Miracle Pregnancy: Management of Poor
Responder in In-Vitro Fertilization
Neeta Singh1 Ankita Sethi2*, Garima Patel2 and Monika Saini1
1 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, India
2 DM Reproductive Medicine Resident, Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, India
Submission: June 10, 2022; Published:June 28, 2022
*Corresponding author: Ankita Sethi, DM Reproductive Medicine Resident, Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India
How to cite this article: Arzu Y, Nurettin T, Semih Zeki U. Effect of Prolonged GnRH Agonist Therapy Prior to Frozen Embryo Transfer on IVF-ET
Outcome in Patients with and without Endometrioma Surgery. Glob J Reprod Med. 2022; 9(1): 555754. DOI: 10.19080/GJORM.2022.09.555754.
Background:: Patient-Oriented Strategy Encompassing IndividualizeD Oocyte Number (POSEIDON) 3 and 4 subgroup is common nowadays. We hereby report a case of successful management of POSEIDON 4 patient, who underwent an individualized GnRH antagonist protocol.
Case Presentation:: A 36-year-old woman presented with primary infertility for 10 years. She had undergone multiple cycles of ovulation induction and intrauterine insemination previously. She had previous one IVF failure. Post COVID lockdown, patient was a POSEIDON 4 group patient who underwent second IVF cycle. Three grade 4 oocytes were retrieved after dual trigger. Two 8 celled grade B embryos were transferred on day 3. Patient conceived and had caesarean section at 37 weeks POG, 2.4 kg healthy male baby delivered.
Conclusion:: IVF with self-oocyte can be tried along with proper counselling to decrease the psychological and financial burden on the patient and family, therefore, ruling out oocyte donation as the only treatment option in these patients.
Poor responders are often encountered by Reproductive medicine specialists around the world. A lot of research has been directed towards finding reasonable solutions for this group of patients. The lack of a universal definition has induced a considerable degree of heterogeneity to research on stimulation protocols in poor responders. Several definitions and methods have been proposed for the identification of poor responders, for individualization of their treatment, including the European Society of Human Reproduction and Embryology (ESHRE) Bologna criteria for poor responders, and the Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) criteria [1,2]. Here we present a case of poor responder (POSEIDON 4) and her personalised/individualized successful management.
Patient X, a 36-year-old woman presented with primary infertility for 10 years. She had undergone multiple cycles of ovulation induction and intrauterine insemination previously. Patient was evaluated clinically with thorough history, examination, and investigations. She underwent her first Gonadotrophin releasing Hormone (GnRH) antagonist In-Vitro Fertilization (IVF) cycle in November 2019 as mentioned in protocol (Table 1). The dose of gonadotrophins used was 2625 IU rFSH (Follicle Stimulating Hormone) and 2250 IU HMG (Human Menopausal gonadotrophins), so total 4875 IU of gonadotrophins in first IVF cycle and total 11 days of stimulation. Six oocytes were retrieved after 36 hours of rHCG (recombinant human chorionic gonadotropin) 250 microgram trigger. Serum E2(estradiol) on
day of trigger was 1495 pg/ml and P4 (progesterone) 0.9 ng/ml.
Conventional IVF insemination was performed with two grade
1 and four grade 2 oocytes, which resulted two 2 celled grade Bembryo, which were transferred on day 2. Urine Pregnancy test
(UPT) was done after 16 days which was negative and beta hCG
Patient expressed her wish for second attempt and was
postponed due to COVID-19 (CORONAVIRUS DISEASE-2019)
pandemic. Therefore, DHEAS (Dehydroepiandrosterone
sulfate) supplements were prescribed for 6 months till her
next recruitment. Post lockdown, the initial AFC (antral follicle
count) at start of cycle was low (right ovary=2, left ovary=3).
Antagonist Protocol followed as mentioned in table 2. The total
dose of gonadotrophins used was 3800 IU rFSH and 600 IU HMG,
so total 4400 IU of gonadotrophins in second IVF cycle, total 10
days of stimulation. Three grade 4 oocytes were retrieved post 35
hours of dual trigger (Inj rHCG (Ovitrelle) 250 microgram and inj
leuprolide 1 mg subcutaneously). Initially, ICSI (intracytoplasmic
sperm injection) was planned because of poor fertilization rate
in previous IVF cycle. However, conventional IVF was performed because of poor quality of oocytes. Fortunately, two oocytes
fertilized (2 out of 3) and two 8 celled grade B embryos were
available for transfer on day 3, much better quality as compared
to first IVF cycle. Urine pregnancy test and beta HCG was done
after 16 days, which was positive. Single live intrauterine fetus
was documented at 6 weeks period of gestation and luteal phase
support (Vaginal micronized progesterone 400 mg twice a day and
injection micronized progesterone 100 mg intramuscularly OD)
was continued throughout first trimester. Patient had caesarean
section at 37 weeks POG, 2.4 kg healthy male baby delivered. We
are reporting this to spread the message that POSEIDON 4 patients
can have successful pregnancy outcomes with individualized/
personalized treatment and that oocyte donation is not the only
The ESHRE Bologna criteria 2011 gave the definition of poor
responders . According to Bologna criteria, poor responders are
patients from whom we would expect to retrieve 3 oocytes after
conventional COS and markers for identifying poor responders are
a previous poor response (three oocytes retrieved after COS), AMH
(Anti-mullerian Hormone) <0.5 ng/mL or AFC < 3 [1,3]. Though it
encompasses a broad, heterogeneous group of patients but it is not
considered as clinically relevant for making informed treatment
decisions [4-6]. Because it does not differentiate between oocyte
quality and oocyte quantity . Suboptimal responders are not
widely recognized as a patient subgroup and were categorized
either into normal responders or poor responders [1,7]. The
POSEIDON Group bridged this gap and formulated these criteria by
consensus that identify different groups of low prognosis patients
. These were developed specifically with the aim of guiding
personalized treatment protocols for second and subsequent
cycles, following unexpected suboptimal or poor response.
POSEIDON criteria offer the best approach to personalization
for poor/suboptimal ovarian responders, to assist the clinical
decision-making, patient counselling and prognostication.
The biomarkers to identify suboptimal responders are:
(a) previous history of suboptimal response (>4 to 9 oocytes
retrieved after COS) (b) AMH > 0.5 to <1.2 ng/mL (c) AFC > 4 to
9. These constitutes 43.3% of patients undergoing IVF treatment
according to study by Polyzos et al. . A recent meta-analysis,
shows that suboptimal responders and potentially other patient
populations are likely to benefit from r-hLH (Recombinant
Luteinizing hormone) supplementation with respect to
implantation, pregnancy, and live birth rates [9-12]. Age is an
important prognostic marker for IVF success, and it is expected
that the younger patient will have a 4 times higher chance of live
birth as compared to the older patient . In POSEIDON group 3
(age < 35 years, AMH <1.2 ng/ml, AFC<5) patients, recommended
protocols are either long GnRH agonist down-regulation or a
“primed” GnRH antagonist co-treatment followed by stimulation
with a maximum dose of 300 rFSH. In selected cases with a
low oocyte yield and based on the estimate made by the ART
(Assisted reproductive technology) calculator, DUO-Stim should
be recommended for oocyte or embryo accumulation to shorten
time to pregnancy [14,15]. With the increasing prevalence of
POSEIDON group 4 patients (age >35 years, AMH <1.2 ng/ml,
AFC <5) due to delay in age of childbearing , the dual effect of
poor ovarian reserve (quantity) and age-related decline of quality
makes this category of patients difficult to handle . Though
oocyte donation is a treatment option but there is a stigma with
it especially in Indian society . At the same time, despite poor
prognosis, we cannot deny IVF with self-oocyte. Therefore, proper
counselling is required explaining the chance of cycle cancellation
and risk of empty follicle syndrome.
The case in discussion received starting dose of 225 IU rFSH
and 225 IU HMG in first IVF cycle, but still patient had poor outcome
in terms of poor quality of oocytes, poor fertilization rate and no clinical pregnancy. Therefore, in the second cycle, even though
patient fits in POSEIDON 4 classification, we took the decision to
administer 450 IU rFSH from day 2 for 5 days, followed by 300 IU
rFSH and 150 IU HMG from day 6 when the antagonist was added.
In first and second cycle, total dose and days of gonadotrophins
used was 4825 IU and 11 days, 4400 IU and 10 days respectively.
This is in complement to the literature that escalating the dose
of gonadotrophins and increased duration of stimulation can
negatively affect the IVF outcome . Another change in treatment
was dual trigger compared to HCG trigger in 1st cycle because it
is associated with better IVF outcome in terms of number of total
embryos and grade 1 embryos in poor responders’ patients .
Following this change in protocol, we had better oocyte yield,
fertilization rate, embryo quality, positive urine pregnancy test
and ongoing pregnancy at 22 weeks POG (period of gestation). As
patient was 36 years old, PGT (Preimplantation Genetic Testing)
could be considered to check the ploidy status of the embryos but
was avoided due to deleterious effect of embryo loss and further
hampering the chance of embryo implantation/viability on biopsy
of day 3 embryos .
Therefore, would conclude that individualized/personalized
treatment is required in POSEIDON 3 and 4 patients, and no fixed
stimulation protocol can be followed. IVF with self-oocyte can be
tried along with proper counselling to decrease the psychological
and financial burden on the patient and family, therefore, ruling
out oocyte donation as the only treatment option in these patients.