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\begin{document}

\title{Successful outcome of a pregnancy derived from premature ovulation in a
gonadotropin-releasing hormone (GnRH) antagonist protocol: a case report}



\author[1]{Daichi Inoue}%
\author[1]{Yoshimasa Asada}%
\author[2]{Tomoko Ando}%
\affil[1]{Asada Ladies Clinic}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{June 02, 2024}


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\selectlanguage{english}
\begin{abstract}
Premature ovulation may occur during controlled ovarian stimulation.
Usually, this is noticed and treatment is canceled before ovum pick up
(OPU). In this case, a 24-year-old woman naturally conceived during the
stimulation and OPU was successfully performed afterwards. Despite
developing severe ovarian hyperstimulation syndrome, she delivered a
healthy baby.%
\end{abstract}%



\sloppy


Successful outcome of a pregnancy derived from premature ovulation in a
gonadotropin-releasing hormone (GnRH) antagonist protocol: a case report

Daichi Inoue\textsuperscript{1}, Yoshimasa Asada\textsuperscript{1},
Tomoko Ando\textsuperscript{2}

1 Asada Ladies Nagoya Clinic

Nagoya Building 5F, Meieki 4-6-17, Nakamura-ku, Nagoya, Aichi, Japan
450-0002

2 Department of Obstetrics and Gynecology, Japanese Red Cross Nagoya
Daiichi Hospital

Mi,chishita-cho 3-35, Nakamura-ku, Nagoya, Aichi, Japan 453-8511

\textbf{Corresponding author}

Daichi Inoue

Asada Ladies Nagoya Clinic, Nagoya Building 5F, Meieki 4-6-17,

Nakamura-ku, Nagoya, Aichi, Japan 450-0002

Tel: +81-052-551-2203

Fax: +81-052-551-2252

E-mail: \emph{d\_inoue@ivf-asada.jp}

Abstract

Premature ovulation may occur during controlled ovarian stimulation.
Usually, this is noticed and treatment is canceled before ovum pick up
(OPU). In this case, a 24-year-old woman naturally conceived during the
stimulation and OPU was successfully performed afterwards. Despite
developing severe ovarian hyperstimulation syndrome, she delivered a
healthy baby.

Key words

gonadotropin-releasing hormone (GnRH) antagonist, ovarian
hyperstimulation syndrome (OHSS), pregnancy, premature ovulation,
premature LH surge

Key Clinical Message

In the gonadotropin-releasing hormone (GnRH) antagonist protocol, it is
necessary to reinforce contraceptive guidance assuming that luteinizing
hormone surge is not detected by measurement of serum level and
ovulation is not suppressed by GnRH antagonist.

\textbf{1 Introduction}

Gonadotropin-releasing hormone (GnRH) antagonists are currently widely
used for controlled ovarian stimulation (COS). GnRH antagonists have the
advantage of preventing severe ovarian hyperstimulation syndrome (OHSS)
by using GnRH agonists as the final oocyte maturation trigger instead of
human chorionic gonadotropin (hCG), which has a long
half-life\textsuperscript{1,2}.

Preventing premature ovulation (PO) completely is difficult. However, Wu
et al.\textsuperscript{3} reported three cases of pregnancy by oocyte
retrieval from residual follicles after PO. Additionally, Vicdan et
al.\textsuperscript{4} reported five cases of PO that were converted
from \emph{in vitro} fertilization (IVF) to intrauterine insemination
(IUI) and two became pregnant. In most cases of PO, it is noticed and
the IVF cycle is canceled. Therefore, there have been few reports of
successful cases of pregnancy after PO.

We report a case of spontaneous pregnancy due to PO in a GnRH antagonist
protocol. No signs of a premature luteinizing hormone (LH) surge or PO
were observed, despite monitoring LH levels and the follicle count
during the COS. Additionally, luteal function was maintained even after
the GnRH agonist trigger so the pregnancy continued, and a healthy live
neonate was delivered.

\textbf{2 Case presentation}

\textbf{2-1 First consultation for assisted reproductive technology}

A 24-year-old woman, gravida 0, para 0 had no special medical history
and a regular 28-day menstrual cycle. Her body mass index was 20.8
kg/m\textsuperscript{2}. After five cycles of timed intercourse and one
cycle of IUI at another hospital, she did not become pregnant and
decided to visit our hospital. Her anti-Mullerian hormone level was 5.34
ng/mL. After the first visit, IUI was performed for two cycles, but she
did not become pregnant. The decision was then made to apply assisted
reproductive technology (ART).

\textbf{2-2 Clinical course of ART}

COS with follicle-stimulating hormone (FSH) (gonal-f, follitropin-alpha,
EMD serono, Japan) or human menopausal gonadotropin (hMG) (ferring,
Ferring Pharma, Japan) were started on the cycle day (CD) 3 and GnRH
antagonist ; cetrorelix acetate (cetrotide) from CD 14. The total
duration of treatment was 20 days, with a total of 6625 units of FSH +
hMG administered (Figure 1).

On the 19th day of stimulation, we decided to retrieve the oocytes (ovum
pick-up {[}OPU{]}) 3 days later, and stimulation was continued until the
20th day. A final oocyte maturation trigger was performed with a GnRH
agonist (leuprolide acetate {[}Lucrin{]}; AbbVie, Illinois, USA)
(subcutaneous administration, 1 mg), and 35 hours later, the oocytes
were retrieved with a transvaginal needle under venous anesthesia. A
total of 31 oocytes (26 \selectlanguage{ngerman}× meiosis-2 stage {[}M2{]}, 2 × meiosis-1 stage
{[}M1{]}, 1 × germinal vesicle stage, and 2 × degenerated oocytes) were
obtained. The unadjusted sperm volume was 3.2 mL, the motile sperm
concentration was 5 M/mL, and the sperm motility was 17.9\%, so
insemination of the M2 oocytes was split. The fertilization result from
intracytoplasmic sperm injection (ICSI) was 21 (12 × 2 pronuclear stage
{[}PN{]}, 1 × 1 PN, 5 × 3 PN, 3 × degeneration {[}Deg{]}) and that for
conventional IVF was five (3 × 2 PN, 1 × 3 PN, 1 × Deg). Confirmation of
fertilization showed 15 × 2 PN embryos and 1 × 1 PN embryo. Therefore, 8
× 2 PN embryos were cryopreserved and the remaining 7 × 2 PN and 1 × 1
PN embryos were cultured for blastocysts. Three blastocysts were formed
by day 7 of culture (3AB, 4AA, 4BC by the Gardner classification).

\textbf{2-3 Clinical course after the OPU}

Abdominal pain began the day after the OPU, and the patient lost
consciousness twice on the 3rd day after the OPU, so she went to a
hospital. A large amount of ascites, bilateral ovarian swelling (right:
56 × 69 mm, left: 62 × 45 mm), a heart rate of 110 bmp, and blood
pressure of 70/50 mmHg were observed at the time of admission. The
patient was immediately hospitalized and diagnosed with hypovolemic
shock and severe OHSS.

No abnormal findings were detected by head magnetic resonance imaging. A
blood test showed the following: albumin level of 2.8 g/dL, creatinine
0.84 mg/dL, sodium 134 mEq/L, potassium 5.5 mEq/L, AST 44 U/L, ALT 20
U/L, WBC 15,300/\selectlanguage{greek}μ\selectlanguage{english}L, hemoglobin 18.7 g/dL, and Ht 54.3\%. A heparin and
dopamine drip infusion was administered.

Her ascites increased from the 8th day after the OPU (6th day of
hospitalization), and a puncture and drainage procedure was performed
twice. On day 11 after the OPU, transvaginal ultrasonography showed a
10-mm gestational sac (GS) in the uterus, and her blood hCG level was
6990 mIU/mL. She was then discharged from the hospital on the 17th day
after the OPU without any increase in ascites. After discharge, the
course of her pregnancy was uneventful, and she gave birth to a female
neonate (3136 g) at 40 weeks+1. At a 1-month postnatal examination, the
infant was healthy without complications.

\textbf{3 Discussion}

The definition of a premature LH surge differs depending on the study.
In our case, if the definition of Kummer et al.\textsuperscript{5} (LH
levels [?] 10 mIU/mL and \textgreater{} 50\% rise from baseline) was used,
an accurate premature LH surge or ovulation could not be predicted or
specified. Therefore, the spontaneous ovulation date of our case was
estimated from two parameters, the GS and crown-rump length (CRL). If a
10-mm GS is detected at 11 days after the OPU and that day is defined as
a menstrual age of 40 days\textsuperscript{6}, the estimated ovulation
date is CD 9. The CRL was 15 mm 28 days after the OPU, and the estimated
gestational age was 7 weeks+4, 8 weeks+2, and 9 weeks by 5, 50, and 95
percentile, respectively. Therefore, the estimated ovulation date was CD
8 (3--13)\textsuperscript{6}. Because the natural menstrual cycle in our
case was 28 days, this suggested that ovulation might have occurred
earlier than it should have in a natural cycle.

If normal COS is in progress, early luteinization and follicular atresia
will occur after a premature LH surge\textsuperscript{7}. However, in
our case, fertilization and implantation occurred after the presumed
spontaneous ovulation day, and follicular development was observed after
this time. A total of 31 oocytes were retrieved by using a GnRH agonist
trigger.

A previous study reported that the outcome of luteal phase ovarian
stimulation (LU) was higher than that for follicular phase ovarian
stimulation (FO) regarding the total dosage of hMG, M2
rate\textsuperscript{7}, number of oocytes collected, fertilization
rate, and the number of day 3 embryos\textsuperscript{8}. Additionally,
a study that compared FO only to FO + LU reported that the FO + LU group
had a higher number of retrieved oocytes, M2 rate, and 2 PN
rate\textsuperscript{9}. Theoretically, continued stimulation after
spontaneous ovulation is therefore possible for retrieving oocytes.

Although good results are obtained with LU, in this case, as a result of
ICSI performed on 21 M2 oocytes in our case, 12 of 21 had 2 PN, but 5
had 3 PN. Higher peak estradiol levels, large oocyte yields, a high
gonadotropin dose, and a lengthy stimulation procedure are considered to
increase 3 PN\textsuperscript{10,11}. Therefore, additional attention
should be paid to stimulation after spontaneous ovulation.

\textbf{4 Conclusion}

In conclusion, because the mechanisms of ovulation and oocyte maturation
remain unclear, strict monitoring and proper contraceptive guidance are
important during COS using the antagonist method. When oocyte retrieval
is performed in a natural pregnancy, the risk of developing severe OHSS
and threats to life increase. Therefore, guidance for contraception
during infertility treatment seems contradictory, but it must be
strictly used.

\textbf{Acknowledgments}

We thank Ellen Knapp, PhD, from Edanz Group (www.edanzediting.com/ac)
for editing a draft of this manuscript.

\textbf{Conflicts of interest}

The authors declare that they have no conflicts of interest regarding
the publication of this case report.

\textbf{Author Contributors}

Daichi Inoue drafted the manuscript.

Yoshimasa Asada reviewed the manuscript.

Tomoko Ando reviewed the manuscript as an attending doctor of OHSS

\textbf{Ethics approval and consent to participate}

Informed consent was provided by the patient.

\textbf{Funding}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{References}

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Comparisons of GnRH Antagonist Protocol Versus GnRH Agonist Long
Protocol in Patients With Normal Ovarian Reserve: A Systematic Review
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3. Frank Shao-Ying Wu, Robert Kuo-Kuang Lee, Yuh-Ming Hwu. 2012.
Encountering Premature Ovulation During Controlled Ovarian
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5. Nicole E Kummer, Vanessa N Weitzman, Claudio A Benadiva, David W
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