormalities by virtue of their age (Berkowitz et al., 1993). To overcome these problems, first trimester ultrasound screening with NT measurements seems to be a promising option.
It has been reported that in twin pregnancies, screening for trisomy 21 by measurement of fetal NT thickness and maternal age had a similar sensitivity to that found in singletons (Pandya et al., 1995b; Snijders et al., 1996). However, ~9% of twins were screened as positive compared with 8% of singletons (Snijders et al., 1998). Some authors believe that increased NT thickness is due to underlying haemodynamic changes associated with heart failure, and may be an early manifestation of twin–twin transfusion syndrome among those monochorionic twins with increased NT thickness (Sebire et al., 1997). Since in the current study there was only one case of monochorionic twins, the information provided by Sebire et al. (1997) cannot be validated.
Our study has carried this issue one step further. Contrary to others who have recently reported obtaining an NT thickness in only ~83% of the singletons (Haddow et al., 1998), we succeeded in measuring it in all of our cases. It is premature to draw any conclusions concerning the sensitivity and false-positive rate of the method, since our series is too small. Nevertheless, we have demonstrated that among these fetuses belonging to higher order multiple gestations, similar NT thickness measurements are exhibited compared with their matched, singleton controls. Moreover, the distribution of 5th, 50th and 95th centiles among the study group was comparable with that of the control group. This validates the practical use of the model of trisomy 21 risk assessment originally obtained in singleton pregnancies (Nicolaides et al., 1992; Pandya et al., 1995a; Snijders et al., 1996, 1998) among individuals of a higher order multiplicity.
We found that the difference between the NT thicknesses of siblings was significantly smaller than that observed in non-siblings. This unexpected finding deserves further explanation. It may be an incidental finding derived from our relatively small series, or it may indicate that NT thickness among normal fetuses is an inborn feature derived from genetic or other environmental factors. Thus, siblings possessing similar genetic inheritance or sharing the same uterus and blood supply exhibit closer NT thicknesses than do random, singleton fetuses.
Women who conceive after assisted reproduction methods are naturally wary of any invasive prenatal diagnostic procedure. Since they receive careful antenatal care early in their pregnancies, and maternal serum markers are less efficient for chromosomal screening in multiple pregnancies, it would seem reasonable to offer them ultrasound screening by NT measurement, which is presently the only available, efficient screening method.
In summary, the above methodology provides additional data for the identification of an abnormal fetus, thus lowering the probability of leaving an abnormal fetus after reducing a normal one (Berkowitz et al., 1993). Our highly selected study population provides evidence that NT thickness measurements are feasible for risk determination. We recommend that a programme of NT measurements should be favourably considered as part of routine antenatal care during the late first trimester in this group of patients.
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Acknowledgments |
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We thank Ms Sally Esakov, BA, for editorial assistance.
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Notes |
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1 To whom correspondence should be addressed
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Submitted on October 19, 1998; accepted on April 16, 1999.
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