ORIGINAL ARTICLE |
https://doi.org/10.5005/jp-journals-10009-1980 |
Evaluation of Baseline Scoring System in In Vitro Fertilization Cycles
1Department of Reproductive Medicine, Dr. Nagori’s Institute for Infertility and Ultrasound, Ahmedabad, Gujarat, India
2Department of Ultrasound, Dr. Nagori’s Institute for Infertility and Ultrasound, Ahmedabad, Gujarat, India
3Dr. Nagori’s Institute for Infertility and Ultrasound, Ahmedabad, Gujarat, India
Corresponding Author: Mohini Sethi, Department of Reproductive Medicine, Dr. Nagori’s Institute for Infertility and Ultrasound, Ahmedabad, Gujarat, India, Phone: +91 9815080221, e-mail: mohinisethi1995@gmail.com
Received on: 09 June 2023; Accepted on: 04 August 2023; Published on: 29 September 2023
ABSTRACT
Aims and Background: In vitro fertilization (IVF) is a method of assisted reproductive technology (ART) in which the ovary is stimulated using gonadotropins. The purpose of this study is to decide the optimum gonadotropin dose that would adequately stimulate the ovaries without leading to hyperstimulation syndrome or cycle cancelation due to understimulation. In this study along with the age and body mass index (BMI) of the patient, various ultrasound parameters have been used for tailoring the appropriate gonadotropin dose for every individual based on a baseline scoring system.
Materials and methods: It was a retrospective study of 61 patients. All consenting patients between the age of 22 and 40 years and BMI between 18 and 34 who were taken for IVF/intracytoplasmic sperm injection (ICSI) cycles by virtue of tubal factor infertility, male factor infertility, dysovulatory infertility (including polycystic ovarian syndrome (PCOS)] and unexplained infertility were included in the study. The baseline scoring system parameters were assessed in relation to the dose of recombinant follicle- stimulating hormone (rFSH) given, luteinizing hormone (LH) supplementation dose added at different times in the cycle, the need to change the dose of gonadotropins, various size ranges of follicles on the day of trigger and their ultimate relation with M2 oocytes retrieved.
Results: Only one patient required a change of dose of gonadotropins. There was no ovarian hyperstimulation or cycle cancelation. There was a significantly higher number of M2 oocytes retrieved in patients where LH supplementation was not done, irrespective of dose or day of addition of LH. There was also a strong positive correlation between follicles 10–15 mm on the day of trigger and the number of prophase oocytes retrieved.
Conclusion: The baseline scoring system is an accurate and reliable method for deciding the dose of gonadotropins in IVF stimulation protocols. The addition of human menopausal gonadotropin (HMG) to rFSH anytime in the cycle at any dose does not show improvement in the number of M2 oocytes retrieved and its use should be judicial. Retrieval of follicles <15 mm may not result in M2 oocytes and so may not be beneficial.
Clinical significance: To individualize the stimulation dose in IVF cycles, other than age and BMI, other ultrasound parameters like antral follicle count (AFC), ovarian volume, and ovarian stromal Doppler studies should be used. This can avoid hyperresponse and cycle cancelation.
How to cite this article: Sethi M, Panchal S, Nagori C. Evaluation of Baseline Scoring System in In Vitro Fertilization Cycles. Donald School J Ultrasound Obstet Gynecol 2023;17(3):184–196.
Source of support: Nil
Conflict of interest: None
Keywords: Assisted reproductive technology cycles, Controlled ovarian stimulation, Ultrasound score
INTRODUCTION
In vitro fertilization (IVF) is a method of assisted reproductive technology (ART) in which the ovary is stimulated using gonadotropins. This is followed by ovum pickup and fertilization of the ova by fresh or frozen ejaculation from the male partner. Embryos are formed in vitro and then transferred to the uterus of the female partner either in the same cycle or a frozen transfer is performed after preparing the endometrium in subsequent cycles. IVF cycles are the mainstay of treatment in severe male factor infertility and tubal factor infertility. For the assisted reproductive cycle to be successful, it is essential that for every patient the stimulation protocol is tailor-made and individualized.1 The purpose of this study is to decide the optimum gonadotropin dose that would adequately stimulate the ovaries without leading to hyperstimulation syndrome or cycle cancelation due to understimulation. Ovarian hyperstimulation syndrome (OHSS) is the most dreaded complication because it not only has high morbidity and patient takes a long to recover, but also may lead to mortality.1 In this study along with the age and BMI of the patient, various ultrasound parameters have been used for tailoring the appropriate gonadotropin dose for every individual based on a baseline scoring system. It evaluates the efficacy and safety of this system in selecting stimulation protocols for IVF cycles.
MATERIALS AND METHODS
This is a retrospective study of 61 patients recruited from November 2022 to April 2023.
This study was approved by the Institutional Ethical Committee. After patient selection and exclusion as per the exclusion criteria, patients were educated about the study, and informed consent for their participation was taken. They were explained about the advantages and disadvantages of the existing standard protocols and the study protocols.
Prestudy Work-up
Inclusion Criteria
All consenting patients between the age of 22 and 40 years and BMI between 18 and 34 who were taken for IVF/intracytoplasmic sperm injection (ICSI) cycles by virtue of tubal factor infertility, male factor infertility, dysovulatory infertility (including PCOS) and unexplained infertility were included in the study.
Exclusion Criteria
All patients with inapproachable ovaries in terms of oocyte retrieval were excluded from the study.
These include patients with ovarian endometrioma of >4 cm, dermoid cyst of >4 cm, hemorrhagic cyst of >4 cm, large hydrosalpinx, severe pelvic inflammatory disease (PID), large fibroids, ovaries that are adherent to the uterus posteriorly, and patients with a history of vaginoplasty.
Technique
After a detailed clinical history and examination including the BMI, a baseline scan was done for all the patients on day 2 or day 3 of their menstrual cycle. The scan was done by Voluson E10 Expert (GE Healthcare), with a transvaginal volume probe real-time intracavitary 5–9, having a frequency range of 5–9 MHz. The assessment was done using B mode ultrasound, color Doppler, power Doppler, three-dimensional (3D), and whenever required, 3D power Doppler.
The position of the uterus, any uterine or cervical abnormalities and endometrial thickness were assessed. Both the ovaries were located and the volume of each ovary was calculated on B mode by measuring the three longest orthogonal diameters as X × Y × Z × 0.523 which is also automatically calculated by the scanner software (Fig. 1). This can also be measured more accurately using the 3D software called “virtual organ computer-aided analysis.” This software rotates the 3D acquired volume for 180° and during that rotation, it records several diameters or measurements of the ovary. This is done as the operator outlines the periphery of the ovary six times at 30° rotation. With the help of these several diameters, the computer reconstructs the exact shape and dimensions of the ovary and calculates the exact volume.
Fig. 1: B mode ultrasound showing longitudinal and transverse sections of ovary showing measurement of three orthogonal diameters to calculate the ovarian volume
Using the eyeballing technique and scrolling across the ovary, the number of antral follicles in each ovary was derived. In case there were multiple antral follicles (>12), another volume analysis software called sono-automated volume calculation (AVC) was used (Fig. 2). This software is based on inversion mode rendering. When inversion mode is used, all fluid-filled structures appear as solid structures. This helps to identify very small fluid-filled spaces also clearly. Sono-AVC further color codes each follicle. These color-coded follicles are seen as colored balls of different shapes. Since the software works on artificial intelligence that identifies all fluid-filled structures as follicles, large vessels, or fluid-filled areas in close vicinity to the ovary, even be identified as follicles. It is also possible that the follicle size may be erroneously calculated as larger or smaller. All these errors are corrected by postprocessing. Once the operator is satisfied that all the follicles are correctly counted, then the report sheet is opened. It displays seven columns of each ovary. The first column denotes the number of antral follicles identified by the software. The second column d(V) is the volume released diameter, the following three columns are the x, y, and z axis diameters of the follicles, following that is the mean diameter and the last column is the follicular volume, respectively.
Fig. 2: Sono-AVC reporting
Following this, the color Doppler was switched on. The ovarian stromal flow was assessed with the pulse repetition frequency of the color Doppler set at 0.3 kHz and the wall filter set at the lowest. The plane with the hilar vessels was identified. The probe was moved away from that plane and the brightest stromal vessel was assessed by spectral pulsed wave Doppler. These vessels should not be hilar or perifollicular vessels. Keeping the sample volume of 2 mm and after angle correction, the resistance index and peak systolic velocity (PSV) of the stromal vessels of both ovaries were documented (Fig. 3).
Fig. 3: Spectral Doppler of the ovarian stromal flow
Table 1 depicts the scoring system and Table 2 shows the dose of gonadotropin used as per the score derived.
| Score | 1 | 2 | 3 | 4 | 5 |
|---|---|---|---|---|---|
| Age | >40 | 35.1–40 | 30.1–35 | 25.1–30 | <25 |
| BMI | >30 | 30–28.1 | 28–25.1 | 25–22.1 | <22 |
| AFC | <5 | 5–10 | 11–15 | 16–20 | >20 |
| Ovarian volume | <3 | 3.1–5 | 5.1–7 | 7.1–10 | >10 |
| Stromal RI | >0.75 | 0.75–0.66 | 0.65–0.56 | 0.55–0.45 | <0.45 |
| Stromal PSV | <3 | 3.1–5 | 5.1–7 | 7.1–10 | >10 |
| Score | IVF-FET |
|---|---|
| ≥25 | 150 IU |
| 21–25 | 225 IU |
| 16–20 | 300 IU |
| 11–15 | 375 IU |
| 6–10 | 450 IU |
In the scoring system, the average of both ovaries was taken for parameters like ovarian volume, stromal resistance index (RI), and stromal PSV. Antral follicle count (AFC) was added for both ovaries.
Recombinant follicle-stimulating hormone was used for ovulation induction from day 2 of the cycle. Fixed antagonist protocol using injection (Inj.) Cetrorelix 0.25 mg from day 6 was adopted.
Every patient was scanned on day 5/6 of the stimulation to assess if the follicle was growing.
To calculate the size of multiple follicles, the application of sono-AVC was used which has been described earlier.
An increase in the size of the follicles in either ovary or an increase in endometrial thickness was considered an adequate response, the same dose was continued till at least three follicles of >16 mm were obtained. Once this size was reached, the perifollicular flows were assessed using a color Doppler and pulse wave Doppler. If at least three follicles showed vascularity covering three-fourths of the circumference and at least one vessel showing RI < 0.48 and PSV > 10 cm/seconds, the follicles were considered mature follicles, and the ovulation trigger was given. Till then the stimulation is continued. The dual trigger, which comprises gonadotropin-releasing hormone (GnRH) agonist (Inj. Leuprolide 2 mg) and Inj. urinary human chorionic gonadotrophin (uHCG) (1500 IU) was given after the development of mature follicles. Oocyte retrieval was performed approximately 34–36 hours after the trigger.
The expected number of follicles that would give fertilizable oocytes was considered to be >0.9 cc and was noted from the report of sono-AVC.
If on day 5/6 when the scan was done, no follicular growth or endometrial growth was documented on ultrasound, the response was considered to be inadequate when on days 5 or 6 of stimulation showed no dominant follicle in either ovary or no increase in the endometrial thickness (Flowchart 1). The patient was scanned after 2 days. If the inadequate response persisted, the cycle would be canceled, but this was not noted in any patient.
Flowchart 1: Sono-AVC reporting
If on the day of the trigger, the largest diameter of either ovary was >10 cm or the total volume of both ovaries >180 cc, OHSS would be predicted and the trigger differed. In such cases, only an agonist trigger was used. However, OHSS was not suspected or diagnosed in any patient.
The patient was also educated about symptoms of OHSS like pain and heaviness and was telephonically followed up for the same on days 4 and 8 postoocyte pick up.
Oocyte retrieval was succeeded by denuding the achieved oocytes and grading the oocytes according to their stage of the cycle as metaphase II (mature oocytes), metaphase I, and prophase I. ICSI has performed on metaphase II oocytes and a number of zygotes were documented after 16–18 hours, which were cultured in one-step culture media. A number of embryos were documented on days 3 and 5 and cryopreservation was done.
Accuracy of the baseline score and stimulation protocol was assessed by the incidence of ovarian hyperstimulation, cycle cancelation rate due to poor response, number and type of oocytes obtained, and number of embryos formed on days 3 and 5.
RESULTS
Analysis of scores among patients was tabulated (Table 3). OHSS was not suspected or diagnosed in any patient in terms of large ovarian size/volume on the day of trigger or any patient having complaints postoocyte retrieval. There was no patient with the inadequate response and therefore there was no cycle cancelation.
| Baseline score category | Frequency | Percentage |
|---|---|---|
| 10–20 | 36 | 59.0% |
| >20 | 25 | 41.0% |
The results were categorized under the following headings:
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Percentage of patients that underwent a change in dose of recombinant follicle stimulating hormone (rFSH)–none, once or twice (Table 4 and Fig. 4). There was no patient in which the dose had to be changed twice. This proves the accuracy of the baseline scoring system.
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A number of patients in which human menopausal gonadotropin (HMG) had to be added after seeing the response on days 5/6 (Table 5 and Fig. 5).
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Association between age and M2 oocytes retrieved (Table 6 and Fig. 6)
| Dose change | Frequency | Percentage |
|---|---|---|
| None | 60 | 98.4% |
| Once | 1 | 1.6% |
Fig. 4: Percentage of patients that underwent a change in dose of rFSH–none, once or twice
| HMG added (day 5/6) | Frequency | Percentage |
|---|---|---|
| Yes | 11 | 18.0% |
| No | 50 | 82.0% |
Fig. 5: Number of patients to which HMG had to be added after seeing the response on day 5/6
| Correlation | Spearman correlation coefficient | p-value |
|---|---|---|
| M2 oocytes retrieved vs age (years) | −0.3 | 0.007 |
Fig. 6: Association between age and M2 oocytes retrieved
A moderate negative correlation was seen between M2 oocytes retrieved and age (years) and this correlation was statistically significant (ρ = −0.34, p = 0.007).
For every 1 unit increase in age (years), the M2 oocytes retrieved decreases by 0.35 units.
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Association between BMI and M2 oocytes retrieved (Table 7 and Fig.7).
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Association between AFC and M2 oocytes retrieved (Table 8 and Fig. 8).
| M2 oocytes retrieved | BMI | Kruskal–Wallis test | ||||
|---|---|---|---|---|---|---|
| 18.5–22.9 Kg/m2 | 23.0–24.9 Kg/m2 | 25.0–29.9 Kg/m2 | 30.0–34.9 Kg/m2 | χ2 | p-value | |
| Mean (standard deviation) | 5.58 (3.88) | 5.18 (2.99) | 8.65 (4.33) | 6.12 (3.09) | 7.749 | 0.051 |
Fig. 7: Association between BMI and M2 oocytes retrieved
| Correlation | Spearman correlation coefficient | p-value |
|---|---|---|
| M2 oocytes retrieved vs AFC | 0.8 | <0.001 |
Fig. 8: Association between AFC and M2 oocytes retrieved
A strong positive correlation between M2 oocytes retrieved and AFC and this correlation was statistically significant (ρ = 0.84, p = <0.001).
For every 1 unit increase in AFC, the M2 oocytes retrieved increases by 0.23 units.
| Correlation | Spearman correlation coefficient | p-value |
|---|---|---|
| M2 oocytes retrieved vs ovarian volume (cc) | 0.5 | <0.001 |
Fig. 9: Association between ovarian volume and M2 oocytes retrieved
There was a moderate positive correlation between M2 oocytes retrieved and ovarian volume (cc) and this correlation was statistically significant (ρ = 0.5, p = <0.001).
For every 1 unit increase in ovarian volume (cc), the M2 oocytes retrieved increases by 0.59 units.
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Association between stromal RI and metaphase 1 + metaphase 2 (M1 + M2) oocyte yield (Table 10 and Fig. 10).
| Correlation | Spearman correlation coefficient | p-value |
|---|---|---|
| M1 + M2 oocyte yield (%) vs stromal RI | −0.3 | 0.025 |
Fig. 10: Association between stromal RI and M1 + M2 oocyte yield
A weak negative correlation was seen between M1 + M2 oocyte yield (%) and stromal RI, and this correlation was statistically significant (ρ = −0.29, p = 0.025).
For every 1 unit increase in stromal RI, the M1 + M2 oocyte yield (%) decreases by 61.88 units.
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Association between different categories of ovarian stromal PSV and M2 oocytes retrieved (Table 11).
| M2 oocytes retrieved | Stromal PSV category | Kruskal–Wallis test | |||
|---|---|---|---|---|---|
| <3 | 3–10 | >10 | χ2 | p-value | |
| Mean (standard deviation) | 2.00 (NA) | 6.79 (3.93) | 7.33 (6.81) | 2.302 | 0.316 |
| Median (IQR) | 2 (2–2) | 6 (4–9) | 5 (3.5–10) | ||
IQR, Interquartile range.
The mean of M2 oocytes retrieved in the stromal PSV category <3 cm/second group was 2.00, 3–10 cm/second group was 6.79 and >10 cm/second group was 7.33.
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Association between different categories of ovarian stromal RI and M2 oocytes retrieved (Table 12).
| M2 oocytes retrieved | Stromal RI category | Wilcoxon and Mann–Whitney U test | ||
|---|---|---|---|---|
| <0.45 | 0.45–0.75 | W | p-value | |
| Mean (standard deviation) | 7.00 (4.21) | 6.64 (4.02) | 389.500 | 0.808 |
| Median (IQR) | 7 (3–10) | 5 (3.75–9) | ||
The mean M2 oocytes retrieved in the stromal RI < 0.45 group was 7.00 and the mean M2 oocytes retrieved in the stromal RI 0.45–0.75 group was 6.64.
| Correlation | Spearman correlation coefficient | p-value |
|---|---|---|
| M2 oocytes retrieved vs baseline score | 0.7 | <0.001 |
Fig. 11: Association between baseline score and M2 oocytes retrieved
There was a strong positive correlation between M2 oocytes retrieved and baseline score, and this correlation was statistically significant (ρ = 0.65, p ≤ 0.001).
For every 1 unit increase in baseline score, the M2 oocytes retrieved increases by 0.77 units.
-
Association between different categories of baseline score and M1 + M2 retrieved (Table 14 and Fig. 12).
| M1 + M2 oocytes retrieved | Baseline score category | Wilcoxon and Mann–Whitney U test | ||
|---|---|---|---|---|
| 10–20 | >20 | W | p-value | |
| Mean (standard deviation) | 5.33 (3.30) | 10.44 (4.49) | 149.500 | <0.001 |
| Median (IQR) | 4 (3–6.25) | 10 (7–13) | ||
Fig. 12: Association between different categories of baseline score and M1 + M2 retrieved
The mean M1 + M2 oocytes retrieved in the baseline score 10–20 group was 5.33 and the mean M1 + M2 oocytes retrieved in the baseline score >20 group was 10.44.
There was a significant difference between the two groups in terms of M1 + M2 oocytes retrieved (W = 149.500, p ≤ 0.001), with the median M1 + M2 oocytes retrieved being highest in the baseline score >20 groups.
-
Distribution among stromal RI categories in which HMG was given (either from day 2 or day 5/6) or not given in the cycle (Table 15 and Fig. 13).
| Stromal RI category | HMG added (overall) | Chi-squared test | |||
|---|---|---|---|---|---|
| Yes | No | Total | χ2 | p-value | |
| <0.45 | 8 (27.6%) | 9 (28.1%) | 17 (27.9%) | 0.002 | 0.963 |
| 0.45–0.75 | 21 (72.4%) | 23 (71.9%) | 44 (72.1%) | ||
| Total | 29 (100.0%) | 32 (100.0%) | 61 (100.0%) | ||
Fig. 13: Distribution among stromal RI categories in which HMG was given (either from day 2 or day 5/6) or not given in the cycle
There was no significant difference between the various groups in terms of the distribution of the stromal RI category (χ2 = 0.002, p = 0.963). This may be due to the absence of documentation of 3D power Doppler indices for the ovarian stroma. Studies that have used 3D power Doppler indices have proved this parameter to be an essential one.
| HMG added (overall) | Baseline score category | Chi-squared test | |||
|---|---|---|---|---|---|
| 10–20 | >20 | Total | χ2 | p-value | |
| Yes | 26 (72.2%) | 3 (12.0%) | 29 (47.5%) | 21.455 | <0.001 |
| No | 10 (27.8%) | 22 (88.0%) | 32 (52.5%) | ||
| Total | 36 (100.0%) | 25 (100.0%) | 61 (100.0%) | ||
Fig. 14: Association between baseline score and addition of HMG anytime (day 2 or day 5/6) in the cycle
There was a significant difference between the various groups in terms of the distribution of HMG added (overall) (χ2 = 21.455, p ≤ 0.001). This proves that a higher score on the baseline scan pertains to hyper-responders and a lower dose pertains to poor responders. More number of poor responders required HMG to be added.
-
Association between the dose of HMG added to rFSH after baseline scan and M2 oocytes retrieved (Table 17 and Fig. 15).
| M2 oocytes retrieved | HMG dose added (baseline) | Kruskal–Wallis test | |||
|---|---|---|---|---|---|
| None | 75 mg | 150 mg | χ2 | p-value | |
| Mean (standard deviation) | 7.98 (3.96) | 3.88 (2.42) | 2.00 (NA) | 18.124 | <0.001 |
| Median (IQR) | 7 (5–10.5) | 3 (2–4) | 2 (2–2) | ||
Fig. 15: Association between the dose of HMG added to rFSH after baseline scan and M2 oocytes retrieved
There was a significant difference between the three groups in terms of M2 oocytes retrieved (χ2 = 18.124, p ≤ 0.001), with the median M2 oocytes retrieved being highest in the group where HMG was not supplemented to rFSH after the baseline scan. This probably may be due to the fact that HMG addition was required only in the patients who did not respond to rFSH or had a very low baseline score, indicating poor reserve and poor response. In fact, higher doses of HMG may result in a lesser number of M2 oocytes and thus is detrimental to ova.
| M2 oocytes retrieved | HMG added (day 5/6) | Wilcoxon and Mann–Whitney U test | ||
|---|---|---|---|---|
| Yes | No | W | p-value | |
| Mean (standard deviation) | 5.09 (2.55) | 7.10 (4.23) | 212.500 | 0.243 |
| Median (IQR) | 5 (3.5–5.5) | 7 (3.25–10) | ||
Fig. 16: Association between HMG added on day 5/6 and M2 oocytes retrieved
There was no significant difference between the groups in terms of M2 oocytes retrieved (W = 212.500, p = 0.243).
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Association between HMG added to rFSH anytime in the cycle and M2 oocytes retrieved (Table 19 and Fig. 17).
| M2 oocytes retrieved | HMG added (overall) | Wilcoxon and Mann–Whitney U test | ||
|---|---|---|---|---|
| Yes | No | W | p-value | |
| Mean (standard deviation) | 4.28 (2.49) | 8.97 (3.90) | 137.000 | <0.001 |
| Median (IQR) | 3 (3–5) | 9 (5.75–11.25) | ||
Fig. 17: Association between HMG added to rFSH anytime in the cycle and M2 oocytes retrieved
There was a significant difference between the two groups in terms of M2 oocytes retrieved (W =137.000, p ≤ 0.001), with the median M2 oocytes retrieved being highest when HMG was not added to rFSH anytime in the cycle.
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Association between HMG added to rFSH at different times in the cycle and M2 oocytes retrieved (Table 20 and Fig. 18).
| M2 oocytes retrieved | HMG addition time | Kruskal–Wallis test | |||
|---|---|---|---|---|---|
| Not added | Baseline | Day 5/6 | χ2 | p-value | |
| Mean (standard deviation) | 8.97 (3.90) | 3.78 (2.39) | 5.09 (2.55) | 24.277 | <0.001 |
| Median (IQR) | 9 (5.75–11.25) | 3 (2–4) | 5 (3.5–5.5) | ||
Fig. 18: Association between HMG added to rFSH at different times in the cycle and M2 oocytes retrieved
There was a significant difference between the three groups in terms of M2 oocytes retrieved (χ2 = 24.277, p ≤ 0.001), with the median M2 oocytes retrieved being highest when HMG has not added at the time in the cycle, followed by when HMG was added after seeing the response on day 5/6. This is because luteinizing hormone (LH) receptors develop on the follicles when they are >10 mm in size.
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Association between the expected number of oocytes and percentage oocyte yield (M2 + M1) retrieval (Table 21 and Fig. 19)
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Association between the number of follicles between 10 and 15 mm on the day of trigger and the number of Prophase oocytes retrieved (Table 22 and Fig. 20).
| Correlation | Spearman correlation coefficient | p-value |
|---|---|---|
| M1 + M2 oocyte yield (%) vs expected number of oocytes | −0.3 | 0.028 |
Fig. 19: Association between the expected number of oocytes and percentage oocyte yield (M2 + M1) retrieval
| Correlation | Spearman correlation coefficient | p-value |
|---|---|---|
| Number of follicles 10–15 mm (day of trigger) vs number of prophase oocytes retrieved | 0.7 | <0.001 |
Fig. 20: Association between the number of follicles between 10 and 15 mm on the day of trigger and the number of prophase oocytes retrieved
There was a strong positive correlation between the number of follicles 10–15 mm (day of the trigger) and the number of prophase oocytes retrieved and this correlation was statistically significant (ρ =0.73, p ≤ 0.001).
For every 1 unit increase in the number of follicles 10–15 mm (day of the trigger), the number of prophase oocytes retrieved increases by 0.18 units.
Further analysis was done and the same association was derived separately for follicles of size 10–12 mm and 13–15 mm on the day of trigger. There was a strong positive correlation between the number of prophase oocytes retrieved and a number of follicles 10–12 mm and 13–15 mm (day of the trigger) and this correlation was statistically significant (ρ = 0.6, p ≤ 0.001).
For every 1 unit increase in the number of follicles 10–12 mm (day of the trigger), the number of prophase oocytes retrieved increases by 0.29 units.
For every 1 unit increase in the number of follicles 13–15 mm (day of the trigger), the NUMBER OF PROPHASE OOCYTES retrieved increases by 0.24 units.
This proves that we require follicles > 15 mm in size on the day of the trigger to expect an M2 oocyte after retrieval. Up to 15 mm, only prophase oocytes can be expected. This is contrary to a few studies that state that follicles of up to 10 mm in size should be aspirated during oocyte retrieval.
DISCUSSION
Ng et al.2 in 2003 conducted a study on 119 Chinese women with known fertility. On the second to the fourth day of the menstrual cycle, these women underwent transvaginal ultrasounds with color Doppler to determine the ovarian volume, AFC, and ovarian stromal PSV, and their blood samples for serum FSH and inhibin B were collected. The results concluded that AFC was the only ovarian reserve marker that was significantly different among four age-groups (≤20, 21–30, 31–40, and >40 years) and it declined linearly at the rate of 3.8% per year.2 This was followed by FSH levels and ovarian volume. This was followed by an observational study in 2005 conducted by Klinkert et al.3 which derived that the AFC is a better predictor of ongoing pregnancy in IVF patients aged >38 years of age than is basal FSH. Another study was performed by Saleh et al.4 in 2006 over 135 women aged ≤ 35 years. The patients were divided into two groups—group I patients with antral follicles ≤ 10 (n = 65) and group II patients with antral follicles >/11 (n = 70). Women with antral follicles ≤ 10 needed more stimulation days and higher total gonadotropin doses and tended to have lower pregnancy rates. In 2013, La Marca and D’Ippolito et al.5 suggested that ovarian response to corifollitropin α is dependent on predictors like baseline FSH, AFC, age, and a higher ovarian response is seen with an increasing AFC and the number of oocytes per retrieval decreased with increasing baseline FSH and age. Hashish et al.6 in 2014 in a retrospective observational multicentric study including 233 ovulatory patients concluded that age, basal FSH, BMI, and estrogen (E2) after downregulation were important predictors of ovarian response with long agonist ovarian stimulation protocol and can decide the appropriate starting dose of GN. In 2017, Magnusson et al.7 reassured by studying 308 patients over 3 years that the addition of antimullerian hormone (AMH) to age, AFC, or BMI for deciding the dose on stimulation protocol did not alter the ovarian response, that is, 5–12 oocytes, or decrease the frequency of OHSS or canceled cycles due to poor ovarian response. Thus, AFC has been included in the baseline scoring system and AMH has been omitted. The above studies also potentiate the obvious inclusion of age and BMI as parameters upon which the gonadotropin stimulation dose should be decided. With increasing age and BMI, higher doses of gonadotropins are needed by the patient.
The inclusion of ovarian volume and stromal vascular parameters in the baseline scoring system has been influenced by the following studies.
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Zaidi et al.8 in their study of 105 females suggested that mean ovarian PSV was significantly correlated with the follicular response and ovarian stromal PSV was significantly lower in the poor response group. The adjusted odds of a poor response increased significantly by an estimated 22% per cm/second decrease in velocity (p = 0.02).
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Engmann et al.9 in a prospective observational study of 88 females undergoing IVF showed that ovarian stromal PSV was the most important single independent predictor of ovarian response in patients with normal basal serum FSH level, as compared to age, basal FSH, E2, or FSH:LH ratio. Patients with PSV ≥ 10 cm/seconds had a significantly higher number of mature oocytes retrieved (11 vs 5.5) and a higher clinical pregnancy rate (35.3% vs 11.3%) as compared to patients with PSV <10 cm/second, after controlling for age.
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Kupesic and Kurjak10 have emphasized the role of 3D ultrasound in determining ovarian reserve and response by evaluation of AFC, ovarian volume, ovarian stroma, and ovarian stromal blood flow. Amongst these, total AFC achieved the best predictive value for favorable IVF outcome, followed by ovarian stromal flow index, total ovarian volume, total ovarian stromal area and age.
In a prospective study of 145 patients, Todorovic et al.11 showed that the total number of antral follicles and ovarian stromal blood flow are the two most significant predictors of ovarian reserve and response.
In a prospective study on 65 women undergoing IVF, Merce et al.,12 ovarian volume, AFC ≥ 2 mm, and 3D power Doppler indices, vascularisation index (VI), flow index (FI), and vascularisation flow index (VFI) were evaluated by on the day of pituitary suppression control. These measurements, age and BMI were correlated with the number of follicles >10 mm on the day of trigger and the number of oocytes retrieved and reported that ovarian volume, antral follicular count, VI, FI, and VFI correlated significantly (p < 0.01) with the number of follicles and oocytes retrieved.
Arora et al.13 in their study in 2015, concluded that ovarian stromal blood flow was found to be negatively correlated with age and number of follicles grown, negatively correlated with ovarian stromal resistance index and pulsatility index. Thus, Ovarian blood flow predicts ovarian response to gonadotropins.
Another study in 2017 compared IVF outcomes between patients receiving FSH alone and those receiving FSH combined with LH from the beginning. The study reported higher clinical pregnancy rates and live birth rates in the group that received LH supplementation.14
In a prospective study in 2020 by Marchiani et al.15 on 13 women stimulated with FSH monotherapy and 28 women stimulated with FSH + LH, 111 follicular fluids (FF) and 205 FF were collected respectively. Steroid levels were measured in FF and their relation to ovarian stimulation protocol, oocyte maturity, fertilization, and quality of blastocysts was evaluated. Progesterone, 17-hydroxy-progesterone, and estradiol were more expressed in follicular fluid yielding a mature oocyte (p < 0.01) in the FSH + LH protocol. The results indicated that LH supplementation in hypo-responsive women modifies ovarian steroid production, is similar to normal physiology, and may improve ovarian response.
A study by Eftekhar and Tabibnejad16 in 2021 has also proved that rLH supplementation improves response to ovulation induction in women with hypogonadotropic hypogonadism and those hyporesponsive to follicle-stimulating hormone monotherapy and poor responder women 36–39 years of age.
In 2022, Wang et al.17 stated that recombinant LH (R-LH) supplementation to r-FSH in the GnRH antagonist protocol was significantly associated with a higher live birth rate in fresh and frozen embryo transfer (FET) cycles, and improved embryo quality without increasing the OHSS rate and cycle cancelation rate.
Even Cochrane review suggests that HMG or LH has a role in poor responders and may ultimately improve the live birth rate or yield of M2 oocytes.
A systematic review published in the Cochrane Database of Systematic Reviews in 201818 analyzed randomized controlled trials (RCTs) evaluating the efficacy of adding LH to FSH during ovarian stimulation in IVF or ICSI cycles. The review concluded that adding LH improved live birth rates in women with reduced ovarian response, but the evidence was limited. It suggested that further high-quality RCTs were needed to confirm the findings.
Various studies state that LH supplementation can be considered in patients with a predicted poor response, particularly those with low baseline LH levels or a history of poor ovarian response.16,19 The recommendations were based on expert opinion and available evidence. Still, one more study also suggests that HMG may improve the live birth rates in poor responders.
A study published in the Reprod Biol Endocrinol, 2021 found that early LH supplementation in IVF cycles improved the number of mature oocytes retrieved and clinical pregnancy rates in patients with a predicted poor response.19
The results of all these studies comply with the method and results of the present study which indicates that LH/HMG has a role in poor responders, who are the patients, who have less ovarian stromal blood flow and do not adequately respond to the planned dose of rFSH.
CONCLUSION
The above results prove the reliability of the baseline score as there was not a single case of OHSS or cycle cancelation. From the above study, we also reach the conclusion that the addition of HMG to rFSH at anytime in the cycle at any dose does not show improvement in the number of M2 oocytes retrieved. Though this study sample is small to conclude that the addition of LH or HMG would make a difference in the M2 oocyte yield and live birth rate. Another inference derived from this study is that retrieval of follicles < 15 mm may not result in M2 oocytes and so may not be beneficial.
Clinical Significance
To individualize the stimulation dose in IVF cycles, other than age and BMI, other ultrasound parameters like AFC, ovarian volume, and ovarian stromal Doppler studies should be used. This can avoid hyperresponse and cycle cancelation.
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