early pregnancy lose

Australian and New Zealand Journal of Obstetrics and Gynaecology 2006; 46: 413418

2006 The Authors 413Journal compilation 2006 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

Blackwell Publishing Asia Original ArticleYolk sac in early pregnancy loss

The quality and size of yolk sac in early pregnancy loss

Fu-Nan CHO,1 San-Nung CHEN,1 Ming-Hong TAI2 and Tsung-Lung YANG31Department of Obstetrics and Gynecology, 2Department of Medical Education and Research and 3Department of Radiology,

Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

AbstractBackground: Accurate differentiation between normal pregnancy and pregnancy loss in early gestation remains aclinical challenge.

Aims: To determine whether ultrasound findings of yolk sac size and morphology are valuable in relation topregnancy loss at six to ten weeks gestation.

Methods: Transvaginal ultrasonography was performed in 111 normal singleton pregnancies, 25 anembryonicgestations, and 18 missed abortions. Mean diameters of gestational sac and yolk sac were measured. The relationshipbetween yolk sacs and gestational sacs in normal pregnancies was depicted. The yolk sacs ultrasound findings incases of pregnancy loss were recorded.

Results: In normal pregnancies with embryonic heartbeats, a deformed or an absent yolk sac was never detected.Sequential appearance of yolk sac, embryonic heartbeats and amniotic membrane was essential for normal pregnancy.The largest yolk sac in viable pregnancies was 8.1 mm. Findings in anembryonic gestations included an absent yolksac, an irregular-shaped yolk sac and a relatively large yolk sac (> 95% upper confidence limits, in 11 cases). Incases of missed abortion with prior existing embryonic heartbeats, abnormal findings included a relatively large, aprogressively regressing, a relatively small, and a deformed yolk sac (an irregular-shaped yolk sac, an echogenic spot,or a band).

Conclusion: A very large yolk sac may exist in normal pregnancy. When embryonic heartbeats exist, the poor qualityand early regression of a yolk sac are more specific than the large size of a yolk sac in predicting pregnancy loss. Whenan embryo is undetectable, a relatively large yolk sac, even of normal shape, may be an indicator of miscarriage.

Key words: gestational sac, miscarriage, pregnancy loss, transvaginal ultrasonography, yolk sac.

Introduction

Accurate differentiation between normal pregnancy andpregnancy loss in early gestation remains a clinical challenge.Previous studies have described the association betweenembryonic well-beings and the characteristics of gestationalsac,1,2 yolk sac,38 amniotic cavity,9,10 and embryonicheartbeats.11,12 Despite the advent of three-dimensionalultrasound,1315 two-dimensional transvaginal ultrasoundremains a simple and convenient way to assess pregnancy status.There are discriminatory criteria in predicting spontaneouspregnancy losses, including 8-mm mean diameter ofgestational sac (MD-GS) without a visible yolk sac4 and1620-mm MD-GS without embryonic heartbeats;16,17

however, various exceptions to these criteria exist.1,18 Inaddition, pregnancies with a very large yolk sac are almostalways associated with poor outcomes.7 This study wasdesigned to determine the value of yolk sac findings inpredicting early pregnancy outcomes.

Materials and methods

One hundred and fifty-four women with a singleton pregnancybetween six and ten weeks gestation were enrolled in thisstudy from June 1998 to May 2004. Gestational age was basedon one or more of the following criteria: (i) last menstrualperiod if the woman had a regular menstrual cycle; (ii) basalbody temperature charts; (iii) sperm insemination date;(iv) or the crownrump length (CRL) from early ultrasoundif available. The institutional human ethics committee inour hospital had approved this research.

Correspondence: Dr Fu-Nan Cho, Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Road, Kaohsiung, Taiwan 813. Email: [email protected]

DOI: 10.1111/j.1479-828X.2006.00627.x

Received 16 February 2006; accepted 06 June 2006.

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414 2006 The AuthorsJournal compilation 2006 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists; 46: 413418

All patients received transvaginal ultrasonography (ATL,HDI-3000, Washington, USA; 7-MHz transducer) by thesame senior staff (Fu-Nan Cho) member to eliminate inter-observer variance. Patients presenting with obvious bleeding(including incomplete miscarriage), incomplete data (includ-ing three cases lost to follow up), and examination by otherstaff members were excluded from this study. One hundredand eleven normal cases were followed until 36 weeksgestation or birth. Forty-three cases with poor outcome wereidentified as either miscarriage without a visible embryo(anembryonic gestation, at adjusted gestation > 6+4 weeksor at least 18 days after positive urine pregnancy test) ormiscarriage with a visible embryo lacking heartbeats (missedabortion, with a CRL > 5 mm or adjusted gestation > 6+4

weeks). The mean values of the three inner diameters ofgestational sac and yolk sac were measured. The CRL andembryonic heart rate, if detectable, were measured at the sametime. Serum beta-human chorionic gonadotropin (-HCG)(3rd IS WHO 75/537, BRAHMS, Germany) and follow-upultrasound examinations (in three to ten days) were performedin cases with uncertain diagnosis and unknown dating toconfirm the poor outcomes. The relationship between yolksac and gestational sac in normal cases was determined, withthe mean, upper, and lower 95% confidence limits beingcalculated and depicted. The findings in cases with miscarriagewere presented and analysed.

Results

Findings in normal pregnancies

In 111 normal pregnancies with embryonic heartbeats, anabsent or a deformed yolk sac was never detected. The yolksacs were nearly spherical in shape. The mean diameter ofyolk sac (MD-YS) increased progressively with advancinggestation (Fig. 1). Six of 111 (5.8%) cases were above the upper95% confidence limits. The largest MD-YS was 8.1 mm witha CRL of 28.7 mm. The smallest MD-YS was 2.3 mm, witha living embryo detected. The smallest MD-GS with a livingembryo was 9.3 mm. The smallest CRL with positive heartbeatswas 3 mm. The embryonic heart rates increased withadvancing gestation. The slowest embryonic heart rate was100 b.p.m. with a CRL of 3 mm. The fastest embryonicheart rate was 192 b.p.m. with a CRL of 35 mm.

Findings in 25 cases of miscarriage without a visible embryo (anembryonic gestation)

1 Twelve cases without a visible yolk sac: The diagnosis wasmade only when the fertilisation date or serum-HCG valuewas available. Of these cases, the smallest MD-GS was 11 mmwhen pregnancy loss was confirmed (-HCG: 6210 miu/mL).

2 Thirteen cases with a visible yolk sac: One case showedan irregular-shaped yolk sac that turned into an echogenicband eventually. Another case showed a normal yolk sac(2.8 mm in MD). The remaining 11 cases had a normalshape, but relatively large yolk sacs (4.2, 4.7, 4.9, 5.3, 5.4,

5.9, 6.2, 6.3, 7.8, 8.6, and 8.7 mm in MD, respectively)in relation to the gestational sac (beyond upper 95%confidence limits) (Figs 2, 3). Regression of the yolk sac(to 6.8 mm) was found four days later in the last case.The size of yolk sac in most normal pregnancies (105/

111) was within upper and lower 95% confidence limits. Theyolk sacs in 24 anembryonic gestations were noted beyondupper or lower 95% confidence limits, including a relativelylarge yolk sac, a deformed yolk sac, and an absent yolk sac.A very small gestational sac (relative to the gestational sacs

Figure 1 The relationship between the mean diameter of theyolk sac (MD-YS) and the gestational sac (MD-GS) in 111normal cases with a living embryo. The mean, upper, and lower95% confidence limits are indicated by three curves. YS diameter= 2.73 + 0.0623(GS diameter) 0.0028(GS diameter2) + 0.000047(GS diameter3); r = 0.549, n = 110, P < 0.0001. Of note, withnormal embryonic heartbeats, six yolk sacs are located above thecurve of the upper 95% confidence limits.

Figure 2 The relationship between yolk sac and gestational sacin 25 cases of miscarriage without a visible embryo. Threecurves are derived from Figure 1. Of note, in the absence of avisible living embryo, a relatively large yolk sac may be anindicator of miscarriage.

Yolk sac in early pregnancy loss

2006 The Authors 415Journal compilation 2006 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists; 46: 413418

of normal pregnancies at the same gestation) was shown inthree cases of anembryonic gestation without a visible yolk sac.

Findings in 18 cases of miscarriage with a visible embryo lacking heartbeat

The data are summarised in Table 1. In case one, a yolk sacwas undetectable at first. Three days later, an echogenicspot of yolk sac and embryonic heartbeat were detected.

Unfortunately, miscarriage occurred over the subsequent sevendays. In case two, a yolk sac was invisible initially. After one week,a yolk sac was visible, but without embryonic heartbeat.Regression of the yolk sac occurred over the next seven days.In case three, the embryo was undetectable with MD-YS of3.3 mm. Miscarriage was diagnosed ten days later. In case four,a small gestational sac and a very large yolk sac (6.6 mm inMD) were found with normal embryonic heartbeat. The yolksac turned into an echogenic band with normal embryonicheartbeat six days later (Fig. 4). In case five, a relatively largeyolk sac was noted with positive heartbeat. After one week,miscarriage was noted. Regression of the yolk sac was notedover the next week. In cases six to 12, a deformed yolk sac andan absent yolk sac were noted. In case 13, a relatively largeamniotic cavity (11.1 mm in mean diameter) with a very smallembryo was found. In case 14, a relatively large amniotic cavity(14 mm in mean diameter) with a small CRL was noted.In cases 15 and 16, the amniotic membrane was visible,but neither yolk sac nor embryonic heartbeat was detected.Interestingly, the amniotic cavity continued to grow even withoutembryonic heartbeat. The yolk sac appeared as an echogenicspot six days later in case 15 (Fig. 5). In case 17, slow embryonicheartbeat and a small yolk sac were noted. Miscarriage wasfound ten days later. In case 18, pregnancy loss was un-expectedly noted. These findings showed that, even with positiveembryonic heartbeats, miscarriage ensued when associated

Figure 3 Ultrasound findings in a case of anembryonic gestation.Without a visible embryo, a very large yolk sac (arrow; 8.7 mmin mean diameter) may render the diagnosis of miscarriage.

Table 1 The detailed information in 18 cases of miscarriage with an embryo

Patients CRL FHB YS GS Remarks

Ma 1 10.0 Invisible YS and embryoMa 1.1 5 100 Spot 17.3 Echogenic YSMa 1.2 7.6 Spot 20.6 Echogenic YS, EHB ()Ma 2 19.3 -HCG = 65000 miu/mLMa 2.1 5.7 4.6 24.7 Large YSMa 2.2 3.4 25.3 Regressive YS, no embryoMa 3 3.3 12.7 Large YS, no embryoMa 3.1 4.4 3.4 19.3Ma 4 4.3 120 6.6 9.0 Absolutely large YSMa 4.1 8.9 150 Band 10.0 Echogenic band of YSMa 5 5.1 100 5.3 18.0 Large YSMa 5.1 6.8 3.6 19.3 Regression of YSMa 5.2 6.8 2.6 20.3 Regression of YSMa 6 11.8 2.7 27.4 Deformed YSMa 7 16.5 170 3.8 36.3 Deformed YS. No EHB laterMa 8 8.5 2.2 17.7 Deformed YSMa 9 9.7 25.0 Invisible YSMa 10 19.6 28.3 Invisible YSMa 11 7.6 20.7 Invisible YSMa 12 3.9 21.6 Invisible YSMa 13 3 1.7 17.6 Large ACMa 14 6.7 2.2 28.0 Large ACMa 15 13.2 36.0 Visible AC (13.3), invisible YSMa 15.1 14 Spot 32.7 Growing AC (18.3), echogenic YSMa 16 5.5 9.8 Visible AC, invisible YSMa 17 5.7 85 1.9 15.3 Slow EHB, small YSMa 18 8.8 160 3.7 26.7 No EHB later

Ma1, first case of miscarriage; Ma1.1, the first follow up; Ma 1.2, the second follow up. EHB, embryonic heartbeats; CRL, crownrump length; YS, yolk sac; GS, gestational sac; and AC, amniotic cavity were stated as mm in mean diameter.

F.-N. Cho et al.


with a relatively large, a progressively regressing, a relatively small(with slow heartbeats), and a deformed yolk sac (an irregular-shaped yolk sac, an echogenic spot, or a band) (Fig. 6).

Discussion

Sequential appearance of a yolk sac, embryonic heartbeat,and an amniotic cavity is essential for normal pregnancy. In

our cases with a live birth, a deformed yolk sac never occurred.In addition, from observation of normal pregnancies in our andanother reports,4 totalling 382 cases, embryonic heartbeatshave always been detectable when a yolk sac reaches 3.3 mmin mean diameter. We believe that, if a living embryo is notdetected by transvaginal ultrasound, the presence of arelatively large yolk sac (beyond upper 95% confidence limits,4.2 mm in mean diameter at least), even with normal shape, canstill lead to the diagnosis of miscarriage, as in this study therewere no cases of successful pregnancy following a ultrasoundscan reporting a yolk sac greater than the 95th centile unlessa viable embryo was also seen during the assessment.

Of note, a relatively large yolk sac, with normal shape andnormal embryonic heartbeat, should not be hastily identified

Figure 4 Ultrasound findings of a case with miscarriage. (A) Alarge yolk sac (6.6 mm in mean diameter; arrowheads) in a smallgestational sac; an embryo (+) with heartbeats (120 b.p.m.).(B) The yolk sac turned into an echogenic band (arrow) 6 dayslater with an embryo (F). (C) Pregnancy loss ensued despitenormal heartbeats (150 b.p.m.; large arrows).

Figure 5 A case of miscarriage with a yolk sac shown as anechogenic spot (large arrow). The amniotic cavity (small arrows)kept growing despite negative embryonic heartbeats (theembryo was not visible in this view).

Figure 6 Diagram of the relationship between yolk sac (YS)and gestational sac in 18 cases of miscarriage with a visibleembryo lacking heartbeats. Six cases with serial sonography aredepicted by arrows. Yolk sacs are typical of abnormal quality,especially as an echogenic spot, an echogenic band, or aprogressively regressing YS. For cases with YS located in thenormal range, they were associated (with exception of one case)with other abnormal findings, such as a deformed YS, a relativelylarge amniotic cavity, and slower embryonic heartbeats.

Yolk sac in early pregnancy loss

2006 The Authors 417Journal compilation 2006 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists; 46: 413418

as an abnormal pregnancy. In the normal cases of our study,the maximal MD-YS was 8.1 mm, which is higher than thevalue of 5.6 mm as reported in a previous study.4 To ourknowledge, this is the largest yolk sac associated with a livebirth.20 In this case, the placenta was implanted into the septumof a bicornuate uterus. The unusual growth of the yolk sacmay be influenced by environmental factors.20

To precisely diagnose pregnancy failure in an emptygestational sac (without an embryo and a yolk sac), thediscriminatory gestational date should be confirmed.17 Asignificant difference between the size of the gestational sacin normal and abnormal pregnancies should appear aftersix weeks gestation (8.2 vs 4.5 mm) due in part to the differentvascularisation.2 In one of our normal cases, neither a livingembryo nor a yolk sac was detectable initially with a MD-GSof 10 mm. Accordingly, the diagnosis of anembryonicgestation without a yolk sac should not be made if a MD-GSis 10 mm or less, which is larger than the value of 8 mmmentioned in previous studies,1,4 unless the adjusted gestationreaches 6+4 weeks. This is possibly attributed to the factthat some normal cases may have a relatively fast-growinggestational sac.

The findings of an invisible yolk sac and a deformed yolksac have been reported as typical signs of pregnancy loss.46

Furthermore, as a deformed yolk sac has never occurred innormal cases, it may be used to predict pregnancy lossbefore embryonic heartbeats appear.19 The abnormal yolksac findings in viable pregnancies (with normal embryonicheartbeat) that went on miscarriage include a large yolk sac,an echogenic spot, an echogenic band, an irregular-shapeyolk sac, and an early regressing yolk sac during the follow-up examination. Besides, the existence of a visible amnioticcavity, but without a living embryo, has been reported as a

sign of early miscarriage.911 We observed that an absent yolksac or a deformed yolk sac has been associated with this sign.Interestingly, the growth of amniotic cavity can still proceeddespite embryo demise. To predict early pregnancy loss,use of the integration of abnormal findings of yolk sac,gestational sac and amniotic cavity may be more helpfuland convincible. These concepts may be exploited to clinicalpractice in embryo reduction. Our study is limited by a smallnumber of patients with pregnancy loss. Further prospectivelylarge-scale studies are warranted to define the new criteriafit for new high-resolution ultrasound equipment. A briefsummary of previous reports is showed in Table 2.

Conclusion

The sequential appearance of yolk sac, embryonic heartbeatand amniotic membrane is essential for normal pregnancy.In normal pregnancy, a very large yolk sac may exist. Whenembryonic heartbeats exist, the poor quality and earlyregression of the yolk sac may be more specific than a largeyolk sac in predicting early pregnancy loss. When an embryois undetectable, a relatively large yolk sac, even of normalshape, may be an indicator of miscarriage.

References1 Rowling SE, Coleman BG, Langer JE, Arger PH, Nisenbaum HL,

Horii SC. First-trimester US parameters of failed pregnancy.Radiology 1997; 203: 211217.

2 OH JS, Wright G, Coulam B. Gestational sac in very earlypregnancy as a predictor of fetal outcome. Ultrasound ObstetGynecol 2002; 20: 267269.

Table 2 Brief summary of published reports regarding the characteristics of yolk sac in pregnancy loss using two-dimensional transvaginalultrasound

Authors Gestation Cases number Study, sonologist Remarks

Kurtz et al.3 < 12 weeks 163 normal, 49 miscarriage

Prospective, multiple

The presence or absence of YS is not a predicting sign

Lindsay et al.4 < 10 weeks 327 normal, 159 miscarriage


Miscarriage occur with (i) YS > 5.6 mm, (ii) absent YS in a 8-mm GS

Stampone et al.5 < 12 weeks 101 normal, 16 miscarriage


Predict miscarriage by > or < 2 SD of YS diameter

Rowling et al.1 < 13 weeks NA Retrospective, multiple

Live birth may occur with absent YS in a 8-mm GS

Kucuk et al.7 < 12 weeks 219 normal, 31 miscarriage



Mara and Foster6 710 weeks 1 case report Embryonic death when associated with YS regression

Chama et al.8 < 12 weeks 70 normal, 35 miscarriage



Our study 610 weeks 111 normal, 43 miscarriage

Prospective, one staff member

An echogenic spot or a band, A large YS in anembryonic gestation, Detailed follow-up findings available

GS, gestational sac; YS, yolk sac; SD, standard deviation.NA, not available because of mixed results from transabdominal or vaginal scan.

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