A successful pregnancy and delivery outcome for a 46‐year‐old woman following in vitro fertilization

Abstract

Background:  Decreased conception rate with advanced maternal age has been well demonstrated. Although this decline becomes apparent at 35 years of age, and accelerates rapidly in women over 40 years of age, we are able to report pregnancy and delivery case for a 46‐year‐old with in vitro fertilization and embryo transfer (IVF‐ET). We report a rare case of a successful delivery of a healthy infant by a 46‐year‐old women following IVF‐ET.

Methods:  She tried three times with conventional IVF and two times cryopreserved embryo transfer, but she failed to conceive. Low‐dose dexamethasone was co‐treated the last two times with IVF on the first day of the beginning menstrual cycle daily and continued until retrieval day. We obtained good quality embryos and she became pregnant at the sixth time of IVF which was carried out at the morula and early blastocyst stage.

Result:  She finally conceived following co‐treatment with low‐dose dexamethasone. She delivered vaginally a single male infant with no congenital abnormalities at 40 weeks’ (3416 g; 46, XY).

Conclusion:  We have demonstrated a successful pregnancy due to obtaining quality embryos using co‐treatment low‐dose dexamethasone and delivery outcome for a 46‐year‐old woman using IVF. (Reprod Med Biol 2004; 3: 39–42)

INTRODUCTION

ASSISTED REPRODUCTIVE TECHNOLOGY (ART) has improved to the point of achieving pregnancies for severely infertile couples; however, it has not been successful in the production of oocytes in women of advanced maternal age with poor ovarian function. One possible explanation for this situation is a decreased ovarian reserve; the prevalence of follicles decreases at the age of 37. ¹ , ² In the past, decreased uterine receptivity was not considered to be an infertility factor for older women; ³ however, recent studies involving oocyte donation have found a significant decrease in implantation and pregnancy rates for women aged 40–49, when compared to women less than 40 years of age. ⁴ Thus, controversy continues in regard to the uterine receptivity of older women.

Generally, successful pregnancy outcomes after ART in women >41 years are rare; however, the present report documents a 46‐year‐old woman who delivered a healthy infant following conventional in vitro fertilization (IVF).

CASE REPORT

IN SEPTEMBER 1999, a 42‐year‐old woman and her 37‐year‐old husband were referred to our clinic (Yoshida Lady's Clinic, Sendai, Miyagi, Japan). They had been married for more than 1 year. Hysterosalpingography revealed an obstruction of the left fallopian tube and a small ovarian cyst. Her menstrual cycles were regular, occurring every 30 days. Serum hormonal levels were normal: luteinizing hormone (LH) 5.4 was mIU/mL; follicle‐stimulating hormone (FSH) was 8.0 mIU/mL; prolactin was 3.6 ng/L; and estradiol was 33 pg/mL. Tumor markers were normal: CA‐125 was 9; CA19‐9 was 19; and carcinoembryonic antigen was <1.0. Her husband's semen analysis was within normal limits: volume was 2.5 ± 0.5 mL; sperm count was 74.7 × 10⁶ ± 37.7 × 10⁶/mL; motility was 72.9 ± 7.8%; and abnormal morphology was 25.3 ± 2.5%.

We advised her in regard to timing of intercourse, and treated her with artificial insemination. These measures were unsuccessful; therefore, we offered IVF. We explained to the couple that the chance of a successful pregnancy outcome was low because of her age.

Two IVF‐embryo transfer (IVF‐ET) cycles were unsuccessful. With the third attempt, one frozen‐thawed embryo was transferred, and a chemical pregnancy was recognized; however, it did not continue. Two further IVF‐ET cycles were unsuccessful. Subsequently, in January 2003, a sixth attempt was made. We retrieved three oocytes from ovaries, which had been co‐treated with low‐dose dexamethasone (1 mg/day); dexamethasone was administered 1 mg/day on the first day of the beginning menstrual cycle daily at approximately 10:00 pm and continued until retrieval oocyte day. The same regimen had been followed during the fifth treatment cycles. She had selected short protocol for ovulation induction, gonadotrophin releasing hormone‐agonist (Buserelin, Hoechst AG, Japan), 900 µg/day, was used from the beginning of the first day of the menstrual cycle and controlled ovarian hyperstimulation (COH) was inducted with FSH‐human menopausal gonadotropin (hMG) from day 3 of menstrual cycle. Ovulation was triggered with 10 000 IU of human chorionic gonadotropin (hCG) when COH had resulted in the development of at least two follicles more than 18 mm in diameter. Transvaginal oocyte retrieval was conducted approximately 34–36 h after hCG administration. Transvaginal ultrasound guided oocyte retrieval was carried out using our conventional aspiration needle (NM‐1831 N, Naka‐medical, Tokyo, Japan) with manual aspiration using a syringe. Aspiration was done under intravenous anesthesia.

The low yield of three oocytes commonly occurs in older women. All oocyte handling procedures were conducted on warm stages following conventional methods.

After insemination, all three oocytes formed two pronuclei (2 PN). Until day 3 (D3), we used the IVC‐TWO medium (In Vitro Care, San Diego, CA, USA) with 10 mg/mL human serum albumin (In Vitro Care); they were then cultured until day 4 into Sydney IVF Blastocyst medium (Cook, Eight Mile Plains, QLD, Australia) under conditions at 37°C in an atmosphere of 5% CO₂, 5% O₂, and 90% N₂. We estimated three embryos at the D3 stage following modified criteria of Veeck; ⁵ grade 1, 2 and 3 towards eight cells cleavage and no fragments, five cells cleavage with 10% fragments and six cells cleavage with 20% fragments, respectively. Two of the three embryos developed to the compacted morula stage from grade 2 and 3, and one developed to the early blastocyst stage from grade 1; all three embryos were transferred 96 h (day 4) after insemination. Table 1 shows the process and results of treatment. For luteal support, the patient inserted a 200 mg progesterone vaginal suppository twice a day for 16 days, beginning 24 h prior to the embryo transfer.

Table 1.

The process and results of treatment before/after ART

Date				Pregnancy
Before date
1998	Married	Woman: 41, Husband: 37
1999	First visit	Timing intercourse		–
2000		AIH (Two times)		–
After date	Treatment procedure	Number of retrieved oocytes	Embryo transfer	Pregnancy
April 2000	Short protocol	2	F	–
July 2000	Short protocol	1	F	–
September 2000	Short protocol	10	C	+
				Chemical
March 2001	Short protocol	3	F	–
August 2002	Dexamethasone	4	C	–
	Short protocol
January 2003	Dexamethasone	3	F	+
	Short protocol			Delivery

AIH, artificial insemination with the husband's semen; ART, assisted reproductive technology; C, cryopreserved embryo transfer; F, fresh.

Two weeks after embryo transfer; the urine hCG level was more than 25 mIU/mL by qualitative analysis. At 6 weeks’ gestation, a singleton pregnancy and a fetal heartbeat was confirmed by transvaginal ultrasound. In October 2003, an uneventful delivery occurred at 40 weeks and 2 days of gestation. The infant was a normal, healthy male (3416 g; 46, XY).

DISCUSSION

THE PRESENT CASE study demonstrates that oocytes, which were retrieved from a 46‐year‐old woman who underwent six IVF treatment cycles, were able to develop from the 2 PN stage to the compacted morula and early blastocyst stages. Following embryo transfer, a full‐term pregnancy ensued.

Decreased fertility with increasing maternal age has been well‐documented. ⁶ , ⁷ This decline becomes apparent at 35 years of age, and accelerates rapidly in women more than 40 years of age. ⁸ , ⁹ The treatment of more than 2000 women by donor insemination clearly demonstrates that the decline in the pregnancy rate can be solely attributed to an increase in maternal age, independent of other factors, such as sperm quality or frequency of intercourse. ¹⁰

It is currently unresolved whether oocyte quality or implantation capability is the most significant factor for achievement of pregnancy. Indeed, both factors may play an important role in a woman's fertility. The number of follicles decreases significantly after the age of 37¹/₂. ¹ , ² Moreover, there is an increase in oocyte aneuploidy in this age group. Even with conventional IVF and intracytoplasmic sperm injection (ICSI), clinical results are much poorer in women over 40 years of age. ¹¹ , ¹² Possible factors that can impair fertility are: (i) a history of past pelvic infections that may have caused declination of the fallopian tube endothelium ¹³ and endometrial damage; (ii) reduced vascular perfusion of the uterus as demonstrated by Doppler ultrasound; ¹⁴ and (iii) an increase in the frequency of fibroids and/or endometriosis in older women.

In the current case we used the standard short protocol treatment to produce oocytes for this patient. This patient has regular menstrual cycle and has a small number of follicles of the ovaries by ultrasound examination. We checked hormonal levels, for example LH, FSH and testosterone and there were normal levels and did not have polycystic ovary patterns. With the fifth attempt, we used dexamethasone combined with hMG for ovarian stimulation. With this regimen, we harvested good‐quality oocytes; therefore, with the sixth treatment cycle we again used dexamethasone, and again harvested good‐quality embryos. We tried to check low responder and aged patients using dexamethasone and we had a good outcome for folliculogenesis to improve ovarian dysfunction for both of them. We had good quality embryo using dexamethasone due to using other steroids. Also this small dosage of dexamethasone (1 mg) is safe for the patient.

We propose that dexamethasone acted both directly and indirectly on the ovary. Dexamethasone may both facilitate ovarian function and inhibit the action of 11‐β‐hydroxysteroid dehydrogenase, resulting in an increased cortisol/cortisone ratio and direct enhancement of follicular development. ¹⁵ Another indirect effect is an increase in serum growth hormone, leading to an increase in serum insulin growth factor‐1 (IGF‐1), and consequently, increased follicular fluid IGF‐1 concentrations. These substances improve folliculogenesis; ¹⁵ however, the mechanism underlying the beneficial effects of dexamethasone is unclear. It is apparent from the present case study that dexamethasone therapy during the follicular phase can enhance follicular development and ovulation. To our knowledge, this is the first report of a successful pregnancy outcome for a 46‐year‐old woman after IVF or ICSI treatment in Japan.

Informed consent must be given to infertile couples prior to undergoing IVF. The incidence of chromosomal abnormalities increases with maternal age, and the presence of these abnormalities impairs oocytogenesis. ¹⁶ We recommend chromosome analysis for all patients with severe infertility who undergo IVF‐ET; however, this couple refused genetic screening prior to delivery. Proper counseling in cases such as this is as important as providing efficacious treatment. In the future we expect to treat a higher number of women of advanced maternal age; therefore, we must inform these patients of the risks and benefits of undergoing fertility treatment and the possible implications for the future health of their child.