OB-GYN CLINICAL CLERK’S CRITICAL APPRAISAL OF AN ARTICLE ON THERAPY

Name of Clerk: Maria Felicia D. Tuazon

Group No.: Group 6 Team 5
Date Submitted: September 24, 2020

Clinical Scenario MF is a 33 year old, Married, Roman Catholic from Pasig City, with unremarkable medical
history, has just finished a post-graduate program which was the main reason why she and her
husband delayed getting pregnant. They had come to your clinic to discuss possibility of
undergoing In Vitro Fertilization (IVF).

MF and her husband had been trying to get pregnant for 1 year by having intercourse without
using birth control methods, but have been unable to conceive. She had consulted to your practice
because her mentor had been successful in conceiving through IVF.

You had previously stumbled upon a scientific journal looking into the significance of serum
progesterone and endometrial thickness to know if freeze-only embryo transfer would be
beneficial for this patient.
Title of Article IVF Transfer of Fresh or Frozen Embryos in Women without Polycystic Ovaries
and Complete
Reference Citation:
Source Vuong, L. N., Dang, V. Q., Ho, T. M., Huynh, B. G., Ha, D. T., Pham, T. D., ... & Mol, B. W.
(2018). IVF transfer of fresh or frozen embryos in women without polycystic ovaries. New
England Journal of Medicine, 378(2), 137-147.

Link: https://pubmed.ncbi.nlm.nih.gov/29320655/ or
https://www.nejm.org/doi/10.1056/NEJMoa1703768?url_ver=Z39.88-
2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Research P: Women without PCOS from an infertile couple desirous of an IVF pregnancy
Question I: Freeze-only embryo transfer
C: Fresh embryo transfer
O: Ongoing pregnancy after the first transfer of embryos (detectable heart rate after 12 weeks of
gestation)- primary outcome
Secondary outcomes- rates of implantation, frequencies of ectopic pregnancy,
miscarriage, multiple pregnancy, the ovarian hyperstimulation syndrome in the primary
cycle, or pregnancy complications
M: Randomized Clinical Trial

Would women, without PCOS, from an infertile couple desirous of an IVF pregnancy have a
better chance of having an ongoing pregnancy after the first transfer of embryos from a freeze-
only embryo transfer compared to a fresh embryo transfer?

Note: Why patients without PCOS? Women with PCOS who undergo IVF have lower rates of
ovarian hyper-stimulation syndrome (OHSS) with the transfer of frozen rather than fresh
embryos.
Are the results valid?
1. Were the Yes (page 138, paragraph 3- Methods: Study design and oversight; page 138, paragraph 7-
patients Methods: Study Procedures)
randomized?
The study conducted a single center, randomized controlled trial at a private unit at the My Duc
Hospital in Ho Chi Minh City, Vietnam.
 The women were randomly assigned in a 1:1 ratio to receive either fresh embryos or frozen
embryos by means of block randomization by an independent study coordinator using a
computer-generated random list (with a block size of 2,4, or 8).
2. Were all the Yes (page 140, paragraph 5- Results: Study patients; page 141- Results: Outcomes at 12 months,
patients who Figure 1)
entered the
trial properly Follow-up data were complete for all the women in the study. All 782 patients were included in
accounted for the intention-to-treat analysis.
at its
conclusion?

3. Were the No (page 140, paragraph 4,5- Results: Study patients; page 141, paragraph 1- Results: Outcomes
patients at 12 months)
analyzed in
the groups to Of the 782 patients who underwent randomization, 391 were assigned to frozen-embryo transfer
which they and the same number were assigned to fresh-embryo transfer. After randomization, 9 women
were in the frozen-embryo group opted to undergo transfer of fresh embryos, whereas 10 women
in the fresh-embryo group opted to undergo transfer of frozen embryos.
randomized?
At 12 months after randomization, 582 transfers had been performed in the frozen-embryo group;
391 women had undergone one transfer, 157 had undergone two transfers, 31 had undergone
three transfers, and 3 had undergone four transfers. In the fresh-embryo group, there had been
391 fresh transfers and 224 frozen transfers; 391 women had undergone one transfer, 172 had
undergone two transfers, 45 had undergone three transfers, and 7 had undergone four transfers.

4. Were the No
patients,
health The patients, physicians, research staff were not blinded. There was no mention in the study
workers, and protocol that these people were blinded for the study.
study
personnel
blinded to
treatment?

5. Were the Yes (page 142, table 1- Demographic and Clinical Characteristics of the Patients at Baseline)
groups
similar at the The 2 groups were well matched at baseline. To mention, mean age was 32 ± 4 years, mean
start of the duration of infertility was 57 months, approximately two-thirds of patients had primary infertility,
trial? and mean body mass index was 20.8 ± 2.2 kg/m2 in both groups. In 84% of patients this was the
first IVF attempt, approximately two-thirds had primary infertility and the most common
indication for IVF was male factor infertility (43% and 40% of patients in the freeze-only and
fresh transfer groups, respectively). The total dose of FSH (2731 ± 851 and 2656 ± 869 IU),
progesterone level on day of trigger (1.4 ± 0.8 and 1.3 ± 1.1 ng/ml), and estradiol level on trigger
(2019 ± 1470 and 2029 ± 1616 pg/ml) were similar in the freeze-only and fresh transfer groups.
There were also no significant between-group differences in the number of oocytes retrieved,
number of metaphase II, fertilized (two-pronuclear), cleavage or good day 3 embryos, or the
number of embryos transferred.

There were no significant differences between the two groups as calculated by means of the
Wilcoxon test and the Chi-square test.
6. Aside from No (page 139, paragraph 2,4- Methods: Intervention, Follow-up)
the The endometrium of patients under the frozen-embryo group were prepared with the use
experimental of oral estradiol valerate at a dose of 8 mg per day, starting on the second or third day of
intervention, the menstrual cycle, prior to embryo transfer.
were the • It is important to note that this is routinely done. Women undergoing embryo transfer
groups treated with frozen embryos require priming with exogenous estrogen and progesterone. And
equally? another meta-analysis concluded that no specific protocol for endometrial preparation
was superior to any other; all led to similar results in terms of endometrial receptivity
and implantation rate [1].

Both the fresh-embryo group and frozen-embryo group were given 800mg of vaginal
progesterone per day starting 3 days before embryo transfer in the frozen-embryo group, and
starting on the day of oocyte retrieval in the fresh-embryo group starting on the day of oocyte
retrieval in the fresh-embryo group; both drug regimens continued until pregnancy testing was
performed.

2 weeks after embryo transfer, serum beta hCG was measured. If the pregnancy test was positive
(hCG, >5 mIU per milliliter), luteal-phase support was continued until 7 weeks of gestation, and
ultrasonography of the pelvis was performed at gestational weeks 7 and 12. For the remainder of
the pregnancy and neonatal period, the women were followed and treated on the basis of routine
clinical practice.
What are the results?
7. How large Primary Outcome: was ongoing pregnancy after the first transfer of embryos. Ongoing
was the pregnancy was defined as pregnancy with a detectable heart rate after 12 weeks of gestation. On
treatment the day that oocyte maturation was trigerred, there were no significant differences in estradiol
effect? and progesterone levels between the overall study population and the patients who chose elective
embryo freezing.

Table 1. Fertility Outcomes and Treatment Complications after the 1st Embryo Transfer.
Frozen- Fresh-Embryo 95% Risk Ratio P-value
Embryo Group Group CI (95% CI) **
(n = 391) (n = 391)

Ongoing 142 (36.3%) 135 (34.5%) 1.8 1.05 0.65

pregnancy (%)

** P values were calculated by means of Fisher’s exact test and Student’s t-test.

Table 2. Fertility Outcomes and Treatment Complications at 12 months.

Frozen- Fresh-Embryo 95% Risk Ratio P-value
Embryo Group Group CI (95% CI) **
(n = 391) (n = 391)

Ongoing 212 (54.2%) 209 (53.5%) 0.8 1.01 0.89

pregnancy (%)

** P values were calculated by means of Fisher’s exact test and Student’s t-test.

After the first embryo transfer, rates of implantation, clinical pregnancy, and live birth did not
differ significantly between the frozen-embryo group and the fresh-embryo group. Also, there
was no significant between-group difference in the live-birth rate after the first cycle or at 12
months or in the 12-month rate of ongoing pregnancy.
 Secondary Outcomes:
Secondary outcomes were the rates of implantation, clinical pregnancy, ectopic pregnancy,
miscarriage, live birth, multiple pregnancy, treatment complications.

Table 3. Fertility Outcomes and Treatment Complications after the 1st Embryo Transfer.
Frozen- Fresh-Embryo 95% CI Risk P-value
Embryo Group Group Ratio **
(n = 391) (n = 391) (95% CI)

Positive 296 (75.7%) 287 (73.4%) 2.3 1.03 0.51

Pregnancy Test

Clinical 260 (66.5%) 261 (66.8%) -0.3 1.0 1.00

Pregnancy

Implantation 336/1152 340/1223 1.4 1.05 0.47

(29.2%) (27.8%)

Ectopic 13 (3.3%) 20 (5.1%) -1.8 0.65 0.29

Pregnancy

Miscarriage 47 (12.0) 38 (9.7%) 2.3 1.24 0.36

** P values were calculated by means of Fisher’s exact test and Student’s t-test.

There were no significant between group differences in the frequencies of ectopic pregnancy,
miscarriage, multiple pregnancy, the ovarian hyperstimulation syndrome in the primary cycle, or
pregnancy complications.

8. How precise Table 1. Fertility Outcomes and Treatment Complications after the 1st Embryo Transfer.
was the 95% CI Risk Ratio (95% CI) P-value **
estimate of
the treatment Ongoing pregnancy (%) 1.8 (-5.2 to 8.7) 1.05 (0.87 to 1.27) 0.65
effect?
** P values were calculated by means of Fisher’s exact test and Student’s t-test.

Table 2. Fertility Outcomes and Treatment Complications at 12 months.

95% CI Risk Ratio (95% CI) P-value **

Ongoing pregnancy (%) 0.8 (-6.5 to 8.0) 1.01 (0.89 to 1.15) 0.89
** P values were calculated by means of Fisher’s exact test and Student’s t-test.

Table 3. Fertility Outcomes and Treatment Complications after the 1st Embryo Transfer.
95% CI Risk Ratio (95% CI) P-value **

Positive Pregnancy Test 2.3 (-4.1 to 8.7) 1.03 (0.95 to 1.12) 0.51

Clinical Pregnancy -0.3 ( -7.1 to 6.6) 1.0 (0.90 to 1.10) 1.00

Implantation 1.4 (-2.4 to 5.1) 1.05 (0.92 to 1.19) 0.47

 Ectopic Pregnancy -1.8 (-4.9 to 1.3) 0.65 (0.33 to 1.29) 0.29

Miscarriage 2.3 (-2.3 to 6.9) 1.24 (0.83 to 1.85) 0.36

** P values were calculated by means of Fisher’s exact test and Student’s t-test.

The P-values for all outcomes (ongoing pregnancy, positive pregnancy test, clinical pregnancy,
implantation, ectopic pregnancy, and miscarriage) are greater than 0.05 and the 95% confidence
interval include the null value (RR=1) for outcomes measured, then there is insufficient
evidence to conclude that the outcome of the groups are statistically significantly different.
How can I apply the results to patient care?
9. Were the Yes (page 142, table 1- Demographic and Clinical Characteristics of the Patients at Baseline)
study patients
similar to the The age of participants in the study include those 32 ± 4 years old., the duration of infertility of
patients in my the enrolled couples were at 56-58 ± 41 months, and majority (83.9-84.4%) have no previous
practice? IVF attempts. Majority of the couples have primary infertility (2.7-66.2%) and majority also have
male factors as their indication for IVF.

The clinical picture of the patient/couple concerned is similar to the picture of the participants.
More information is needed on the infertility of the couple and must still be investigated on prior
to the start of this contemplated intervention.
10. Were all Yes (page 139, paragraph 5- Methods: Outcomes)
clinically
important Aside for the primary and secondary outcomes mention above, for pregnancies that continued
outcomes beyond 24 weeks the following were recorded: pregnancy-induced hypertension, preeclampsia,
considered? and the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome;
antepartum hemorrhage gestational diabetes mellitus and obstetrical outcomes (including
gestational age at delivery, cesarean section- elective, suspected fetal distress, and nonprogressive
labor; vaginal-instrumental delivery, increased peripartum blood loss, birth weight, macrosomia,
small size for gestational age, prematurity, admission to a neonatal intensive care unit, perinatal
death, and congenital malformations diagnosed at birth. The total duration of follow-up was 12
months, including a post hoc analysis of the ongoing pregnancy rate.
11. Are the likely Given the patient’s state (unremarkable history, primary infertility, no previous IVF attempts, and
treatment no PCOS), I would not strongly recommend the freeze-only embryo transfer. This study did
benefits not significant difference in the rate of ongoing pregnancy or live birth between frozen-embryo
worth the transfer and fresh-embryo transfer in women without the polycystic ovary syndrome who were
potential undergoing IVF.
harm and
Factoring in the cost of the cryoprecipitation procedure, without considering the IVF cost itself,
costs?
is already costly. As of 2018 [2], IVF process is already 200,000 pesos to 400, 000 pesos and an
additional 100,000 pesos for frozen-embryo transfer.

Other references:
[1] Glujovsky D, Pesce R, Fiszbajn G, et al. Endometrial preparation for women undergoing embryo transfer with frozen
embryos or embryos derived from donor oocytes. Cochrane Database Syst Rev 2010; :CD006359.
[2] https://transferwise.com/us/blog/cost-of-having-a-baby-in-philippines