[Names of the authors]
Tomomi Hashimotoa, Akira
Nakabayashia, Keiko Yanagisawab,
Chihiro Tomaa, Yu Horibea, Tsutomu
Tabataa
[Title]
Treatment of Type 2 diabetes mellitus case leading to successful IVF
pregnancy and birth outcome.
[Affilations and addresses of the authors]
a Department of Obsterics and Gynecology, Tokyo
Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666,
Japan
b Diabetes Center, Tokyo Women’s Medical University,
8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
[Corresponding author details]
Akira Nakabayashi
E-mail:nakabayashi.akira@twmu.ac.jp
8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Phone: +81-3-3353-8111
Fax: +81-3-5269-7619
[Key Clinical Message]
In type 2 diabetes patients, attempting oocyte retrieval for
egg cryopreservation without having established glycemic control does
not yield good results. Strict dietary treatment and appropriate insulin
administration is the best way to pregnancy.
[Abstract]
In type 2 diabetes patients, attempting oocyte retrieval for
egg cryopreservation without having established glycemic control does
not yield good results. Strict dietary treatment and appropriate insulin
administration is the best way to pregnancy.
[Keywords]
Hyperglycemia
Insulin therapy
In vitro fertilization (IVF)
Type 2 diabetes mellitus
Obesity
Oocyte retrieval
[Introduction]
It is not uncommon for obese diabetic patients with irregular
menstruation and ovulation to seek fertility treatment in order to have
a baby. Hyperglycemia during pregnancy increases the frequency of
complications such as gestational hypertension, premature birth,
stillbirth, and shoulder dystocia associated with delivery of an
oversized baby, and may be a factor in congenital malformations of the
baby. Therefore, it is imperative to improve blood glucose levels before
pregnancy is attempted. Pregnancies complicated by obesity also increase
the incidence of issues such as gestational hypertension and thrombosis,
as well as perinatal problems such as increased necessity of cesarean
section, and increased instance of blood loss during delivery. On the
other hand, by performing in vitro fertilization (IVF), fertilized eggs
obtained before weight loss and blood glucose improvement can be frozen,
and thawed embryos can be transferred after weight and blood glucose
levels are improved. While it is possible to avoid the decline in
fertility associated with aging, the effectiveness of this method has
not been clinically verified.
In this case study, at the patient’s insistence, oocyte retrieval was
performed at a time when blood glucose levels and body weight were not
yet under control. However, pregnancy and delivery were ultimately
achieved with an oocyte obtained after control had been established. For
each of the three oocyte retrieval procedures, we noted and compared the
amount of gonadotropin used, number of oocytes retrieved, the
fertilization rate, and the number of resulting frozen embryos, along
with the changes in blood glucose levels and body weight.
[Case Report]
A 38-year-old married woman, diagnosed with type 2 diabetes mellitus
(HbA1c: 9.0%) and hypertension at the age of 35, was prescribed oral
hypoglycemic and antihypertensive medication for the condition. No
diabetes-related complications such as retinopathy, nephropathy, or
neuropathy were observed. When she visited her previous doctor with
complaints of irregular menstruation and desire to have a baby,
transvaginal ultrasonography showed endometrial thickening, and she was
referred to our hospital because atypical endometrial hyperplasia was
suspected after performing total endometrial curettage. According to the
endometrial cytology performed at our hospital this case was categorized
atypical endometrial cells of undetermined significance, and the
endometrial histology showed no signs of malignancy. The histological
specimen from the previous doctor was re-examined and our diagnosis was
suspected endometrial hyperplasia without atypia. The results of blood
tests performed on the 19th day of the menstrual cycle, this showed
luteinizing hormone(LH) 6.9 mIU/ml, follicle stimulating hormone 7.1
mIU/ml, estradiol 41.4 pg/ml, and progesterone <0.2 ng/ml,
indicating irregular menstruation associated with an ovulation disorder.
As for her diabetes, her HbA1c, which had been around 7%, had risen to
the 8% range after being prescribed Metformin Hydrochloride and
selective Dipeptidyl Peptidase-4 inhibitors. The patient was referred to
the Diabetes Center at our hospital because her HbA1c was not under
control despite the change to multiple daily injection. A physical
examination was performed at the patient’s first visit to the Diabetes
Center, and the following metrics were recorded; height of 167 cm,
weight of 120 kg, Body Mass Index(BMI) of 43.0, and an HbA1c of 8.9%.
The patient, who had been diagnosed with suspected endometrial
hyperplasia without atypia in our hospital, wanted to achieve an early
pregnancy, and strongly desired oocyte retrieval as soon as possible,
and prior to glycemic control being established. The patient’s
anti-Mullerian hormone reading was 2.16 ng/ml. For the first oocyte
retrieval performed before her admission for diabetes management,
ovarian stimulation with Clomiphen Citrate and human menopausal
gonadotropin(hMG) was performed and a total of 3,300 IU of hMG was
administered. Ten follicles were aspirated, two oocytes obtained, and
one viable embryos was achieved and subsequently frozen (Table 1). Since
the patient requested more oocyte retrievals, a second oocyte retrieval
procedure was performed after confirming that there were no residual
follicles during menstruation. Her blood glucose level and body weight
were similar to that when the first oocyte retrieval was conducted. This
time, the antagonist method of ovarian stimulation was used, and a total
of 3,600 IU of hMG was administered. On this occasion, eight follicles
were aspirated, three oocytes acquired, and one viable embryo frozen
(Table 1).
The patient was then admitted to the Diabetes Center, where she was
placed on a 1200 kcal/day diet, and her insulin dose adjusted. Her
fasting blood glucose level, which had been over 140 mg/dl, decreased to
less than 100 mg/dl, and her 2-hour postprandial level, which had been
around 200 mg/dl, decreased to less than 140 mg/dl. During the 11 days
of hospitalization, HbA1c decreased to 7.0% by the following month
(Fig. 1A). However, weight loss was deemed unsatisfactory, reducing from
120 to 117 kg only (Fig. 1B). Nevertheless a third oocyte retrieval
procedure was performed after discharge. This time flare protocol was
used for ovarian stimulation, and a total of 3,600 IU of hMG was
administered. Eight follicles were aspirated, six oocytes acquired, and
five viable embryos frozen (Table 1). After the patient’s weight was
reduced to 107 kg, a frozen embryo (10cells, +few fragments) obtained
from the second oocyte retrieval procedure was thawed and transferred
during the HRT cycle, but did not result in pregnancy. The pregnancy was
subsequently achieved by transferring an embryo (early blastocyst)
obtained from the third oocyte retrieval procedure. Tight glycemic
control was maintained with insulin treatment throughout the pregnancy,
and a baby boy weighing 3,144 g was delivered by cesarean section at 38
weeks and 2 days of the pregnancy. The patient gained 18kg during
pregnancy, however, no maternal complications and no congenital
abnormalities resulted.
[Discussion]
In this case, it was difficult for the patient to lose weight through
her efforts alone, so she was admitted to hospital, where she was placed
on a strict diet of 20 kcal/kg of her ideal weight, which triggered her
weight loss. She eventually lost 13 kg. Weight loss alone was not
sufficient to lower her blood glucose level, and hence insulin dosage
was adjusted to achieve a good level after 11 days of hospitalization.
Comparing the two oocyte retrieval procedures performed before
hospitalization and the one after, there was no change in the total
gonadotropin dosage in each case, which was because the weight loss was
only 3 kg (about 3%), and hence there was relatively little change in
body size. As for the fertilization rate, although it was low in the
second oocyte retrieval procedure, overall it was satisfactory, and it
was judged not have changed significantly from before and after
hospitalization. However, the number of viable embryos appeared higher
after hospitalization than before. From study on mice, there are reports
that maternal-fetal diabetes affects oocyte maturation, development, and
granulosa cell apoptosis[1], and that hyperglycemia decreases
LH-luteinizing hormone /choriogonadotropin receptor expression[2],
suggesting that improving blood glucose levels may have positively
impacted oocyte retrieval in this case.
With regard to obesity and pregnancy rate, it has been reported that
spontaneous pregnancy decreases linearly in infertile women with
ovulation when BMI exceeds 29[3]. In addition, a meta-analysis
reported that women with a BMI of 30 or more had a lower production rate
after IVF (RR: 0.85) compared to women of normal weight[4]. However,
a randomized study of obese infertile patients with a BMI of between 30
and 35 who underwent intensive weight loss by caloric restriction before
IVF, reported an average weight loss of 9.44 kg but no improvement in
reproduction rate[5]. Furthermore, bariatric surgery prior to IVF
has already been performed, but it was also reported that there was no
significant effect on reproductive rate[6]. In this case, the
patient’s weight loss was slow and her final BMI was 38, which was not
ideal in terms of both perinatal and reproduction. However, permission
for pregnancy was obtained from the perinatal physician at this
facility, provided that she continued to manage her diet during
pregnancy to minimize risk of perinatal complications. Consequently,
transfer of the thawed embryo was allowed to proceed.
[Conclusion]
In order to avoid an age-related decline in fertility, it is technically
possible to perform oocyte retrieval early and cryopreserve the
fertilized eggs. However, in diabetic patients, high blood glucose may
affect the oocyte retrieval results, so it is desirable to perform
oocyte retrieval after controlling blood glucose, in order to increase
the likelihood of achieving pregnancy. In this case, the success of IVF
may have been related to improvement in blood glucose levels through
education on diabetes, including strict dietary treatment through
hospitalization, and appropriate insulin administration.
[Acknowledgement]
We thank the patient for consenting to the publication.
[Discrosures]
The authors declare no conflict of interest.
[Author contribution]
TH and AN: involved in preparing and writing the manuscript. KY, CT, YH,
and TT: critically reviewed and approved the final manuscript version
for submission. All authors: participated in the procedure and the
management of the patient.
[References]
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preovulatory oocyte maturation, development, and granulosa cell
apoptosis. Endocrinology 2005;146(5):2445-53
2. Jaewang L, Hoi CL, So YK Geum JC, Teresa KW. Poorly-Controlled Type 1
Diabetes Mellitus Impairs LH-LHCGR Signaling in the Ovaries and
Decreases Female Fertility in Mice. Yonsei Med J 2019;60(7):667-678.
3. Jan WS, Pieternel S, Marinus JE, Dik FH, Peter GH, Jan MB, et al.
Obesity affects spontaneous pregnancy chances in subfertile, ovulatory
women. Human Reproduction 2008;23(2):324-328
4. Nathalie S, Stéphanie H, Vanessa B, Elisangela A, Vanessa G, Marina
C, et al. Female obesity is negatively associated with live birth rate
following IVF: a systematic review and meta-analysis. Human Reproduction
Update 2019;25(4):439-451
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6. V Grzegorczyk-Martin, T Fréour, A De Bantel Finet, E Bonnet, M
Merzouk, J Roset, et al. IVF outcomes in patients with a history of
bariatric surgery: a multicenter retrospective cohort study. Human
Reproduction 2020;35(12):2755-2762.
[Table1] Results of oocyte retrieval prior to and post inpatient
treatment for insulin adjustment