Human Reproduction, Vol.30, No.1 pp. 81 –87, 2015 Advanced Access publication on October 31, 2014 doi:10.1093/humrep/deu272

ORIGINAL ARTICLE Infertility

Can you ever collect too many oocytes? Rosalind Briggs 1, Gabor Kovacs 2,*, Vivien MacLachlan2, Caroline Motteram 2, and H.W. Gordon Baker 3 1

Medical School, University of Edinburgh, Edinburgh, UK 2Monash IVF, Richmond, VIC 3121, Australia 3University of Melbourne, Carlton, VIC, Australia

Submitted on December 6, 2013; resubmitted on September 11, 2014; accepted on September 22, 2014

study question: Does the chance of pregnancy keep improving with increasing number of oocytes, or can you collect too many? summary answer: Clinical pregnancy (CP) and live birth (LB) rates per embryo transfer varied from 10.2 and 9.2% following one oocyte collected to 37.7 and 31.3% when .16 oocytes were collected. Regression modelling indicated success rates increased or at least stayed the same with number of oocytes collected.

what is known already: It has been suggested that if .15 oocytes are collected, the success rate for fresh embryo transfers decreases. As this is counterintuitive, as more oocytes should result in more embryos, with a better choice of quality embryos, we decided to analyse the recent experience in a busy IVF unit.

study design, size duration: A retrospective analysis of clinical pregnancy and live birth outcome, with respect to number of oocytes collected at Monash IVF for the 2-year period between August 2010 and July 2012, where patients under the age of 45 years underwent a fresh embryo transfer. This included 7697 stimulated cycles for IVF and ICSI.

participant/materials, setting, methods: Statistical analysis involved data tables and graphs comparing oocyte number with outcome. Results of women who had their first oocyte collection with an embryo transfer within the reference period were analysed by logistic regression analysis including other covariates that might influence pregnancy outcome. Analysis was also carried out of all the 7679 oocyte collections undertaken, resulting in fresh embryo transfers by generalized estimating equations to allow for the within subject correlation in outcomes for repeated treatments.

main results and the role of chance: The number of oocytes collected varied from 1 to 48. Clinical pregnancy and live birth rates per embryo transfer varied from 10.2 and 9.2% when only one oocyte was collected to 37.7 and 31.3% when .16 oocytes were collected. Regression modelling indicated success rates increased or at least stayed the same or with the number of oocytes collected. The percentage of women with embryos cryopreserved increased from under 20% with ,4 oocytes collected to over 70% with .16 oocytes collected. There was a slight increase (from 18 to 22%) in oocyte immaturity and a more marked increase (from 0 to 3%) in cancelling fresh transfers to prevent Ovarian Hyperstimulation Syndrome (OHSS) with increase in number of oocytes collected above 16. The results of this study suggest that you cannot collect too many oocytes as both clinical pregnancy and live birth rates do not decrease with high numbers of oocytes collected. However, once .15 oocytes are collected, everything gets quite uncertain.

limitations, reasons for caution: As the data become sparse above 15 oocytes, we could not demonstrate a significant increase in pregnancy rates above this number. Larger studies would be required to answer the question whether there is a plateau, or rates continue to increase. The negative of aggressive stimulation to produce many oocytes is that the risk of OHSS increases, and this is the most serious complication of ovarian stimulation.

study funding/completing of interest(s): No funding was required. There is no conflict of interest, except that G.K., V.M. and C.M. are shareholders in Monash IVF Pty Ltd. Key words: ovarian stimulation / pregnancy rate / oocyte numbers

& The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected]

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*Correspondence address. Monash IVF, Pelaco Building, Goodwood, St Epworth, Richmond, VIC 3121, Australia. E-mail. [email protected]

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Introduction

Materials and Methods Our retrospective study looked at women treated in stimulated cycles at Monash IVF for the 2-year period between August 2010 and July 2012, where the patient underwent a fresh embryo transfer. This included 7697 stimulated cycles for IVF and ICSI. Exclusion criteria comprised, cycles in which no oocytes were collected (96), no oocyte fertilized (675), all embryos were frozen (44) to avoid OHHS, the patient was an oocyte donor, or the oocyte collection was performed when the woman was aged 45 years or over (29 cycles in 25 women only one of whom had a baby). To estimate the impact of embryo cryopreservation, results for all patients aged ,45 using their own frozen embryos in the same time-period (August 2010 and July 2012) were analysed. This included some patients in the fresh embryo transfer group above and other patients but excluded those using donated oocytes or embryos. A total of 7257 embryos were thawed, 5807 were transferred in 5352 procedures, 1384 were discarded because they were no longer required by the patient or failed to survive and 66 were refrozen. We extracted the data from the Monash IVF Patient Management System (PMS), and then analysed it using Microsoft Excel and Genstat. Clinical pregnancy (CP) was defined as a fetal heart visualized on ultrasound scan at between 6 and 7 weeks gestation, and a live birth (LB) was defined as one

Figure 1 Clinical pregnancy (CP) and live birth (LB) rates with respect to number of oocytes collected (results with over 20 oocytes are grouped (18– 19, 20 – 21, 22 – 23, 24 – 27, .28) because of small numbers). Error bars are 95% confidence limits.

Table I Clinical pregnancy (CP) and live birth (LB) outcome with respect to number of oocytes collected for 3060 fresh embryo transfers after the woman’s first oocyte collection. Oocytes collected

Embryo transfers

CP

CPR %

LB

LBR %

........................................................................................ 1

39

4

10.3

4

10.3

2

111

22

19.8

16

14.4

3

189

52

27.5

39

20.6

4

248

64

25.8

49

19.8

5

270

82

30.4

60

22.2

6

244

83

34.0

69

28.3

7

285

98

34.4

79

27.7

8

241

83

34.4

68

28.2

9

219

69

31.5

61

27.9

10

217

63

29.0

49

22.6

11

230

85

37.0

69

30.0

12

195

63

32.3

54

27.7

13

174

62

35.6

50

28.7

14

152

70

46.1

54

35.5

15

107

41

38.3

39

36.4

16

121

64

52.9

54

44.6

17

106

52

49.1

44

41.5

18–19

139

57

41.0

47

33.8

20–21

84

29

34.5

23

27.4

22–23

84

35

41.7

28

33.3

24–27

78

39

50.0

34

43.6

.28

67

23

34.3

20

29.9

or more live babies delivered beyond 20 weeks of gestation. Factors potentially influencing pregnancy and birth rates after IVF and ICSI were also retrieved including female age, fertilization rate, number and stage of

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The first successful IVF live births were a result of natural cycles (Steptoe and Edwards, 1978; Lopata et al., 1980). However, the success rate of these cycles was low. This led to the utilization of stimulated cycles, which were pioneered with the use of Clomiphene Citrate (Trounson et al., 1981), and later with FSH (Jones et al., 1982). Controlled ovarian hyperstimulation (COH) became routine and there have been many modifications of treatment since, including the use of highly purified FSH and the use of GnRH agonists and later GnRH antagonists to inhibit ovulation. Along with their success, stimulated cycles led to other problems, including ovarian hyper-stimulation syndrome (OHSS). It has also been suggested that the high level of estrogen in COH cycles may be detrimental to oocyte quality as well as to the endometrium. Higher doses of hormones used in stimulated cycles can produce higher yields of oocytes but it has been reported that excessive stimulation and high levels of estrogen, may compromise results. There have been several previous studies suggesting that beyond a certain number of oocytes collected the pregnancy rate in the stimulated cycle with fresh embryo transfer, starts to decline. The optimum number of oocytes varied from 13 (van der Gaast et al., 2006), 15 to 20 (Sunkara et al., 2011), or as wide a range as 6 to 15 (Ji et al., 2013), whilst a study by Kok and colleagues (Kok et al., 2006) suggested that although high responders had a higher percentage of immature oocytes, the pregnancy outcome was not impaired. The suggestion that one can have ‘too many oocytes?’ is anti-intuitive, as if there are more oocytes available for fertilization, there should be a higher number of embryos produced, giving greater choice for embryo transfer and a better outcome. These studies include cycles using older stimulation protocols, and the purpose of the current study was to investigate if their conclusions remain true for more modern stimulation protocols and with the evolution of delayed transfer at the blastocyst stage. We therefore carried out a retrospective analysis of clinical pregnancy and live birth outcome, with respect to number of oocytes collected.

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Pregnancy rate increases with oocyte numbers

statistically significant are reported. As some factors such as age and blastocyst transfer are related to both number of oocytes collected and the pregnancy outcome, the significance of possible interactions between them was tested. As no identifying data were used, institutional ethics committee approval was not required. The study was approved by the Monash IVF Research Committee.

Results The number of oocytes collected varied from 1 to 48. CP rate per embryo transfer varied from 10.2% when only one oocyte was collected to 37.7% when .16 oocytes were collected. LB rate per embryo transfer varied from 9.2% following collection of 1 oocyte to 31.3% following collection of .16 oocytes. The rates of both of these outcomes increased as the number of oocytes collected increased but there was considerable scatter about the trend both for all the cycles (Fig. 1) and for first oocyte collections (Table I). The effects of age and blastocyst transfer are shown in Figs 2 and 3. In this data set stimulation protocol and BMI had no significant association with CP or LB rates and are not reported separately. To allow for the other factors, which affect pregnancy rates, logistic regression analysis was performed on the results for women having their

Figure 2 Clinical pregnancy (CP) and live birth (LB) rates with respect to number of oocytes collected by age groups (results with under 2 and over 19 oocytes have been grouped because of small numbers).

Figure 3 Outcome with respect to stage of transfer groups (results with over 19 oocytes for the blastocyst group and over 13 oocytes for the cleavage group have been grouped because of small numbers).

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embryos transferred, number of previous ART treatments and a previous birth from ART (Baker et al., 2000), ovarian stimulation by agonist or antagonist protocols and BMI of the women. To facilitate statistical analysis, data tables were constructed, of numbers of CP and LB by oocyte numbers in different subgroups, and these results were plotted on graphs with exact 95% confidence limits for proportions. In order to have sufficient numbers for tabulation and graphing oocyte numbers were grouped as indicated in the figure and table legends. Age was grouped as: under 35, 35 – 39 and over 40. As the study includes some women who have had previous treatments, and some of the women had several cycles within the study period, regression modelling was done in two ways. First, the 3600 patients who had their first oocyte collection with an embryo transfer within the reference period were analysed by logistic regression analysis, including the explanatory variables for CP and LB rates. With age as a continuous variable with no effect up to age 35 (ages below 35 were recoded to 35), fertilization rate (proportion of oocytes collected which fertilized normally), blastocyst (Day 5 or 6) or cleavage stage transfer (Day 2 – 4), the number of embryos transferred (one or two), and the number of oocytes collected, log transformed because of skewed distribution. The second analysis involved all the 7697 oocyte collections with fresh embryo transfers. We used generalized estimating equations (GEE) with exchangeable correlation structure and sandwich estimation of standard errors to allow for the within subject correlation in outcomes for repeated treatments, using the above covariates and previous birth from ART and oocyte collection number log transformed because of skewness. Parsimonious models with only those factors usually

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Briggs et al.

Table II Logistic regression models for clinical pregnancy and live birth rates following embryo transfers after the woman’s first oocyte collection in 3600 patients.* Parameter

Estimate

SE

t

P

OR

95% CL

............................................................................................................................................................................................. Clinical pregnancy 5.066

0.638

7.94

,0.001

20.189

0.016

211.58

,0.001

Constant Age

0.83

0.80– 0.85 1.19– 1.80

Blastocyst

0.383

0.105

3.65

,0.001

1.47

Fertilization rate

0.004

0.002

2.42

0.016

1.00

1.00– 1.01

Two embryo transfer

0.281

0.131

2.14

0.032

1.33

1.02– 1.71

Log oocyte number

0.366

0.166

2.20

0.028

1.44

1.04– 2.00

6.094

0.726

8.39

,0.001

20.229

0.019

212.15

,0.001

0.80

0.77– 0.83

0.443

0.114

3.88

,0.001

1.56

1.25– 1.95

Constant Age Blastocyst Fertilization rate

0.006

0.002

3.15

0.002

1.01

1.00– 1.01

Two embryo transfer

0.209

0.143

1.46

0.144

1.23

0.93– 1.63

Log oocyte number

0.375

0.178

2.11

0.034

1.46

1.03– 2.06

*Final models including all factors independently significant for at least one outcome. Age was included as a continuous variable from 35 years (ages ,35 were recoded to 35). Fertilization rate was percentage of oocytes with normal fertilization and oocyte number was log transformed. Binary factors were: blastocyst, transfer of Day 5 or 6 embryos versus earlier stage embryos and two embryo transfer, double versus single embryo transfer.

Table III Clinical pregnancy (CP) and live birth (LB) outcome tabulated by oocyte number, age group and blastocyst versus cleavage stage fresh embryo transfer following the first oocyte collection in 3600 patients. Age group 39

...................................................

...................................................

Total

Total

CP

CP%

LB

LB%

CP

CP%

LB

LB%

............................................................................................................................................................................................. Cleavage stage transfers 1– 3

89

33

37

26

29

106

28

26

21

20

104

8

8

5

5

4– 5

114

33

29

27

24

106

28

26

18

17

88

10

11

6

7

6– 7

71

22

31

21

30

64

20

31

12

19

48

4

8

2

4

8– 9

58

20

34

18

31

42

10

24

6

14

17

2

12

1

6

10–12

38

11

29

8

21

33

3

9

3

9

15

3

20

1

7

13–16

18

8

44

7

39

12

4

33

3

25

6

0

0

0

0

17–43

17

5

29

3

18

8

4

50

2

25

3

0

0

0

0

Blastocyst transfer 1– 3

14

6

43

5

36

13

3

23

2

15

13

0

0

0

0

4– 5

75

39

52

31

41

84

25

30

18

21

51

11

22

9

18

6– 7

157

69

44

61

39

129

52

40

42

33

60

14

23

10

17

8– 9

164

64

39

55

34

139

51

37

45

32

40

5

13

4

10

10–12

291

118

41

103

35

186

62

33

47

25

79

14

18

10

13

13–16

302

141

47

122

40

164

77

47

60

37

52

7

13

5

10

17–43

335

163

49

141

42

153

53

35

44

29

42

10

24

6

14

first oocyte collection. There was no evidence of a decline in the CP or LB rates with oocyte number, there being weakly significant (P , 0.05) upward trends with log oocyte number (Table II). There were no significant interactions between age and oocyte number or blastocyst transfer and oocyte number on the outcomes. Table III shows the effects of age

group and blastocyst transfer on CP and LB. The upward trend CP and LB with oocyte number is only clear in the 30- to 34-year age group. When all 7697 cycles were analysed by GEE, oocyte collection number and previous ART birth were also significantly related to pregnancy rates and there was a more significant increase in both CP and

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Live birth

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Pregnancy rate increases with oocyte numbers

Table IV Binomial generalized estimating equation analysis of clinical pregnancy and live birth rates.* Parameter

Estimate

SE

t

P

OR

95% CL

............................................................................................................................................................................................. Clinical pregnancy 4.161

0.429

9.69

,0.001

Age

20.165

0.011

15.68

,0.001

0.85

0.83–0.87

Log treatment number

Constant

0.125

8.85

,0.001

0.33

0.26–0.42

0.503

0.085

5.93

,0.001

1.65

1.40–1.95

Fertilization rate

0.005

0.001

3.62

,0.001

1.00

1.00–1.01

Blastocyst

0.313

0.071

4.40

,0.001

1.37

1.19–1.57

Two embryo transfer

0.313

0.072

4.33

,0.001

1.37

1.19–1.58

Log oocyte number

0.390

0.118

3.31

0.001

1.48

1.17–1.86

5.402

0.497

10.87

,0.001

Age

20.211

0.013

16.81

,0.001

0.81

0.79–0.83

Log treatment number

21.147

0.137

8.37

,0.001

0.32

0.24–0.42

Previous ART birth

0.519

0.093

5.60

,0.001

1.68

1.40–2.01

Fertilization rate

0.006

0.001

4.06

,0.001

1.01

1.00–1.01

Blastocyst

0.350

0.080

4.39

,0.001

1.42

1.22–1.66

Two embryo transfer

0.269

0.078

3.43

0.001

1.31

1.12–1.53

Log oocyte number

0.443

0.130

3.41

0.001

1.56

1.21–2.00

Live birth Constant

*Final models including all factors independently significant. Age was included as a continuous variable from 35 years (ages ,35 were recoded to 35). Treatment number and oocyte number were included log transformed. Fertilization rate was percentage of oocytes with normal fertilization. Binary factors were: blastocyst, transfer of Day 5 or 6 embryos versus earlier stage embryos and two embryo transfer, double versus single embryo transfer.

Table V The changes in oocyte immaturity (in ICSI cycles), pregnancy (CP) and birth rates (LB), average numbers of embryos frozen and percentage of treatments with embryo cryopreservation following fresh embryo transfers, calculated potential extra births from transfer of the cryopreserved embryos and percentage with freeze all embryos to prevent OHSS with the numbers of oocytes grouped into seven bands. Oocyte number

Treatments

ICSI

% immature oocytes

% CP

% LB

Average embryos frozen

% with embryos frozen

Potential births from FET

% freeze all for OHHS

............................................................................................................................................................................................. 1– 3

754

597

12.7

18.7

13.1

0.2

16.2

25

0

4– 5

1047

784

18.3

24.0

17.3

0.4

32.8

83

0

6– 7

1157

890

18.3

28.3

22.6

0.6

39.2

126

0

8– 9

1070

851

20.8

27.2

22.5

0.8

45.4

161

0

10–12

1369

1046

20.5

29.9

23.4

1.1

53.0

281

0.4

13–16

1158

888

21.3

34.6

28.3

1.7

62.3

351

0.3

17–43

1142

880

21.8

37.7

31.3

2.7

74.4

552

3.1

LB with log oocyte number (Table IV). There were no significant interactions between age and oocyte number or blastocyst transfer and oocyte number on the outcomes. We also examined the relationship between oocyte immaturity and number of oocytes collected in those patients who had ICSI and confirmed a significant upward trend (P , 0.001) to 22% in those with .16 oocytes collected (Table V). The proportion of women with embryos cryopreserved and the average numbers of embryos frozen increased markedly with the

number of oocytes collected. Patients aged ,45 using their own frozen embryos in the same time (August 2010 and July 2012) had 1658 clinical pregnancies (31% per transfer) and 1299 births (24% per transfer). The birth rate per thawed embryo was 18% (1299/7257). These figures were used to calculate the potential number of extra births from use of frozen embryos in Table V. The 44 patients who had embryo cryopreservation and no fresh embryo transfer in the time of the study had 10– 53, mean 26 oocytes collected and 257 mean 5.8 embryos frozen. While these ‘freeze all’

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21.109

Previous ART birth

86 treatments were only 0.6% of the total they were 1.2% of those with 10 or more oocytes collected (Table V) and the frequency of freeze all increased with the number of oocytes collected (.16, 2.6%, .20, 3.0%, .24 6.7%, .28 11.7%).

Briggs et al.

We did not investigate the cause of subfertility, as all patients were already undergoing IVF or ICSI and the reason for treatment is not relevant with respect to this study.

Conclusion Discussion

Authors’ roles R.B. helped design the study, tabulated and analysed all the data, helped to write manuscript. C.M. and V.M. helped design the study and facilitated the data extraction. G.B. carried out the statistical analysis. G.K. designed the study and helped write the manuscript.

Funding No funding was required or obtained.

Conflict of interest There is no conflict of interest, except that G.K., V.M. and C.M. are shareholders in Monash IVF Pty Ltd.

References Alama P, Bellver J, Vidal C, Giles J. GnRH analogues in the prevention of ovarian hyperstimulation syndrome. Int J Endocrinol Metab 2013; 11:107 – 116. Baker HWG, Saunders DM, Tyler JPP, Lamont B, Burge D, Fiske L, Oke K, Johnston WIH. Difficulties associated with comparison of results between ART clinics: an attempt to standardize reporting methods. Reprod Technol 2000;10:103 – 111. Ji J, Liu Y, Tong XH, Luo L, Ma J, Chen Z. The optimum number of oocytes in IVF treatment: an analysis of 2455 cycles in China. Hum Reprod 2013; 28:2728 – 2734. Jones HW Jr, Jones GS, Andrews MC, Acosta A, Bundren C, Garcia J, Sandow B, Veeck L, Wilkes C, Witmyer J et al. The program for in vitro fertilization at Norfolk. Fertil Steril 1982;38:14 –21. Kasum M, Danolic D, Oreskovic S, Jezek D, Beketic-Oreskovic L, Pekez M. Thrombosis following ovarian hyperstimulation syndrome. Gynecol Endocrinol 2014;11:1 –5 (epub ahead of print). Kok JD, Looman CW, Weima SM, teVelde ER. A high number of oocytes obtained after ovarian hyperstimulation for in vitro fertilization or intracytoplasmic sperm injection is not associated with decreased pregnancy outcome. Fertil Steril 2006;85:918– 924. Lopata A, Johnston IW, Hoult IJ, Speirs AI. Pregnancy following intrauterine implantation of an embryo obtained by in vitro fertilization of a preovulatory egg. Fertil Steril 1980;33:117 –120.

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Our findings suggest that pregnancy and live birth rates do not decrease with increasing numbers of eggs collected, so as long as there is not OHSS, you cannot collect too many oocytes. OHSS is the most common serious complication of COH, with potentially fatal complications of venous thrombo-embolism, or arterial thrombosis (usually cerebral) (Kasum et al., 2014). The type of OHSS associated with multiple follicles and the collection of many oocytes is referred to as ‘early phase’ and usually occurs within 9 days of hCG administration. With the use of the GnRH antagonist protocols for COH, and the option of using a GnRH agonist for final oocyte maturation, the use of hCG can be omitted, and the risk of significant OHSS is virtually eliminated (Alama et al., 2013). This therefore reduces the risk of OHSS associated with collecting many oocytes. The graphs indicate a curvilinear relationship with steep rise in pregnancy rates with 1– 3 oocytes collected and a tendency to flatten after 15 oocytes. Regression modelling suggests a continued logarithmic increase with oocyte number, particularly when all cycles were analysed, but this was less significant when only ‘first cycles’ were considered. As the data become sparse above 15 oocytes, we could not demonstrate a significant increase in pregnancy rates above this number because the lack of statistical power means that there is great uncertainty. Larger studies would be required to answer the question whether there is a plateau, or rates continue to increase. The results do refute the proposition of a decline in pregnancy and live birth rates from fresh transfers after collection of large numbers of oocytes. Kok and colleagues made the point that although the pregnancy rate is not impaired as oocytes numbers increase, the proportion of immature oocytes increased (Kok et al., 2006). We show a similar but less steep rise in immature oocytes. Despite this, the proportion of women having embryos cryopreserved, the average number of embryos frozen and calculated potential births from these increase dramatically with higher numbers of oocytes collected. Monash IVF transfer policy over this period has been that women, with four or more oocytes fertilized, are advised to undergo a blastocyst transfer whereas with three or less transfer at the cleavage stage is recommended. This is why there are no blastocyst transfers for women who only had one oocyte collected. Following this policy, women who have a large number of oocytes are unlikely to undergo a cleavage stage transfer and that is why there are no data for cleavage stage transfer when .20 oocytes were collected. For those cycles where a large number of oocytes were associated with significant clinical OHSS, no embryo transfer occurred for safety reasons. As a result, these cycles were excluded from analysis even though many would have achieved a pregnancy, as a result of subsequent frozen embryo transfer (Maheshwari and Bhattacharya, 2013). Often when there was concern about OHSS, an agonist trigger (nafarelin acetate, two sniffs) was used to achieve follicular maturation. Because of the negative effect on the endometrium, these cycles became ‘freeze all’ cycles, where no fresh embryo transfer was undertaken.

The results of this study suggest that you cannot collect too many oocytes as both clinical pregnancy and live birth rates continue to increase as number of oocytes collected increases. Obtaining more embryos from one oocyte collection also increases the chance of cryopreservation and subsequent frozen embryo transfers and reduces the need for repeated ovarian stimulation and oocyte collections. The patient has a decreased risk of complications and a better chance of pregnancy. However, OHSS continues to be the commonest serious complication of COH and so the risk of it occurring must be considered when stimulation doses are decided.

Pregnancy rate increases with oocyte numbers

Maheshwari A, Bhattacharya S. Elective frozen replacement cycles for all: ready for prime time? Hum Reprod 2013;28:6 – 9. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet 1978;2:366. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod 2011;26:1768 – 1774.

87 Trounson AO, Leeton JF, Wood C, Webb J, Wood J. Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science 1981;212:681 – 682. van der Gaast MH, Eijkemans MJ, van der NET JB, de Boer EJ, Burger CW, van Leeuwen FE, Fauser BC, Macklon NS et al. Optimum number of oocytes for a successful first IVF treatment cycle. Reprod Biomed Online 2006;13:476 – 480.

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Can you ever collect too many oocytes?

Does the chance of pregnancy keep improving with increasing number of oocytes, or can you collect too many?...
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