Blastocyst Versus Cleavage Stage Transfer

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Blastocyst versus cleavage stage transfer in in vitrofertilization: differences in neonatal outcome?

Bengt Kallen, M.D., Ph.D.,a Orvar Finnstrom, M.D., Ph.D.,

b Anna Lindam, M.Sc.,c Emma Nilsson, Ph.D.,c

Karl-Gosta Nygren, M.D., Ph.D.,d and Petra Otterblad Olausson, Ph.D.c

a Tornblad Institute, University of Lund, Lund b Department of Paediatrics, University Hospital, Linkoping c Centre for

Epidemiology, National Board of Health and Welfare, Stockholm and d IVF and Fertility Clinic, Sophiahemmet, Stockholm,

Sweden

Objective: To compare neonatal outcome of blastocyst and cleavage stage embryo transfers after IVF.Design: Register study.Setting: Births recorded in the Swedish Medical Birth Register after IVF performed, 20022006.Patient(s): Treatments reported from all Swedish IVF clinics.Intervention(s): None.Main Outcome Measure(s): Some neonatal characteristics were compared in 1,311 infants born after blastocyst-stage transfer and 12,562 infants born after cleavage-stage transfer. Comparisons were also made with all births,

20022007 (n 598,687).

Result(s): After adjusting for year of birth, maternal age, parity, smoking habits, and body mass index, the risk ofpreterm birth among singletons was significantly greater after blastocyst-stage transfer than after cleavage-stage

transfer. The risk of congenital malformations was also significantly higher. When the analysis was restricted to

clinics where blastocyst transfers were made, the risk estimates increased for preterm birth, low birth weight,low APGAR score, and respiratory diagnoses, but did not change for congenital malformations.

Conclusion(s): The results indicate a small increase in risk associated with blastocyst transfer, perhaps owing to thelonger period of in vitro culture. There is a possibility that this effect is due, at least in part, to a selection of women

for blastocyst transfers. Further studies are needed either to verify or to refute the found associations. (Fertil Steril

2010;94:16803. 2010 by American Society for Reproductive Medicine.)

Key Words: Blastocyst, preterm birth, stillbirth, congenital malformations

During the past decade, extension of embryo culture to 56 days has

become part of the routine IVF procedures in some clinics. The em-

bryo then develops into a blastocyst. A number of studies, summa-rized in a Cochrane review (1), demonstrated a higher pregnancy

rate and live birth rate after blastocyst transfer than after cleavage-

stage transfer. When an equal number of embryos was transferred,

the summarizing odds ratio (OR) for a live birth was 1.35 (95% con-

fidence interval [CI], 1.051.74). Another metaanalysis found a sim-

ilar OR of 1.39 (95% CI, 1.101.76) (2). A recent study (3) verified

the higher pregnancy rate after fresh blastocyst transfer than after

cleavage-stage transfer, but for frozen embryos the opposite was

seen; therefore, the total pregnancy rate was similar when both fresh

and frozen embryo transfers were included. Few studies have inves-

tigated the neonatal outcomes after blastocyst transfer. An increased

rate of monozygotic twinning and an increased sex ratio have been

found (4, 5). One study described a normal malformation rate for200 infants (n 5) born after blastocyst transfer (6). In this study,

we have analyzed neonatal outcomes including a number of neona-

tal diagnoses and the presence of congenital malformations in neo-

nates born after blastocyst transfer, and we compared them with

neonates after cleavage-stage embryo transfer.

MATERIALS AND METHODSData were collected from all IVF clinics in Sweden regarding IVF treatments

with an embryo transfer during the period 20022006. Information was re-

quested on the identification number of the woman, the date of embryo trans-

fer, IVF method, and embryo age at transfer. All reported IVF infants were

included in the study. To study delivery outcomes, we used information

from the Swedish Medical Birth Register (7), which supplied information

on parity, smoking habitsin earlypregnancy, prepregnancyweight and height

(which made it possible to calculate body mass index [BMI]), years of un-

wanted childlessness, birth weight, and gestational duration. Small-for-ges-

tational age (SGA) was calculated using normal graphs for singletons,

based on data in the Medical Birth Register (8). Information on congenital

malformations was obtained from three sources: the Medical Birth Register

(International Classification of Diseases [ICD] codes given at the pediatric

examination of the newborn), the Register of Birth Defects (former Register

of Congenital Malformations, primarily based on reports from neonatolo-

gists), and the National Patient Register (formerly the Hospital Discharge

Register) (9). Respiratory diagnoses were defined as ICD-10 codes P22P28.

Comparisons were made between infants born after blastocyst transfer and

those born after cleavage-stage transfer. Comparisons were also made be-

tween infants born after blastocyst transfer or after cleavage-stage transfer

and all infants born during 20022007 and registered in the Medical Birth

Register (n 598,687).

All diagnoses with an ICD-10 code beginning with Q (i.e., Chapter 17,

congenital malformations, deformations, and chromosomal anomalies)

were primarily included to define malformations. To reduce variability,

some common and relatively frequent minor anomalies with little clinical

Received October 13, 2009; revised and accepted December 7, 2009;

published online February 4, 2010.

Supported by a grant from Evy and Gunnar Sandberg Foundation, Lund,

Sweden, to B.K.

B.K.has nothing to disclose.O.F. hasnothingto disclose. A.L. hasnothing

to disclose. E.N. has nothing to disclose. K.-G.N. has nothing to

disclose. O.P.O. has nothing to disclose.

Reprint requests: Bengt Kallen, M.D., Ph.D., Tornblad Institute, Biskops-

gatan 7, SE-223 62 Lund, Sweden (TEL: 46-46-222-7536; FAX:

46-46-222-4223; E-mail: [email protected]).

Fertility and Sterility Vol. 94, No. 5, October 2010 0015-0282/$36.00Copyright 2010 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2009.12.027

1680
mailto:[email protected]:[email protected]


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importance were excluded: preauricular appendix, tongue tie, patent ductus

arteriosus in preterm infants, undescended testicle, hip luxation, hip sublux-

ation, clicking hip, single umbilical artery, and nevus. The remaining malfor-

mations were called relatively severe malformations, although some mild

conditions could be included. An analysis of cardiovascular anomalies (ex-

cept patent ductus in preterm infants and single umbilical artery) was also

made. Identification of vanishing twins was made from the observation

of two emryonic sacs in early pregnancy followed by a singleton birth.

ORswere estimatedusing theMantel-Haenszel procedureand the95% CIs

were estimated with Miettinens method. Adjustments were made for year of

birth,maternalage, parity, smoking habits, and prepregnancy BMI. When the

expected numberwas less than 10,risk ratiosas observed over expected num-

bers were calculated instead, and the 95% CIs were based on exact Poisson

distributions.

This study was performed within the responsibilities of the National Board

of Health and Welfare; therefore, no ethical approval from outside ethical

committees was needed.

RESULTSThis study is based on 1,311 infants born to 1,190 women after blas-

tocyst transfer and 12,562 infants born to 11,548 women after cleav-

age-stage transfer. Births occurred during 20022007. There were

115 twin pairs (228 recorded infants, two missing twins) and four

triplet sets (12 recorded infants) after blastocyst transfer and 1,022

twin pairs (2,022 recorded infants, 22 missing twins) and seven trip-

let sets (21 recorded infants) after cleavage-stage transfer. The rate

of multiple births was thus 10% and 8.9%, respectively, and the

two rates do not differ significantly (c2 1.56; P0.21).

Infant sex was known for both twins in 113 pairs after blastocyst

transfer and in 1,000 pairs after cleavage-stage transfer (c2 0.01;

P0.95). The percentage of like-sexed twins was similar: 52 and

53%, respectively. Among singletons born after blastocyst transfer,

there were signs of vanishing twins in 1% after cleavage stage trans-

fer in 1.8 % (c2 3.2; P0.07).

There were slightly fewer intracytoplasmic sperm injection

procedures associated with blastocyst transfer (43%) than with

cleavage-stage transfer (46%), but this difference may be random

(c2 3.4; P0.07).

Table 1 describes some maternal characteristics in the two

groups. They differ in regard to maternal age, parity, and BMI,

whereas no certain difference is seen between the groups in regard

to smoking and years of unwanted childlessness when stated.

Table 2 shows data on preterm birth, low birth weight, and SGA

for singleton infants. Infants born after blastocyst transfer are more

often born preterm than are infants born after cleavage-stage trans-

fer. Both groups show a higher risk of preterm birth than does the

population (OR, 1.66; 95% CI, 1.352.05; and OR, 1.24; 95% CI,

1.151.34, respectively). No statistically significant differences

exist in regard to low birth weight or SGA, but for low birth weight

the risk estimate is higher after blastocyst than after cleavage-stage

transfer.

Table 2 also shows neonatal data. These refer to all infants born

and thus include multiples. Although all ORs are higher after blas-

tocyst than after cleavage-stage transfer, none of the differences rea-

ches statistical significance. The four variables tabulated are also

strongly related.

Data on congenital malformations are also presented in Table 2.

The ORs for any congenital malformation vs. population figures was

higher after blastocyst transfer (OR, 1.53; 95% CI, 1.231.90) than

after cleavage-stage transfer (OR, 1.11; 95% CI, 1.021.21), and

a direct comparison between the two types of embryo transfer

showed statistically significant higher risk for the former group.

When the analysis was restricted to relatively severe

TABLE 1

Comparison of some maternal characteristics after blastocyst and cleavage stage transfer: embryo transfers 20022006.

Blastocyst transfer Cleavage-stage transfer

Characteristic No. %a No. % c2 Pvalue

Maternal age, y


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malformations, the ORs changed only marginally, and the differ-

ence between the two groups remained significant. When only car-

diovascular defects were studied, no significant difference between

the groups was seen.

Among the 61 relatively severe malformations, there were four

infants with CNS malformations (three of them with spina bifida),

18 with cardiovascular defects, three with cleft palate, five with

ureter malformations, four with hypospadias, four with pes equino-

varus, two with hand malformations, and three with Down

syndrome. Other malformations occurred in only one case each

among them was one infant with Goldenhar syndrome and one

with sirenomelia. Compared with the risk of spina bifida after

cleavage stage transfer (11 cases), the risk after blastocyst transfer

is nonsignificantly increased (P0.10).

IVF followed by blastocyst transfer was reported from only half

of the IVF clinics, and a large majority (n 986) came from one

clinic. Analyses were therefore made adjusting for IVF clinic (the

three largest ones with 986, 87, and 74 cases, respectively, and all

TABLE 2

Comparison of neonatal characteristics of infants born after blastocyst or cleavage-stage transfer: embryo transfers 20022006.

Blastocyst transfer Cleavage-stage transfer

Neonatal characteristic

No. with

outcome Total no.

No. with

outcome Total no. OR 95% CI


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other clinics with at least one blastocyst transfer together). The sam-

ple of cleavage-stage transfer was then reduced to approximately

half (6,178 infants among a total of 12,562). Table 3 presents the

results. All estimates that did not refer to congenital malformations

increased and some (

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Blastocyst Versus Cleavage Stage Transfer