FETM

BTS

SgsNm((wsms

tcwghp

D

A

2

irst and Second Trimestervaluation of Risk for Fetal Aneuploidy:he Secondary Outcomes of the FASTER Trialary D’Alton, MD, and Jane Cleary-Goldman, MD

The FASTER Trial was a multicenter National Institute of Child Health and Human Devel-opment sponsored study of Down syndrome screening in a large unselected obstetricpopulation using first and second trimester maternal serum markers and first trimesternuchal translucency sonography. The following paper will describe the FASTER Trial. It willreview the outcomes of pregnancies complicated by cystic hygroma and the FASTER Trial’sfindings regarding first trimester nasal bone ultrasonography and screening for aneuploidy.Although the study’s first and foremost goal was to compare various first and secondtrimester methods of screening for Down syndrome, the FASTER Trial has revealed awealth of information not only on screening for aneuploidy but also on other obstetricissues.Semin Perinatol 29:240-246 © 2005 Elsevier Inc. All rights reserved.

padmsc

mNBw(t

SPTfIscyu(ip

ackground on the FASTER Trial:he NICHD Multicenter Downyndrome Screening Studyince its inception in the early 1990s, first trimesterscreening for Down syndrome has evolved from a sono-

raphic measurement of the fetal nuchal translucency (NT)pace to a risk assessment program based on a combination ofT and first trimester maternal serum markers. These serumarkers include pregnancy associated plasma protein-A

PAPP-A) and free-beta human chorionic gonadotropinBhCG).1,2 Risk assessment using NT ultrasound togetherith first trimester serum markers is known as Combined

creening. A recent meta-analysis demonstrated that first tri-ester Combined screening detects 82% of cases of Down

yndrome at a 5% false-positive rate.3

In the United States, the second trimester Quad screen ishe most popular screening test for Down syndrome. It isomprised of second trimester maternal serum markershich include alphafetoprotein (AFP), total hCG, unconju-ated estriol (uE3), and inhibin-A.4 This screening techniqueas an estimated detection rate of 67% to 81% for a false-ositive rate of 5%.5,6

ivision of Maternal Fetal Medicine, Columbia University Medical Center,New York, NY.

ddress reprint requests to Jane Cleary-Goldman, MD, Columbia Presbyte-rian Medical Center, 622 W. 168th Street, PH-16-66, New York, NY

a10032. E-mail: jec32@columbia.edu

40 0146-0005/05/$-see front matter © 2005 Elsevier Inc. All rights reserved.doi:10.1053/j.semperi.2005.06.006

Until recently, there was a paucity of information guidinghysicians and patients on how to choose between the firstnd second trimester approaches for screening for Down syn-rome. In addition, more complex options for risk assess-ent combining first and second trimester techniques for

creening as well as second trimester ultrasound have be-ome available.

The FASTER study was designed to (1) define the perfor-ance of first trimester screening for Down syndrome usingT sonography and the serum markers PAPP-A and freehCG, (2) compare the performance of this form of screeningith current standard of care second trimester screening, and

3) describe optimal combinations of first and second trimes-er tests for Down syndrome screening.

tudy Population andatient Risk Assessmenthe FASTER Trial was a prospective observational study per-

ormed at 15 clinical centers throughout the United States.nstitutional Review Board approval was obtained from allites, and all participating patients gave informed and writtenonsent. Patients were included in the trial if they were 16ears of age or older, and if they had a singleton live intra-terine pregnancy with a crown rump length of 36 to 79 mm10 weeks 3 days to 13 weeks 6 days). Patients were excludedf they had obtained a prior NT measurement in the currentregnancy, or if anencephaly or cystic hygroma was detected

t the time of NT ultrasound. Patients identified with a sep-

tsp

mrfsrwshsaap

swiDwsopswwcnowsp

DTeppta1srt

m

tdtstp

ld

FHAdnpini

oanpccsshgtc

urbNcdmpta

lnbnp

nnghtfsFmsso

FASTER Trial update 241

ated cystic hygroma in the first trimester were followed in aeparate study for karyotype and for complete obstetric andediatric outcome.The FASTER protocol included the first trimester measure-ent of NT, PAPP-A, and free BhCG. A total of 102 sonog-

aphers received uniform training in NT sonography andollowed a standard ultrasound protocol. All sonographersubmitted a minimum of 50 adequate images to a centraleviewer to demonstrate NT ultrasound proficiency. Patientsere asked to return at 15 to 18 weeks gestation for Quad

creening, which consisted of AFP, total hCG, uE3, and in-ibin-A. All biochemical analyses were performed by usingtandard assay techniques at a central laboratory (Womennd Infants Hospital, Rhode Island). The commercially avail-ble alpha software system was used to calculate individualatient risk assessment.Once they had completed screening, patients were given

eparate first and second trimester risk assessment resultsith 4 outcomes being possible. A first trimester screen-pos-

tive result was defined as a greater than 1 in 150 term risk forown syndrome. A second trimester screen-positive resultas defined as a greater than 1 in 300 term risk for Down

yndrome. Both screening tests were negative for the majorityf patients. For a minority of patients, both screens wereositive. For the remainder, the first and second trimestercreening results were discrepant. Formal genetic counselingith the option of amniocentesis was provided for patientsith positive screening results. All patients were followed for

omplete pregnancy and pediatric outcome. This study didot include first trimester intervention. Patients were notffered chorionic villus sampling in the first trimester if theyere screen-positive because both first and second trimester

creening results were not revealed until the entire screeningrotocol had been completed.

ata Collection and Statistical Analysiso maximize ascertainment, trained research coordinators atach clinical site recorded patient information using a pur-ose-designed computerized tracking system. All cases ofositive first or second trimester screening underwent fur-her detailed pediatric review. Likewise, any case with anbnormal pregnancy or pediatric outcome and an additional0% random sample of normal cases underwent more exten-ive review. A single pediatric geneticist performed all of thiseview. Karyotype information was obtained from amniocen-esis, analysis of miscarriage samples, or neonatal cord blood.

DMSTAT, based in Boston, was the independent dataanagement group for the study.Statistical analyses were performed at the Wolfson Insti-

ute of Preventative Medicine in London. These included aiscordant pairs analysis to compare first and second trimes-er screening, directly observed screening performance re-ults, and modeled screening performance results. In addi-ion, an independent data review group confirmed therincipal results of this study.

The principal results of the FASTER Trial are pending pub- o

ication in a peer review journal. As a result, they will not beiscussed in this review article.

irst Trimester Septated Cysticygroma: The FASTER Trial

fetal cystic hygroma is a congenital malformation in whichistended fluid-filled spaces develop in the region of the fetaleck. Cystic hygroma can be diagnosed early or late in theregnancy. Those diagnosed later in pregnancy tend to be

solated lymphangiomas, and those diagnosed early in preg-ancy may be associated with adverse obstetric outcomes,

ncluding chromosomal or anatomical abnormalities.Retrospective case series describing the prenatal diagnosis

f this condition suggest that, when a cystic hygroma is di-gnosed early in pregnancy, it is associated with a poor prog-osis. Septations appear to be associated with an even worserognosis. Counseling patients with a pregnancy compli-ated by cystic hygroma early in pregnancy is difficult be-ause most data on these pregnancies have been derived fromeries of selectively referred cases which are likely not repre-entative of the general population. In addition, past studiesave used unclear and inconsistent definitions of cystic hy-roma. Pregnancy follow-up is generally quite limited, andhere is little information on the longer term pediatric out-ome of these pregnancies.7-13

As more and more patients are undergoing first trimesterltrasound due to the increasing popularity of first trimesterisk assessment, the prenatal diagnosis of cystic hygroma isecoming more frequent. Differentiating between increasedT and septated or nonseptated cystic hygroma can be diffi-

ult. Likewise, it is uncertain whether there is any prognosticifference between these findings. Detailed outcome infor-ation regarding cystic hygroma is needed to enable accurateatient counseling. The FASTER study provided the oppor-unity to evaluate the clinical significance of the diagnosis ofseptated cystic hygroma in the first trimester.14

The objectives of this study were to (1) assess the preva-ence of septated cystic hygroma in the first trimester of preg-ancy in the general population, (2) define the associationetween this finding and fetal malformations, (3) evaluate theatural history of septated cystic hygroma, and (4) describeediatric outcomes of survivors.There were 134 cases of septated cystic hygroma diag-

osed at the time of NT in the FASTER Trial (1 in 285 preg-ancies). A standardized definition of septated cystic hy-roma was used. To be diagnosed with a septated cysticygroma, there needed to be an enlarged hypoechoic space athe back of the fetal neck extending along the length of theetal back. Septations needed to be clearly visible (Fig. 1). Theame standardized protocol for NT assessment used in theASTER Trial was utilized to obtain sonographic measure-ents of the septated cystic hygroma. Whenever this diagno-

is was made, the patient was immediately informed, coun-eled regarding its association with fetal aneuploidy, andffered fetal karyotyping by chorionic villus sampling. For

ngoing pregnancies, sonographic evaluation of fetal anat-

oewewsaci

sAewDTTtseT(n1Osaepimtwct3maw

No

haThpAcdmppptato

FBiRnthmsfwstt

F

Fn

242 M. D’Alton and J. Cleary-Goldman

my was performed at 18 to 22 weeks gestation, and fetalchocardiography was obtained. All ongoing pregnanciesere followed for pregnancy and pediatric outcomes. To

valuate later pediatric outcome, parents of surviving infantsere contacted at least 1 year after they had completed the

tudy. In addition, to objectively confirm pediatric outcomend development, the follow-up protocol included directommunication by central study personnel with the surviv-ng child’s pediatrician.

Patients whose fetuses had a septated cystic hygroma wereignificantly older and were significantly more likely to be ofsian ethnic background when compared with the patientsnrolled in the FASTER Trial. A chromosomal abnormalityas diagnosed in 67 cases (51%). There were 25 cases ofown syndrome, 19 cases of Turner syndrome, 13 cases ofrisomy 18, 6 cases of Trisomy 13, and 3 cases of triploidy.here was one case of mosaic deletion of chromosome 9. In

he cystic hygroma cases, the mean NT measurements wereignificantly larger in aneuploid cases compared with nonan-uploid cases (P � 0.01), and they were significantly larger inurner syndrome cases compared with other aneuploid casesP � 0.001). In the remaining 65 cases, 22 (34%) were diag-osed with major structural fetal malformations. There were6 cardiac malformations and 6 skeletal malformations.verall, 67.4% (89/132) of all pregnancies diagnosed with

eptated cystic hygroma were complicated by a chromosomalbnormality or by a major fetal structural abnormality. Sev-nty-nine patients (60%) chose an elective termination ofregnancy. Twenty cases were complicated by spontaneous

ntrauterine fetal demise. Fifteen of these fetuses had a chro-osomal abnormality or a structural abnormality on antena-

al ultrasound. In the 23 cases of septated cystic hygromaithout malformation that were followed expectantly, the

ystic hygroma resolved in 18 cases (78%) at a mean gesta-ional age of 18.2 weeks (standard deviation 3.7 range 15 to0 weeks.) Ninety-five percent (22/23) of the cases with nor-al karyotype and normal antenatal ultrasound were normal

t longer term pediatric follow-up. Meanwhile, 1/23 (5%)

igure 1 Septated cystic hygroma in a 13-week fetus.

as diagnosed with cerebral palsy and developmental delay. o

ormal longer term pediatric outcome was observed in 17%f cases (22 of 132).In the FASTER Trial, the prevalence of a septated cystic

ygroma in the first trimester was 1/285, which is consider-bly more common than previously thought. The FASTERrial has determined that the finding of a septated cysticygroma on first trimester ultrasound is an extremely strongredictor of fetal aneuploidy and anatomical abnormalities.lthough the diagnosis of a septated cystic hygroma is con-erning, it is important to note that only 1/23 of fetusesiagnosed with this problem who were thought to be chro-osomally and structurally normal during the antepartumeriod was diagnosed with an abnormality at longer termediatric follow up. Thus, the FASTER Trial suggests thatatients who have a pregnancy complicated by an early sep-ated cystic hygroma who have a normal karyotype, a normalnatomical survey, and a normal fetal echo can be reassuredhat their fetus is likely to have a normal longer term pediatricutcome.

irst Trimester Nasalone Evaluation for Aneuploidy

n the General Populationecent studies have suggested that the evaluation of fetalasal bones in the first and second trimesters may help iden-ify fetuses at increased risk for fetal aneuploidy. Absent orypoplastic nasal bones have been thought to be a powerfularker for fetal aneuploidy.15-17 However, the majority of

tudies on nasal bone in the first trimester have been per-ormed at specialized centers where the majority of patientsere high risk and were already undergoing chorionic villus

ampling.16,18-20 Data are needed to determine whether firstrimester nasal bone sonography is a good screening tool forhe general population (Fig. 2). With this in mind, evaluation

igure 2 First-trimester fetal profile demonstrating presence of theasal bone. (Color version of figure is available online)

f the nasal bone in the first trimester was added to the

Fswtaenapr

(tbcowsDwc1c

bDladfiwwwwt

vas

fnabmhafslm

ctqinFjgthccits

tceofitp

OAvDiolaidPwlgwa

Fmm

FASTER Trial update 243

ASTER protocol, but only in the last 7 months of thetudy.21 Only 9208 patients enrolled in the FASTER Trialere eligible for this form of sonography. Unfortunately, a

otal of 2884 patients were not enrolled in this study becausenonnasal bone certified sonographer performed the NT

xamination. The total number of patients who underwentasal bone sonography was 6324, and complete pregnancynd pediatric outcome was obtained on 98.5% of cases (6228atients), indicating that outcome ascertainment was accu-ate.

An adequate image of the fetal profile was obtained in 76%4801) of cases (Fig. 3). Trained sonographers failed to ob-ain an adequate view in 24% (1523) of patients. The nasalones were described as being present in 99.5% (4779) ofases. They were described as being absent in only 0.5% (22)f cases. In the group of 4779 patients where the nasal bonesere thought to be present, there were 9 cases of Down

yndrome and 1 case of trisomy 18. There were no cases ofown syndrome and 1 case of trisomy 18 in the 22 patientshere nasal bones were thought to be absent. There were 2

ases of Down syndrome and no cases of trisomy 18 in the523 patients in which nasal bone sonography was techni-ally unsatisfactory.

The observed performance characteristics of absent nasalones as a screening tool for aneuploidy are as follows: 0%own syndrome detection rate, although it did have a very

ow false-positive rate of only 0.4%. When evaluating forneuploidy overall, absence of the nasal bones had a 7.7%etection rate for a low 0.3% false-positive rate. Success ofrst trimester sonographic evaluation of the fetal nasal bonesas highly dependent on the gestational age. Imaging failureas significantly more likely at 10 and 13 weeks, comparedith 11 and 12 weeks gestation. The mean body mass indexas also greater in patients with failed nasal bone sonography

igure 3 Pregnancy outcome among 6324 cases in which first-tri-ester nasal bone sonography was attempted. (Reprinted with per-ission.21)

han in those with successful nasal bone sonography. Trans- t

aginal ultrasound and failure to obtain the NT was alsossociated with failure to adequately perform nasal boneonography.

To evaluate the possibility that this screening test per-ormed poorly because the sonographers were unskilled atasal bone sonography, 13 cases of aneuploidy were furthernalyzed. The number of first trimester NT scans that hadeen performed by each of the 13 sonographers before aissed case was determined. On average, these sonographersad done approximately 750 NT scans before missing anneuploid case with nasal bone evaluation. Most had per-ormed even more, with some completing up to 2000 to 3000cans. Therefore, it was felt that sonographer inexperience orack of skill was not a valid explanation for the poor perfor-

ance of this screening method in the FASTER Trial.In addition, it is interesting to note that nasal bone imaging

ould not be obtained in 24% of cases, despite the fact thathe sonographers were highly trained and experienced. Auality-control program had been in place to monitor ongo-

ng performance of nasal bone ultrasound. There is no expla-ation for the high failure rate of nasal bone ultrasound in theASTER Trial. Proposed reasons include that criteria for

udging adequate nasal bone images may have been too strin-ent and that perhaps the sonographers were less precise inheir technique than they would have been if the populationad been high risk for aneuploidy. The sonographers alsoould have been less compulsive with their technique be-ause nasal bone was not being used clinically. In addition, its possible that if the sonographers had been given more timeo perform this ultrasound that they would have been moreuccessful.

In conclusion, the FASTER Trial suggests that absence ofhe fetal nasal bones during first trimester sonography is un-ommon. In the hands of highly trained and highly experi-nced sonographers, adequate nasal bone imaging cannot bebtained in many cases. According to the FASTER Trial’sndings, first trimester nasal bone sonography does not seemo have a role in general population screening for fetal aneu-loidy.

ther Publications to Datelthough the FASTER Trial’s ultimate goal was to comparearious first and second trimester methods of screening forown syndrome, the FASTER Trial has revealed a wealth of

nformation not only on screening for aneuploidy but also onther obstetric issues. Several studies have already been pub-ished and many more will be forthcoming. For example,nalysis of pregnancy outcomes from the FASTER Trial hasndicated that first trimester vaginal bleeding is an indepen-ent risk factor for adverse obstetric outcomes (Table 1).22

atients with light or heavy vaginal bleeding within the 4eeks before enrollment in the FASTER Trial were more

ikely to experience a spontaneous loss before 24 weeks ofestation and cesarean delivery. Patients with light bleedingere at risk for preeclampsia, preterm delivery, and placental

bruption. Intrauterine growth restriction, preterm prema-

ure rupture of membranes, and placental abruption were all

am

ibtagipbf

pA�e(sb

wBrsptc

iotyimiabois

T

IGPPP

PPC

*†

‡

T

GGPBBPOP

IPP

*†

‡

244 M. D’Alton and J. Cleary-Goldman

ssociated with heavy vaginal bleeding during the first tri-ester.The FASTER Trial has also given additional insight on the

mpact of obesity on obstetric outcomes.23 Obesity and mor-id obesity had a statistically significant association with ges-ational hypertension, preeclampsia, gestational diabetes,nd macrosomia (fetal birth weight greater than 4000 g andreater than 4500 g) (Table 2). Obesity also seems to be anndependent risk factor for cesarean delivery. In nulliparousatients, the cesarean delivery rate was 20.7% for the nono-ese control group, 33.8% for the obese group, and 47.4%or morbidly obese patients.

Abnormal first trimester maternal serum markers ap-ear to be indicators of adverse pregnancy outcomes.24

ccording to the FASTER Trial, patients with PAPPA of5th percentile were significantly more likely to experi-

nce spontaneous fetal loss at �24 weeks of gestationTable 3). They were also at risk for gestational hyperten-ion, preeclampsia, preterm premature rupture of mem-ranes, placental abruption, preterm birth, and low birth

able 1 Obstetric Complications by Amount of Vaginal Bleed

Outcome

Light Bleeding* v

Adjusted Odds Rati(95% Confidence Inter

ntrauterine growth restriction 1.4 (0.9-2.1)estational hypertension 1.0 (0.9-1.3)reeclampsia 1.4 (1.1-1.8)reterm delivery 1.3 (1.1-1.7)reterm premature rupture ofmembranes 1.3 (0.9-1.9)

lacenta abruption 1.6 (1.1-2.6)lacenta previa 0.9 (0.5-1.8)esarean delivery 1.1 (1.01-1.3)

Light bleeding: defined as spotting only.Control: no bleeding.Heavy bleeding: defined as similar to menses.

able 2 Obstetric Complications by Maternal Body Mass Ind

Outcome

Obese* vs Co

Adjusted Odds Rati(95% Confidence Inter

estational diabetes 2.6 (2.1-3.4)estational hypertension 2.5 (2.1-3.0)reeclampsia 1.6 (1.1-2.25)irth weight >4,500 grams 2.0 (1.4-3.0)irth weight >4,000 grams 1.7 (1.4-2.0)reterm delivery 1.1 (0.9-1.5)perative vaginal delivery 1.0 (0.8-1.3)reterm premature rupture ofmembranes 1.3 (0.9-2.0)

ntrauterine growth restriction 0.9 (0.5-1.6)lacenta previa 1.3 (0.7-2.5)lacental abruption 1.0 (0.6-1.9)

Obese � body mass index 30-34.9.Control � body mass index <30.

Morbidly obese � body mass index >35.

eight. Meanwhile, NT at �99th percentile and freehCG at �1st percentile were associated with an increasedisk of spontaneous loss at �24 weeks of gestation. Thistudy suggests that it seems reasonable to follow carefullyregnancies with abnormal first trimester serum markerso potentially avert a portion of adverse perinatal out-omes.

In addition, the FASTER Trial has provided updatednformation on the effect of advancing maternal age onbstetric outcomes in an unselected obstetric popula-ion.25 Compared with younger women, patients aged 35ears or older at their estimated date of delivery are atncreased risk for miscarriage and for chromosomal abnor-

alities. Women who are 40 years and older are also atncreased risk for gestational diabetes, placenta previa,bruption, cesarean delivery, and perinatal mortality (Ta-le 4). The FASTER Trial suggests that, although overallutcomes for women of advancing maternal age are good,ncreasing maternal age is independently associated withpecific adverse pregnancy outcomes.

trol† Heavy Bleeding‡ vs Control

P ValueAdjusted Odds Ratio

(95% Confidence Interval) P Value

.09 2.6 (1.2-5.6) .02

.67 1.5 (0.9-2.4) .09

.009 1.1 (0.5-2.4) .8

.01 3.0 (1.9-4.5) <.01

.06 3.2 (1.8-5.7) .01

.03 3.6 (1.6-7.9) <.01

.89 2.5 (0.9-6.9) .08

.03 1.4 (1.04-1.8) .02

† Morbidly Obese‡ vs Control

P ValueAdjusted Odds Ratio

(95% Confidence Interval) P Value

<.0001 4.0 (3.1-5.2) <.01<.0001 3.2 (2.6-4.0) <.01

.007 3.3 (2.4-4.5) <.01

.0006 2.4 (1.5-3.8) <.01<.0001 1.9 (1.5-2.3) <.01

.4 1.5 (1.1-2.1) .01

.9 1.7 (1.2-2.2) <.01

.14 1.3 (0.8-2.2) .2

.82 0.8 (0.4-1.8) .6

.4 0.7 (0.3-2.0) .6

.9 1.0 (0.5-2.2) .9

ing22

s Con

oval)

ex23

ntrol

oval)

STdufiriakdmc

fdbnhfiuTmbsrp

T

SINPPGPBBP

PPGM

T

TMCCGPGPPPPPLMOCP

*

†

‡

FASTER Trial update 245

ummaryhe FASTER Trial was a multicenter study of Down syn-rome screening in a large unselected obstetric populationsing first and second trimester maternal serum markers andrst trimester nuchal translucency sonography. The principalesults are pending publication. Several supplementary stud-es have been published already which have provided valu-ble information on important obstetrical issues. It is nownown that septated cystic hygroma is a frequent findinguring first trimester ultrasound and that it is a powerfularker for fetal aneuploidy. Approximately two-thirds of all

ases will be diagnosed with fetal aneuploidy or with a major

able 3 PAPP-A <5th Percentile and Adverse Obstetric Outc

Outcome Adjusted Od

pontaneous loss at <24 weeks 2.50ntrauterine fetal demise >24 weeks 2.15eonatal death 1.98reterm birth <32 weeks 1.73reterm birth <32 weeks 1.87estational hypertension 1.47reeclampsia 1.54irth weight <10% 2.47irth weight <5% 2.81reterm premature rupture ofmembranes 1.54

lacenta previa 0.78lacental abruption 1.80estational diabetes 1.02acrosomia 0.46

able 4 Obstetric Complications by Maternal Age25 (Adjusted

Outcome

35 to 40 Years CReferent G

Adjusted OR(95% CI)

hreatened abortion 1.0 (0.9, 1.1)iscarriage 2.0 (1.5, 2.6)hromosomal abnormality 4.0 (2.5, 6.3)ongenital anomaly 1.4 (1.1, 1.8)estational hypertension 0.8 (0.7, 1.0)reeclampsia 0.9 (0.7, 1.2)estational diabetes 1.8 (1.5, 2.1)lacenta previa 1.8 (1.3, 2.6)lacental abruption 1.3 (0.9, 1.8)reterm labor 0.9 (0.8, 1.0)PROM‡ 1.2 (0.9, 1.5)reterm delivery 1.0 (0.9, 1.1)ow birth weight 1.1 (0.9, 1.3)acrosomia >4500 g 1.4 (1.1, 1.8)perative delivery 1.1 (0.9, 1.2)esarean delivery 1.6 (1.5, 1.7)erinatal loss 1.1 (0.6, 1.9)

Adjusted models controlled for the effects of site, race, parity, bocondition, previous adverse pregnancy outcome, and use of ass

Referent group includes all patients aged less than 35 years at exp

PPROM � preterm premature rupture of membranes.

etal structural abnormality. It is also associated with fetalemise. Nonetheless, patients with pregnancies complicatedy septated cystic hygroma who have a normal karyotype, aormal anatomic survey, and a normal fetal echo will likelyave a healthy offspring. In addition, in the FASTER Trial,rst trimester nasal bone evaluation was not useful for pop-lation screening for Down syndrome. Although the FASTERrial’s priority was comparing various first and second tri-ester methods of screening for Down syndrome, the data-

ase which was created for the study and the serum bank oftored first and second trimester maternal blood samples rep-esent a wealth of information about pregnancy in a contem-orary unselected obstetric population. The studies regard-

24

tio 95% Confidence Interval P Value

1.76, 3.56 <.0011.11, 4.15 .020.6, 6.57 .26

1.47, 2.04 <.0011.21, 2.90 <.0011.20, 1.82 <.0011.16, 2.03 <.0012.16, 2.81 <.0012.35, 3.35 >.001

1.11, 2.12 .010.38, 1.58 .481.15, 2.84 .010.77, 1.35 .880.24, 0.86 .02

els)*

ared to†

>40 Years Compared toReferent Group†

P ValueAdjusted OR

(95% CI) P Value

0.65 1.1 (0.9, 1.3) 0.31<.001 2.4 (1.6, 3.6) <.001<.001 9.9 (5.8, 17.0) <.001

.003 1.7 (1.2, 2.4) 0.0020.02 1.0 (0.8, 1.4) 0.940.60 1.1 (0.7, 1.6) 0.81

<.001 2.4 (1.9, 3.1) <.0010.001 2.8 (1.6, 4.6) <.0010.21 2.3 (1.3, 3.8) 0.0020.15 0.9 (0.7, 1.2) 0.390.20 1.2 (0.8, 1.9) 0.410.61 1.4 (1.1, 1.7) 0.0010.17 1.6 (1.3, 2.1) <.0010.004 0.8 (0.4, 1.4) 0.380.57 0.9 (0.7, 1.2) 0.54

<.001 2.0 (1.8, 2.3) <.0010.74 2.2 (1.1, 4.5) 0.03

ss index, education, marital status, smoking, pre-existing medicalonception.date of delivery.

omes

ds Ra

Mod

omproup

dy maisted cected

ipfit

R

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

246 M. D’Alton and J. Cleary-Goldman

ng threatened abortion, obesity, first trimester markers andregnancy outcomes, and advancing maternal age are therst of many analyses with important obstetric observationso derive from the FASTER Trial.

eferences1. Nicolaides KH, Azar G, Byrne D, et al: Fetal nuchal translucency: ultra-

sound screening for chromosomal defects in the first trimester of preg-nancy. Br Med J 304:867-869, 1992

2. Wald NJ, Hackshaw AK: Combining ultrasound and biochemistry infirst-trimester screening for Down’s syndrome. Prenat Diagn 17:821-829, 1997

3. Malone FD, D’Alton ME: First-trimester sonographic screening forDown syndrome. Obstet Gynecol 102:1066-1079, 2003

4. Egan JF, Kaminsky LM, Deroche ME, et al: Antenatal Down syndromescreening in the United States in 2001: a survey of maternal–fetal med-icine specialists. Am J Obstet Gynecol 187:1230-1234, 2002

5. Wald NJ, Rodeck C, Hackshaw AK, et al: First and second trimesterantenatal screening for Down’s syndrome: the results of the Serum,Urine and Ultrasound Screening Study (SURUSS). Health Technol As-sess 7:1-77, 2003

6. ACOG Practice Bulletin. Prenatal diagnosis and fetal chromosomal ab-normalities. Number 27, May 2001

7. Benacerraf BR, Frigoletto FD: Prenatal sonographic diagnosis of iso-lated congenital cystic hygroma, unassociated with lymphadema orother morphologic abnormality. J Ultrasound Med 6:63-66, 1987

8. Langer JC, Fitzgerald PG, Desa D, et al: Cervical cystic hygroma in thefetus: clinical spectrum and outcome. J Pediatr Surg 25:58-61, 1990

9. Thomas RL: Prenatal diagnosis of giant cystic hygroma: prognosis,counseling, and management; case presentation and review of the re-cent literature. Prenat Diagn 12:919-923, 1992

0. Gallagher PG, Mahoney MJ, Gosche JR: Cystic hygroma in the fetus andnewborn. Semin Perinatol 23:341-356, 1999

1. Bronshtein M, Rottem S, Yoffe N, et al: First-trimester and early second-trimester diagnosis of nuchal cystic hygroma by transvaginal sonogra-phy; diverse prognosis of the septated from the nonseptated lesion.Am J Obstet Gynecol 161:78-82, 1989

2. Bernstein HS, Filly RA, Goldberg JD, et al: Prognosis of fetuses with a

cystic hygroma. Prenat Diagn 11:349-355, 1991

3. Tanriverdi HA, Hendrik HJ, Ertan AK, et al: Hygroma colli cysticum:prenatal diagnosis and prognosis. Am J Perinatol 18:415-420, 2001

4. Malone FD, Ball RH, Nyberg DA, et al: First trimester septated cystichygroma: a population based screening study (The FASTER Trial).Obstetrics and Gynecology 2005 (Accepted for publication)

5. Cicero S, Curcio P, Papageorghiou A, et al: Absence of nasal bone infetuses with trisomy 21 at 11-14 weeks gestation: an observationalstudy. Lancet 358:1665-1667, 2001

6. Cicero S, Rembouskos G, Vandecruys H, et al: Likelihood ratio fortrisomy 21 in fetuses with absent nasal bone at the 11-14 week scan.Ultrasound Obstet Gynecol 23:218-223, 2004

7. Bromley B, Lieberman E, Shipp TD, et al: Fetal nose bone length: amarker for Down syndrome in the second trimester. J Ultrasound Med21:1387-1394, 2002 [Erratum in J Ultrasound Med 22:162, 2003]

8. Otano L, Aiello H, Igarzabal L, et al: Association between first trimesterabsence of the nasal bone on ultrasound and Down syndrome. PrenatDiagn 22:930-932, 2002

9. Orlandi F, Bilardo CM, Campogrande M, et al: Measurement of nasalbone length at 11-14 weeks of pregnancy and its potential role in Downsyndrome risk assessment. Ultrasound Obstet Gynecol 22:36-39, 2003

0. Viora E, Masturzo B, Errange G, et al: Ultrasound evaluation of fetalnasal bone at 11-14 weeks in a consecutive series of 1906 fetuses.Prenat Diagn 23:784-787, 2003

1. Malone FD, Ball RH, Nyberg DA, et al: First trimester nasal bone eval-uation for aneuploidy in the general population. Obstet Gynecol 104:1222-1228, 2004

2. Weiss JL, Malone FD, Vidaver J, et al: Threatened abortion: a risk factorfor poor pregnancy outcome, a population-based screening study. Am JObstet Gynecol 190:745-750, 2004

3. Weiss JL, Malone FD, Emig D, et al: Obesity, obstetric complicationsand cesarean delivery rate: a population-based screening study. Am JObstet Gynecol 190:1091-1097, 2004

4. Dugoff L, Hobbins JC, Malone FD, et al: First-trimester maternal serumPAPP-A and free-beta subunit human chorionic gonadotropin concen-trations and nuchal translucency are associated with obstetric compli-cations: a population-based screening study (the FASTER Trial). Am JObstet Gynecol 191:1446-1451, 2004

5. Cleary-Goldman J, Malone FD, Vidaver J, et al: Impact of maternal age

on obstetric outcome. Obstet Gynecol 105:983-990, 2005