Follicle Aspirating is an Effective Remedy When Multi-follicles Developed in Donor-sperm Timing-Artificial Insemination

  

    
Characteristics
    
Group A

      N=7
    
GroupB

      N=184
    
Group C

      N=835
    
Group D

      N=309
    
P value for B&D
    
P value for C&D
    
P value

      For

      B&C
  
  

    
Baseline for    maternity
  
  

    
Age (year)
    
36.43±1.90
    
36.73±1.77
    
36.97±2.04
    
37.17±2.11
    
0.130
    
0.140
    
0.138
  
  

    
bFSH (mIU/ml)
    
6.79±1.12
    
6.80±2.25
    
6.77±4.02
    
6.68±2.04
    
0.552
    
0.510
    
0.607
  
  

    
bLH (mIU/ml)
    
4.59±1.03
    
4.16±1.69
    
4.20±2.44
    
4.31±2.33
    
0.397
    
0.482
    
0.828
  
  

    
Endometrial thickness (mm) in the first AI
    
10.19±1.22
    
11.16±1.97
    
10.53±1.95
    
10.94±2.00
    
0.228
    
0.668
    
0.386
  
  

    
Sperm parameter
  
  

    
Concentrition1
    
59.57±8.14
    
62.13±16.65
    
61.07±15.31
    
60.99±14.88
    
0.433
    
0.937
    
0.404
  
  

    
PR1
    
49.29±3.40
    
52.51±7.70
    
50.89±7.50
    
51.50±7.38
    
0.149
    
0.217
    
0.008
  
  

    
Concentrition2
    
82.14±20.86
    
66.27±20.45
    
64.60±18.41
    
65.70±18.92
    
0.187
    
0.375
    
0.278
  
  

    
PR2
    
51.71±10.01
    
52.17±8.40
    
50.34±6.75
    
50.73±7.02
    
0.053
    
0.383
    
0.006
  
  

    
Primary cycle    outcomes
  
  

    
CPR
    
---(2)
    
26.6%(49)
    
21.1%(176)
    
19.7%(61)
    
0.076
    
0.595
    
0.107
  
  

    
MPR
    
---(1)
    
8.2%(4)
    
0%
    
3.3%(2)
    
0.404
    
0.063
    
0.002
  
  

    
Twins
    
---(1)
    
8.2%(4)
    
0%
    
3.3%(2)
    
0.404
    
0.063
    
0.002
  
  

    
H-MPR
    
0
    
0%
    
0%
    
0%
    
-----
    
-------
    
----
  

Table 3: The comparison of basic characteristics and outcomes of Groups for the age 35 or older.

Discussion

In our study, we verified the effectiveness of excess follicle aspirating as a remedy for MFD. Excessive follicle aspirating achieved a comparable clinical pregnancy rate with MFD-patients without aspirating. When two follicles reserved from excessive follicle aspirating, the multi-pregnancy rate was similar while high order pregnancy largely decreased. Multi-pregnancy rate increased significantly with the increased follicle number in patients under 35 years old, and turned to be similar when the age reached 35 or older.

When we talked about MDF, there came a question that what were the detail diameter of dominate follicles? Researchers hold a view much alike. A similar research in China chosen average diameter of 14mm as dominate follicle [17]. In IntraUterine Insemination (IUI) cycles, Teramoto reported the follicles (from 12-14mm) on trigger day were associated with multi-pregnancy rate [18]. Study from Scalici regarded the number of follicle (from 12-15mm) as an independent and significant risk of multi-pregnancy rate [19]. Identically, most studies defined a mature follicle as the average diameter of over 14mm [20,21]. In our centre, we followed the mainstream idea and viewed the average diameter of over 14mm as dominate follicles. Follicles of over 12mm were taken into consideration to aspirate out when taking excessive follicle aspirating to avoid high order multi-pregnancy.

Many studies attributed multi-pregnancy much too ovarian induction [22-24]. Multiple pregnancies are also the major and the most serious iatrogenic complication associated with ovarian stimulation, which in return limited the use of this protocol. Studies confirmed that perinatal mortality rate were increased by 4 and 6 times in gemellary and triple pregnancy, respectively [25,26]. Besides, it was acknowledged that multi-pregnancy increased perinatal complications such as gestational diabetes mellitus, hypertensive disorder complicating pregnancy, premature delivery and so on, those adverse events greatly burdened patients and society [27,18]. Correlation has been reported between follicle number and multi-pregnancy rate in many researches [6,16]. Studies before also suggested the follicle number was predictive for multi-pregnancy [16,29]. In our center, almost triple or greater pregnancies were attributed to multi-follicle development in the last 10 years. In fact, it was not easy to totally avoid multi-follicle development. Researchers worked a lot to pursue a higher clinical pregnancy rate and a lower multi-pregnancy rate. It is basically essential for physicians to take measures to avoid high order pregnancy rate, ensure clinical pregnancy rate and reduce cycle cancellation simultaneously when multi-follicles developed. To our study, follicle aspirating makes the best of both worlds.

In this study, when taking follicle aspirating, MFD patients reached a better clinical pregnancy of 30.7% compared with MFD-patients without aspirating though there was no statistically significance. It was not clear why there was a rising tendency in clinical pregnancy after taking follicle aspirating. We speculated that it may be related to more accurately operating time nearly to ovulation in follicle aspirating group. As commonly reported, MFD patients achieved a better clinical pregnancy rate as two dominate follicle group under the age of 35. When patients reached the age of 35 or older, clinical pregnancy was not improved by the increased follicles. The data suggested the influence of MFD was largely related to maternal age. We didn’t pay much attention to the difference of sperm for the reason that all the sperms were ensured qualified to artificial insemination by sperm bank. A study from a 21 years experience also suggested the clinical pregnancy rate has little to do with sperm count in artificial insemination [30].

It was reported that twin pregnancy rate was of 15-20% and high order pregnancy rate was of about 5% in artificial insemination [31,32], which were close to data in our center. In our research, excess follicle aspirating reduced high order pregnancy rate from 4.4% to nearly 0, instead of a higher twin pregnancy rate of 21.4%. Due to the small sample size, no high order pregnancy occurred in aspirating group. To further verified the effectiveness of excessive follicle aspirating in reducing high order pregnancy rate, we tried to instead follicle aspirating group by two dominate follicles group as they had the same number of dominate follicles reserved. A further comparison conducted between MFD without aspirating and two dominate follicles group has demonstrated the multi-pregnancy rate and high order pregnancy rate were largely declined when follicle number decreased to two in patients under the age of 35. The difference was not found when patients’ age reached 35 or older. The results from comparison stratified by age in our study suggested age was a vital factor to cycle success and multi-pregnancy rate, as found by Immediata in 2020 [30]. Thus, by the date above, we considered follicle aspirating largely decreased the risk of high order pregnancy and fetal reduction subsequently through reducing the number of follicles.

A fact should not be ignored was the higher twin pregnancy rate after excess follicle aspirating. Although, with the progress of fetal medicine and obstetrics, twins were more acceptable by obstetricians and families. It was also necessary to avert gemellary pregnancy since there were still high preterm rate and complications in fetal and pregnant woman compared with singleton pregnancy. Recent years, a growing number of researchers explored the outcomes of fetal reductions from twins to singletons. The studies showed a fetal reduction improved the perinatal outcomes of dichorionic diamniotic twins [33]. Hence, how many follicles are properly to be reserved? ASRM suggested no more than 2 mature follicles was appropriate for women with polycystic ovarian syndrome and hypothalamic an ovulation, while more than 2 mature follicles for women with unexplained or age-related infertility [16]. Early research attached to taking follicle aspirating with 3 dominate follicle left [15], in their study, there were 3 triple-pregnancies and 2 cases of 4-5 fetal pregnancies which finally conducted fetal reduction. In our study, from the perspective of making best use of follicles and patient’s strong willingness, two follicles were reserved. An analyze of one and two dominate follicles development in ovarian stimulation cycles in our study showed that they got quite similar clinical pregnancy rate, while a significant higher twin pregnancy rate in two dominate follicles group (7.5% vs 0.4%). Comparison stratified by age showed that the difference in multi-pregnancy rate was distinct in the age under 35. A study from China got quite similar results [17]. The increased one follicle contributed much to multi-pregnancy rather than clinical pregnancy in young women. From the perspective of singleton pregnancy, one dominate follicle may be more suitable for donor artificial insemination to our study. When there was a need of excess follicles aspirating, it may be safer to keep one dominate follicle left, especially in patients under the age of 35. For patients older than 35, as there were no high order pregnancy occurred and gemellary pregnancy rate was rather low in our study, we suggested whether there was a need to take follicle aspirating depended on individual conditions.

Limitations

Failure to divide the reason of ovarian stimulation and the insufficient samples in aspirating group were the major limitations of our study. With the data increasing, it is possible to design a subgroup analysis basing on subjects such as treatment cycle, menstrual cycle in later research. For the high rate of twin pregnancy with two dominate left, it is worth to explore one dominate follicle reserved when taking follicle aspirating.

Conclusion

In conclusion, in the age of lower than 35, excess follicle aspirating with two dominate follicles reserved ensured a considerable clinical pregnancy rate and a rather low high order multi-pregnancy rate in AID. From the perspective of singleton, it was feasible to keep one dominate reserved. Despite the availability of follicle aspirating, avoiding multi-follicle development remains a top priority for doctors.

Acknowledgements

This work was funded by Medical research foundation of Guangdong Province in China (NO.B2020045).

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