The effects of fresh embryo transfer and frozen-thawed embryo transfer on the perinatal outcomes of single fetuses from mothers with PCOS

Huizhen Li; Lihua Xu; Yanru Niu; Xia Zhu; Xiaomei Gao; Tianzhong Ma

doi:10.1371/journal.pone.0312003

. 2024 Oct 28;19(10):e0312003. doi: 10.1371/journal.pone.0312003

The effects of fresh embryo transfer and frozen-thawed embryo transfer on the perinatal outcomes of single fetuses from mothers with PCOS

Huizhen Li ¹, Lihua Xu ¹, Yanru Niu ², Xia Zhu ¹, Xiaomei Gao ¹, Tianzhong Ma ^1,^*

Editor: Tamara Sljivancanin Jakovljevic³

PMCID: PMC11515985 PMID: 39466793

Abstract

Purpose

To investigate the effects of fresh embryo transfer and frozen-thawed embryo transfer on perinatal outcomes among patients with PCOS.

Method

Patients who underwent in vitro fertilization and embryo transfer at the reproductive medicine center of the Affiliated Hospital of Guangdong Medical University from February 2013 to March 2021 were retrospectively analyzed. Patients were divided into the fresh embryo transfer group and frozen-thawed embryo transfer group according to whether fresh embryo transfer was performed. According to their conditions, patients were further classified into the ET-PCOS group (group A, n = 104), ET-non-PCOS group (group B, n = 212), FET-PCOS group (group C, n = 102), or FET-non-PCOS group (group D, n = 148); the general data, laboratory indicators and pregnancy outcomes of the patients were statistically analyzed, and the perinatal outcomes and related factors between the groups were compared and analyzed.

Results

The level of E₂ on the HCG test day in the ET group was lower than that in the FET group. The natural birth rate of group D was lower than that of group A and group B, and the cesarean section rate was higher than that of group A and group B; the clinical pregnancy rate of group A was higher than that of group B and group D, and the difference was statistically significant (P < 0.05). There was no significant difference in the total abortion rate, early abortion rate or late abortion rate between the groups (P > 0.05). There was no significant difference in gestational age, neonatal sex or neonatal weight between the groups (P > 0.05). The incidence of placenta previa in Group B was significantly lower than that in Group D, and the difference was significant (P < 0.05). The incidence of fetal distress in Group B was significantly lower than that in Groups C and D, and the incidence of neonatal jaundice in Group D was significantly higher than that in Groups A and B (P < 0.05). In the multivariate analysis, the number of high-quality embryos was independent factors affecting clinical pregnancy, and the embryo transfer method was an independent factor affecting fetal distress and neonatal jaundice.

Conclusion

Young PCOS patients without risk of OHSS have a high clinical pregnancy rate with fresh transplant cycles. PCOS disease itself has no significant effect on the perinatal outcomes of the mother or singleton infant. Frozen-thawed embryo transfer may increase the incidence of low placenta, fetal distress and neonatal jaundice.

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disease in women of childbearing age. PCOS is also a common cause of anovulatory infertility, accounting for approximately 80% of anovulatory infertility cases [1, 2]. With the increasing number of infertile people, assisted reproductive technology represents a new treatment for people with infertility [3]. The most critical difference between fresh embryo transfer and frozen-thawed embryo transfer (FET) is the continuous change in the hormone environment after COH. Compared with women with normal ovulation, PCOS patients have a stronger ovarian response. The supraphysiological level of estradiol caused by ovarian stimulation can affect embryo implantation, placental development and blood supply, resulting in adverse outcomes [4–7]. However, FET technology can reduce the supraphysiological state after ovarian stimulation and provide a more favorable intrauterine environment for embryo implantation and placenta formation [8]. However, it is still unclear whether there are differences in perinatal outcomes between women who undergo fresh and frozen-thawed embryo transfer. Therefore, the purpose of this study was to explore and analyze the effects of fresh embryo transfer and frozen-thawed embryo transfer on the perinatal outcomes of singletons from mothers with PCOS.

Materials and methods

Study design and participants

This was a retrospective analysis of patients who underwent IVF-ET-assisted conception at the Reproductive Center of the Affiliated Hospital of Guangdong Medical University between February 1, 2013, and March 27, 2021. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki declaration and its later amendments. This study was approved by the Ethics Committee of the Affiliated Hospital of Guangdong Medical University (PJKT2022-093). The study was initiated on 9/15/2022. Written informed consent was obtained from all patients, and all participants were informed that they could withdraw at any point during the study. The inclusion criteria for the PCOS group were as follows: (i) PCOS in accordance with the 2003 Rotterdam criteria; (ii) less than 35 years of age; (iii) retrieval of more than 5 eggs; (iv) selection of a long protocol; and (v) complete inspection index data in this center. The inclusion criteria for the control group were as follows: (i) less than 35 years of age; (ii) retrieval of more than 5 eggs; (iii) selection of a long protocol; (iv) infertility caused by tubal factors; and (v) complete inspection index data in this center. Patients were excluded from the study if they met any of the following criteria: (i) reproductive system abnormalities or chromosome abnormalities; (ii) twin or multiple pregnancy; (iii) severe mental, endocrine or systemic disease; (iv) myoma of the uterus, endometriosis or tubal factor disease; (v) premature ovarian failure or decreased ovarian function; (vi) a history of uterine surgery; or (vii) missing data or missing visits for external reasons.

A total of 566 patients who met the inclusion criteria were included. Patients were divided into a fresh embryo transfer group and a frozen-thawed embryo transfer group according to whether fresh embryo transfer was performed. They were then divided into fresh embryo transfer and frozen-thawed embryo transfer groups. The patients were further classified into the ET-PCOS group (group A, n = 104), ET-non-PCOS group (group B, n = 212), FET-PCOS group (group C, n = 102), or FET-non-PCOS group (group D, n = 148).

Treatment protocol

A long protocol for ovulation induction was used in the fresh cycle group. After the indicated standard was reached, 3.75 mg of long-acting GnRH-a (afolin, Huiling, Germany) was given on the 2nd—4th day of the menstrual cycle or mid-luteal phase, 0.8–1.875 mg GnRH-a was subcutaneously injected after ovulation on D7, or 0.05–0.1 mg GnRH-a was subcutaneously injected every day after ovulation on D7. When the pituitary downregulation standard [LH< 5 IU/L, E₂< 50 pg/mL, endometrial thickness < 5 mm] was used, exogenous gonadotropin 75–225 U/d [Gonaven, Merck, Germany; Prikon, Mushadong, USA; or Lishenbao, Zhuhai Lizhu] was given for ovulation induction. When the diameter of at least one follicle was 19 mm, the diameter of two follicles was 18 mm, or the diameter of three follicles was 17 mm, the blood E₂ level reached 250–300 pg/mL for each dominant follicle (≥ 16 mm), or more than 60% for follicles greater than 16 mm, the injection of human chorionic gonadotropin (hCG) was 5000–10,000 IU that night. Fresh cleavage-stage embryos or blastocysts were transplanted on day 3 or 5 after fertilization.

In the frozen-thawed cycle group, 2~3 thawed good-quality embryos were selected for resuscitation and transplantation. The following three transplantation protocols were applied. (1) The natural cycle is suitable for patients with normal ovulation and an endometrial thickness > 8 mm. The follicles and endometrium were monitored on the 10th day of menstruation, and follicles >16 mm in size were monitored daily until ovulation. After ovulation, 40 mg progesterone was given daily to promote endometrial progression to the secretory phase, and the embryo was thawed and transferred 3 days later. (2) Hormone replacement cycles are suitable for patients with irregular menstruation, ovulation disorders or previous monitoring of endometrial thinning. From the second to the third day of menstruation, 6–8 mg of estradiol valerate was orally administered daily, and the dosage was adjusted according to the patient’s condition. Endometrial thickness was monitored by B ultrasound after 10–12 days of treatment. If the endometrial thickness was < 8 mm, the dosage of estradiol valerate was increased orally, with a maximum of dose of 10 mg/d. When the endometrial thickness was ≥ 8 mm, a 100 mg/d progesterone needle was used to transform the endometrium, and resuscitation transplantation was performed 3 days later. (3) The ovulation cycle was deemed suitable for patients with a natural cycle endometrial thickness < 8 mm or menorrhagia. These patients were given 75 U of human menopausal gonadotropin (HMG) by intramuscular injection daily from the fifth day of menstruation and underwent B ultrasound monitoring of follicles and the endometrium after 5 days; the dosage was adjusted as needed. hCG (10,000 U) was given to induce ovulation when the dominant follicle diameter was ≥ 18 mm. After ovulation, 40 mg/d progesterone was given to prepare the endometrium for implantation, and 3 days later, the embryo was thawed and transplanted. After transplantation, progesterone (60–80 mg/d) was given.

Serum hCG was detected 14–16 days after transplantation. Serum hCG > 5 U/L was positive. Twenty-eight days after transplantation, guided B ultrasound examination was performed to confirm the presence of an intrauterine pregnancy, and early cardiac motion indicated a clinical pregnancy. Follow-up of the pregnant women and their newborns was performed by telephone.

This study was approved by the Ethics Committee of the Affiliated Hospital of Guangdong Medical University (PJKT2022-093). The conduct of this study is in line with the Declaration of Helsinki.

Statistical analysis

SPSS 26.0 statistical software was used for data analysis. The adoption rate (%) of enumeration data indicates that the comparison of the rates between groups was performed via the χ2 test; normally distributed data are expressed as $\bar{X} \pm SDs$ , the independent sample t test was used for comparisons, and the LSD t test was used for pairwise multiple comparisons. Nonnormally distributed data are presented as the median (quartile range) [M (P25–P75)], and the K‒W test was used for comparisons. The Mann–Whitney U test was used for comparisons between groups. When the number of events was less than 5, the chi-square test and Fisher’s exact test were used to analyze differences between groups, and P < 0.05 indicated that the difference was statistically significant.

Results

Patient characteristics

Our retrospective study included 566 patients: 104 patients in Group A, 212 in Group B, 102 in Group C and 148 in Group D. The patient characteristics are presented in Table 1. The BMI and bFSH and bLH levels in Groups A and C were higher than those in Groups B and D; the level of bE₂ in Group C was higher than that in Group B; The AFC of PCOS patients was higher than that of non-PCOS patients (P < 0.05).

Table 1. General comparison of patient characteristics [M (P25, P75), %].

Group	ET		FET
	ET-PCOS	ET-non-PCOS	FET-PCOS	FET-non-PCOS
	A (n = 104)	B (n = 212)	C (n = 102)	D (n = 148)
Female age	29 (26,30)	30 (28,32)	29 (27, 32)	29 (27,32)
Infertility duration	3 (2,5)	3 (2,5)	3 (2,5)	3 (2,5)
Primary infertility	73.07 (76/104)	58.96 (125/212)	76.47 (78/102)	62.84 (93/148)
BMI (kg/m²)	22.10	20.52	21.78	20.57
BMI (kg/m²)	(20.47,24.41)^{^}^†	(19.25,22.85)	(19.56,24.30)^{^}^†	(19.05,22.94)
bFSH (IU/L)	5.97	6.54	5.79	6.25
bFSH (IU/L)	(5.05,7.14)^{^}^†	(5.62,7.39)	(5,6.82)^{^}^†	(5.6,7.38)
bE₂ (ng/L)	38.45	36.66	42.95	39.39
bE₂ (ng/L)	(27.87,56.45)	(25.76,47.53)	(32.78,57.87)^{^}	(29.26,51.47)
bLH (IU/L)	9.57	5.19	9.37	5.68
bLH (IU/L)	(5.92,14.04)^{^}^†	(3.91,6.97)	(5.84,14.25)^{^}^†	(4.28,7.63)
AFC	25.50	18.00	26.50	21.00
AFC	(24.00,35.75)	(14.00,24.00)^*^#^†	(24.00,40.00)	(16.00,24.00)^*^#
Gravidity
0	20.38(76/373)	33.51(125/373)	21.18(79/373)	24.93(93/373)
1	17.16(23/134)	42.54(57/134)	14.93(20/134)	25.37(34/134)
2	9.76(4/41)	48.78(20.41)	4.88(2/41)	36.59(15/41)
3+	5.56(1/18)	55.56(10/18)	5.56(1/18)	33.33(6/18)
Parity
0	19.80(98/495)	36.16(179/495)	18.79(93/495)	25.25(125/495)
1	8.82(6/68)	45.59(31/68)	13.24(9/68)	32.35(22/68)
2	0.00(0/3)	66.67(2/3)	0.00(0/3)	33.33(1/3)

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Compared with Group A

* P < 0.05; compared with Group B

^ P < 0.05; compared with Group C

# P < 0.05; compared with Group D

† P < 0.05. (Indicates the statistical tests used to evaluate the differences between study groups).

Outcome of ART treatment

There was no significant difference in the total number of Gn days or endometrial thickness on the HCG test day among the groups (P>0.05). However, the E₂ level on the HCG test day, the number of retrieved oocytes and the number of high-quality embryos in the ET group were lower than those in the FET group. The number of IVF cycles in Groups B and D was higher than that in Groups A and C, whereas the opposite was true for ICSI cycles. Additionally, the number of cycles in Groups B and D was higher than that in Groups A and C. The number of day 3 embryos transferred in the ET group was significantly higher than that in the FET group, whereas the number of day 5 embryos transferred in the ET group was lower than that in the FET group (P<0.05) (Table 2).

Table 2. Comparison of ovulation induction, fertilization and embryo transfer [M (P25, P75), %].

Group	ET		FET
	ET-PCOS	ET-non-PCOS	FET-PCOS	FET-non-PCOS
	A (n = 104)	B (n = 212)	C (n = 102)	D (n = 148)
Total gonadotropin dose/(IU)	1625 (1350,1943.75)	1875 (1500,2334.38)	1500 (1187.5,1856.25)	1637.5 (1350,3100)
Gn stimulation duration	11 (9,12)	11 (10,11.75)	10 (9,11)	10 (10,11)
E₂ at trigger day (pg/ml)	2272	2555	4141	3269
E₂ at trigger day (pg/ml)	(1742.5,3768.25)^#^†	(1813.25,3367.25)^#^†	(2206,6803.25)	(2418,6286)
Endometrial thickness on trigger day (mm)	12 (11,13)	12 (11,14)	12 (10,13)	12 (11,14)
Retrieved oocyte number	13.5 (10,16)^#^†	12 (9,15)^#^†	17.5 (13.75,23)	14 (11,19)
Number of good-quality embryos	3 (1,5)^#^†	2 (1,5)^#^†	4 (2,7)	3 (2,6)
Fertilization method
IVF	68.27 (71/104)	83.96 (178/212)^*^#	70.59 (72/102)	84.46 (125/148)^*^#
ICSI	31.73 (33/104)	14.62 (34/212)^*^#	29.41 (30/102)	15.54 (23/148)^*^#
Day of embryo transfer
Day 3	79.81 (83/104)^#^†	84.43 (179/212)^#^†	14.71 (15/102)	20.27 (30/148)
Day 5	20.19 (21/104)^#^†	15.57 (33/212)^#^†	85.29 (87/102)	79.73 (118/148)

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Compared with Group A

* P < 0.05; compared with Group B

^ P < 0.05; compared with Group C

# P < 0.05; compared with Group D

† P < 0.05. (indicates the statistical tests used to evaluate the differences between study groups).

Clinical pregnancy outcomes

In this study, the clinical pregnancy rate of Group A was significantly greater than those of Groups B and D (P>0.05) (Table 3).

Table 3. Comparison of clinical pregnancy outcomes.

Group	ET		FET
	ET-PCOS	ET-non-PCOS	FET-PCOS	FET-non-PCOS
	A (n = 104)	B (n = 212)	C (n = 102)	D (n = 148)
Clinical pregnancy	65.38 (68/104)^{^}^†	52.83 (112/212)	59.80 (61/102)	48.64 (72/148)
Live birth rate	53.85(56/104)	45.75(97/212)	44.12(45/102)	37.84(56/148)
Biochemical pregnancy	8.65 (9/104)	9.91 (21/212)	15.69 (16/102)	10.81 (16/148)
Early spontaneous abortion	13.24 (9/68)	9.82 (11/112)	14.75 (9/61)	15.28 (11/72)
Late abortion	4.41 (3/68)	3.57 (4/112)	8.20 (5/61)	2.78 (2/72)
Total abortion rate	17.65 (12/68)	13.39 (15/112)	22.95 (14/61)	18.06 (13/72)
Medium and heavy OHSS	4.81 (5/104)	3.30 (7/212)	/	/

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Compared with Group A

* P < 0.05; compared with Group B

^ P < 0.05; compared with Group C

# P < 0.05; compared with Group D

† P < 0.05. (Indicates the statistical tests used to evaluate the differences between study groups).

Perinatal outcomes

The perinatal data revealed 254 cycles of clinical pregnancy and delivery: 56 in Group A, 97 in Group B, 45 in Group C and 56 in Group D. The natural birth rate of Group D was significantly lower than that of Group A and Group B, and the cesarean section rate was significantly higher than that of group A and group B (P < 0.05) (Table 4).

Table 4. Comparison of perinatal data [M (P25, P75), X±SD, %].

Group	ET		FET
	ET-PCOS	ET-non-PCOS	FET-PCOS	FET-non-PCOS
	A (n = 56)	B (n = 97)	C (n = 45)	D (n = 56)
Gestational weeks	38.5 (38,39)	39 (38,40)	39 (38,40)	39 (38,39.75)
Mode of delivery
Eutocia	64.29 (36/56)	65.98 (64/97)	46.67 (21/45)	39.29 (22/56)^*^{^}
Abdominal delivery	35.71 (20/56)	34.02 (33/97)	53.33 (24/45)	60.72 (34/56)^*^{^}
Neonatal sex
Male	50 (28/56)	57.73 (56/97)	46.67(21/45)	62.5(35/56)
Female	50 (28/56)	42.27 (41/97)	53.33(24/45)	37.5(21/56)
Neonatal weight/(kg)	3.2 (2.81,3.45)	3.2 (2.9,3.48)	3.1 (2.9,3.5)	3.3 (3.0,3.5)
Large infant	3.57 (2/56)	3.09 (3/97)	0 (0/45)	5.35 (3/56)
Low birth weight infant	3.57 (2/56)	10.71 (6/56)	8.89 (4/45)	0 (0/56)

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Compared with Group A

* P < 0.05; compared with Group B

^ P < 0.05; compared with Group C, # P < 0.05; compared with Group D, † P < 0.05. (Indicates the statistical tests used to evaluate the differences between study groups).

Perinatal complications of pregnant women

A total of 157 pregnant women had clinical deliveries, 234 were followed up, and 11 were lost to follow-up. Among the pregnant women who were followed up, 50 were in group A, 88 were in group B, 42 were in group C, and 54 were in group D. The incidence of placenta previa in group B was significantly lower than that in group D, and the difference was statistically significant (P<0.05). The rates of gestational diabetes mellitus, hypertensive disorders of pregnancy, placenta previa and premature rupture of the membrane were not significantly different among the groups (P>0.05) (Table 5).

Table 5. Perinatal complications of pregnant women [%].

Group	ET		FET
	ET-PCOS	ET-non-PCOS	FET-PCOS	FET-non-PCOS
	A (n = 50)	B (n = 88)	C (n = 42)	D (n = 54)
Gestational diabetes mellitus	18 (9/50)	13.64 (12/88)	14.29 (6/42)	9.26 (5/54)
Hypertensive disorder complicating pregnancy	8 (4/50)	2.27 (2/88)	9.52 (4/42)	5.56 (3/54)
Low placental	2 (1/50)	1.13 (1/88)^†	7.14 (3/42)	12.96 (7/54)
Placenta previa	8 (4/50)	5.68 (5/88)	7.14 (3/42)	7.41 (4/54)
Premature rupture of the membranes	4 (2/50)	6.81 (6/88)	7.14 (3/42)	0 (0/54)

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Compared with Group A, * P < 0.05; compared with Group B, ^ P < 0.05; compared with Group C, # P < 0.05; compared with Group D

† P < 0.05. (Indicates the statistical tests used to evaluate the differences between study groups).

Perinatal outcomes of newborns

There was no significant difference in the incidence of neonatal hospitalization ≥ 3 d, neonatal hypoglycemia or perinatal death among the three groups (P > 0.05). However, in our study, the incidence of fetal distress in Group B was significantly lower than that in Groups C and D, the incidence of neonatal jaundice in Group D was significantly greater than that in Groups A and B, and the difference was significant (P < 0.05) (Table 6).

Table 6. Perinatal outcomes of neonates [%].

Group	ET		FET
	ET-PCOS	ET-non-PCOS	FET-PCOS	FET-non-PCOS
	A (n = 50)	B (n = 88)	C (n = 42)	D (n = 54)
Fetal intrauterine distress	2 (1/50)	0 (0/88)^#^†	9.52 (4/42)	11.11 (6/54)
Neonatal hospitalization ≥ 3 days	16 (8/50)	19.32 (17/88)	23.81 (10/42)	27.78 (15/54)
Icterus neonatorum	12 (6/50)	13.64 (12/88)	33.33 (14/42)	42.59 (23/54)^*^{^}
Neonatal hypoglycemia	4 (2/50)	0 (0/88)	4.76 (2/42)	1.85 (1/54)
Perinatal death	0 (0/50)	1.14 (1/88)	0 (0/42)	0 (0/54)

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Compared with Group A

* P < 0.05; compared with Group B

^ P < 0.05; compared with Group C

# P < 0.05; compared with Group D

† P < 0.05. (Indicates the statistical tests used to evaluate the differences between study groups).

Regression analysis of related factors affecting the clinical pregnancy rate

The results of univariate and multivariate analyses of possible factors affecting the clinical pregnancy rate of infertile patients are presented in Table 7. According to the univariate analysis, bFSH, the number of oocytes retrieved, the number of high-quality embryos, the type of embryo transferred and PCOS were significantly correlated with the clinical pregnancy rate. After multivariate analysis, the number of high-quality embryos (OR = 1.119; 95% CI: 1.042–1.201; p = 0.002) was still independent factors associated with the clinical pregnancy rate (Table 7).

Table 7. Logistic regression analysis of factors affecting the clinical pregnancy rate.

Variables	Univariate analysis p value	OR	(95% CI)	Multivariate analysis p value	OR	(95% CI)
Female age	0.114	0.957	(0.925,1.011)
Infertility duration	0.156	0.948	(0.881,1.021)
bFSH	0.010	0.859	(0.766,0.904)	0.092	0.902	(0.801,1.017)
bLH	0.325	1.019	(0.982,1.057)
bE₂	0.526	0.999	(0.994,1.003)
BMI	0.065	1.057	(0.997,1.120)
AFC	0.002	1.602	(1.010,1.048)	0.184	1.015	(0.993,1.037)
E₂ on trigger day	0.484	1.000	(1.000,1.000)
Endometrial thickness on trigger day	0.181	1.048	(0.979,1.122)
Total gonadotropin dose	0.821	1.000	(1.000,1.000)
Gn stimulation duration	0.228	1.053	(0.968,1.146)
Retrieved oocyte number	0.005	1.043	(1.013,1.074)	0.997	1.000	(0.965,1.037)
Number of good-quality embryos	0.000	1.134	(1.067,1.205)	0.002	1.119	(1.042,1.201)
Fertilization method	0.941	0.985	(0.657,1.477)
Delivery method	0.371	1.164	(0.440,0.885)
Day of embryo transfer	0.020	0.671	(0.480,0.938)	0.793	0.949	(0.644,1.399)
PCOS	0.008	0.624	(0.051,0.874)	0.184	1.015	(0.993,1.037)

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Regression analysis of related factors affecting lowering of the placenta

The possible factors affecting the clinical pregnancy rate of infertile patients were analyzed by univariate and multivariate analyses. In the single-factor analysis, the number of eggs obtained and the method of transplantation were significantly correlated with the low position of the placenta. After multivariate analysis, there was no significant correlation between the included indicators and the incidence of a low placenta (Table 8).

Table 8. Logistic regression analysis of factors affecting low placental position.

Variables	Univariate analysis p value	OR	(95% CI)	Multivariate p-value analysis	OR	(95% CI)
Female age	0.878	0.985	(0.813,1.194)
Infertility duration	0.934	0.989	(0.756,1.293)
bFSH	0.281	0.792	(0.518,1.210)
bLH	0.402	0.935	(0.800,1.094)
bE₂	0.664	0.995	(0.972,1.018)
BMI	0.551	1.067	(0.862,1.321)
AFC	0.705	0.988	(0.927,1.052)
E₂ on trigger day	0.722	1.000	(1.000,1.000)
Endometrial thickness on trigger day	0.433	0.905	(0.706,1.160)
Total gonadotropin dose	0.703	1.000	(0.999,1.001)
Gn stimulation duration	0.964	0.993	(0.723,1.363)
Retrieved oocyte number	0.090	1.073	(0.989,1.164)
Number of good-quality embryos	0.663	1.041	(0.869,1.247)
Fertilization method	0.723	1.275	(0.332,4,902)
Delivery method	0.009	0.126	(0.027,0.591)	0.061	0.153	(0.022,1.089)
Day of embryotransfer	0.048	0.211	(0.045,0.986)	0.763	0.738	(0.102,5.321)
PCOS	0.664	1.313	(0.384,4.493)

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Regression analysis of related factors affecting fetal distress

The possible factors affecting nonfetal distress were analyzed by univariate and multivariate analyses. According to the univariate analysis, there was a significant correlation between the embryo transfer method and the occurrence of fetal distress. In the univariate analysis, only the embryo transfer method was correlated. To reduce the deviation of the results, the indicators with P < 0.1 in the univariate analysis were included in the multivariate analysis. The embryo transfer method (OR = 0.030; 95% CI: 0.003–0.348; p = 0.005) was still a relevant factor for the incidence of fetal distress (Table 9).

Table 9. Logistic regression analysis of the influence on fetal distress.

Variables	Univariate analysis p value	OR	(95% CI)	Multivariate p-value analysis	OR	(95% CI)
Female age	0.095	0.845	(0.693,1.030)	0.125	0.850	(0.691,1.046)
Infertility duration	0.408	1.104	(0.874,1.394)
bFSH	0.684	1.090	(0.721,1.648)
bLH	0.494	1.040	(0.930,1.162)
bE₂	0.685	0.995	(0.971,1.019)
BMI	0.736	1.040	(0.830,1.303)
AFC	0.887	1.005	(0.944,1.069)
E₂ on trigger day	0.056	1.000	(1.000,1.000)	0.416	1.000	(1.000,1.000)
Endometrial thickness on trigger day	0.820	0.971	(0.752,1.253)
Total gonadotropin dose	0.852	1.000	(0.999,1.001)
Gn stimulation duration	0.118	1.235	(0.948,1.609)
Retrieved oocyte number	0.826	0.989	(0.895,1.093)
Number of good-quality embryos	0.338	1.092	(0.912,1.309)
Fertilization method	0.342	0.365	(0.046,2.919)
Delivery method	0.009	0.063	(0.008,0.499)	0.005	0.030	(0.003,0.348)
Day of embryo transfer	0.192	0.407	(0.105,1.572)	0.127	3.670	(0.660,20.397)
PCOS	0.670	0.768	(0.227,2.592)

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Regression analysis of related factors affecting neonatal jaundice

The possible factors affecting the occurrence of neonatal jaundice were analyzed by univariate and multivariate analyses. In the univariate analysis, there was a significant correlation between the transplantation method, embryo transfer method and neonatal jaundice. After multivariate analysis, the transplantation method (OR = 0.219; 95% CI: 0.090–0.533; p = 0.001) was still an independent factor affecting the occurrence of neonatal jaundice (Table 10).

Table 10. Logistic regression analysis of the incidence of neonatal jaundice.

Variables	Univariate analysis p value	OR	(95% CI)	Multivariate analysis p value	OR	(95% CI)
Female age	0.430	1.042	(0.941,1.153)
Infertility duration	0.341	1.066	(0.935,1.214)
bFSH	0.675	1.046	(0.847,1.292)
bLH	0.904	1.004	(0.942,1.070)
bE₂	0.807	0.999	(0.989,1.008)
BMI	0.071	0.893	(0.789,1.010)
AFC	0.951	0.999	(0.967,1.031)
E₂ on trigger day	0.601	1.000	(1.000,1.000)
Endometrial thickness on trigger day	0.936	1.005	(0.886,1.141)
Total gonadotropin dose	0.894	1.000	(1.000,1.000)
Gn stimulation duration	0.773	1.024	(0.871,1.203)
Retrieved oocyte number	0.639	1.012	(0.964,1.061)
Number of good-quality embryos	0.311	1.050	(0.955,1.155)
Fertilization method	0.342	0.680	(0.307,1.507)
Delivery method	0.000	0.239	(0.126,0.455)	0.001	0.219	(0.090,0.533)
Day of embryotransfer	0.007	0.414	(0.218,0.787)	0.779	1.139	(0.459,2.827)
PCOS	0.608	1.178	(0.630,2.201)

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Discussion

With the development of assisted reproductive technology, frozen embryo transfer is becoming increasingly common. However, there is no consensus on whether there are differences in pregnancy complications and pregnancy outcomes between frozen embryo transfer and fresh embryo transfer. This retrospective study compared the clinical pregnancy, perinatal and maternal outcomes of women with PCOS after fresh ET cycles and FET cycles. Moreover, to clarify whether PCOS has an impact on perinatal outcomes, we established a control group of women with tubal infertility. A comparison of the differences in pregnancy outcomes and pregnancy complications between fresh embryo transfer and frozen embryo transfer revealed that PCOS patients could achieve a higher clinical pregnancy rate for a singleton fetus by fresh embryo transfer; moreover, frozen-thawed embryo transfer may increase the incidence of neonatal jaundice and fetal distress in singleton pregnancies. Multivariate analysis revealed that the number of high-quality embryos and the incidence of PCOS were independent factors affecting clinical pregnancy, and the embryo transfer method was an independent factor affecting fetal distress and neonatal jaundice.

In recent years, complications related to assisted reproductive technology have attracted increasing attention. According to the World Report of the International Commission on Monitoring Assisted Reproductive Technology [9–12], the pregnancy loss rates in fresh embryo transfer cycles were 21.8%, 21.1% and 20.2% in 2008, 2009 and 2010, respectively. The early pregnancy loss rates corresponding to FET were 28.9% (2008), 25.4% (2009) and 25.2% (2010). In a study by Carlos Simón et al. [13], the abortion rate after fresh embryo transfer was 5.4%, and that after FET was 14%. A study by Carlos Simón et al. reported that the abortion rate after fresh embryo transfer was 5.4%, whereas that after FET was 14%. The pregnancy loss rate of frozen-thawed embryo transfer was significantly higher than that of fresh embryo transfer. This finding was also verified in our study. Here, we also found that the incidence of early abortion and total abortion in patients who underwent frozen-thawed embryo transfer was higher than that in patients who underwent fresh embryo transfer. The potential cause of early abortion may be the damage related the freezing of embryos during the freezing process. The freezing and thawing process may cause instability of the embryonic genes, an increase in embryonic DNA fragments, and an increase in mitochondrial mutations, resulting in a decrease in the developmental potential of embryos. [14] At the same time, epigenetic changes may also occur in the embryo during the freezing and thawing process, which will have an adverse effect on embryonic development, resulting in an increase in the abortion rate. [14]. Moreover, we found that the clinical pregnancy rate of fresh embryo transfer is higher than that of frozen-thawed embryo transfer, which biases the results in favor of fresh embryo transfer. In contrast to most studies, other studies have reported that the clinical pregnancy rate of frozen-thawed embryo transfer is higher than that of fresh embryo transfer. They showed that in fresh ET cycles, the use of controlled superovulation technology makes the determination of the superphysiological level of estradiol in IVF/ICSI cycles inevitable. High concentrations of E₂ can affect embryo implantation, placental development and the uterine blood supply [15, 16]. Other studies have shown that when E₂ is > 3000 pg/ml, the risk is significantly increased [17]. However, in our study, the level of E₂ on the trigger day of fresh embryo transfer patients was mostly lower than 3000 pg/ml, and the level of E₂ on the trigger day of PCOS patients was lower than that of non-PCOS patients. Moreover, we also found that the clinical pregnancy rate of PCOS patients was higher than that of tubal factor infertility patients (Group A > Group B > Group D, P < 0.05), which may be related to the fact that PCOS patients have more basal follicles, can produce more eggs and can cultivate more high-quality embryos when treated with controlled ovarian hyperstimulation. We also found that the number of high-quality embryos (OR = 1.119; 95% CI: 1.042–1.1201; p = 0.002) was independent factors affecting clinical pregnancy.

Increasing evidence supports the association between IVF and the risk of adverse perinatal outcomes, with analysis suggesting that FET is not superior to fresh ET and that the placenta has long been considered a key predictor of maternal and offspring health [18]. Guo et al. [19] included 1516 women who gave birth to a singleton fetus. The results showed that compared with fresh embryo transfer, frozen-thawed embryo transfer was associated with an increased risk of placenta previa and placental adhesion, indicating that frozen-thawed embryo transfer was an independent risk factor for placental adhesion. Compared with other methods, frozen-thawed embryo transfer is more likely to be associated with blastocyst transfer. When IVF treatment is implemented, poor blastocyst rotation may lead to low placental position and placenta previa. The findings of our study are consistent with those of Guo et al. In our study, the probability of a low placenta in patients who underwent frozen-thawed embryo transfer was higher than that in patients who underwent the fresh embryo transfer(Group D > Group B, P < 0.05). However, after multivariate correction analysis, the embryo transfer method was not an independent factor influencing the occurrence of a low placental position (OR = 0.153). 95% CI: 0.022–1.089; p = 0.061).

In addition, in our study, we found that women who underwent frozen-thawed embryo transfer were more likely to deliver by cesarean section than were women who underwent fresh embryo transfer. This may be related to the psychological course and perinatal examination of patients undergoing treatment by assisted reproductive technology for frozen-thawed embryo transfer. FET greatly prolonged the treatment time, thus prolonging the live birth time, which not only required additional embryo operations but also increased the cost and workload of treatment and increased the degree of psychological pressure on patients. This psychological pressure makes them think that cesarean section is a safer method of delivery, and obstetricians may think that newborns conceived by assisted reproductive technology are more ’precious’. Multiple comprehensive factors lead to a higher cesarean section rate.

With the development of assisted reproductive technology, freezing and thawing technology has been effectively improved, but freezing injury in embryos is still inevitable. Whether embryo transfer has adverse effects on offspring is controversial. With respect to neonatal perinatal outcomes, studies have shown that FET and fresh ET have no significant effect on neonatal perinatal outcomes. However, in our study, we investigated the incidence of fetal distress (Group B < Group C, Group D, P < 0.05) and neonatal jaundice (Group D > Group A, Group B, P < 0.05) after frozen-thawed embryo transfer. Multivariate analysis revealed that embryo transfer was an independent factor affecting the incidence of neonatal jaundice (OR = 0.219; 95% CI: 0.090–0.533; p = 0.001). This finding is basically consistent with the findings of Jiarong Li et al. [20]. However, these diseases have not been reported to be related to FET, and whether they have a potential impact on embryos during the freezing process is still inconclusive. Moreover, owing to the advantages and disadvantages of FET and fresh embryo transfer, further observations and explorations are needed.

In addition, in our study, we found that women who received frozen-thawed embryo transfer were more likely to deliver by cesarean section than women who received fresh embryo transfer, which may be related to the multiple transfers of embryos to pregnant women who received frozen-thawed embryo transfer. This psychological pressure makes them believe that cesarean section is a safer method of delivery; therefore, they prefer cesarean section for delivery.

Conclusions

In summary, young PCOS patients without risk of OHSS have a high clinical pregnancy rate with fresh transplant cycles. PCOS disease itself has no significant effect on the perinatal outcomes of the mother or singleton infant. Frozen-thawed embryo transfer may increase the incidence of low placenta, fetal distress and neonatal jaundice. Further attention needs to be given to the impact of embryo transfer methods on perinatal outcomes to optimize assisted reproductive technology, strengthen pregnancy management and screening, and ensure the health of mothers and children after assisted pregnancy. The advantages and disadvantages of fresh or frozen-thawed embryo transfer still need long-term exploration and research.

Supporting information

S1 Data. Datasets used in the research.

(ZIP)

pone.0312003.s001.zip^{(145.6KB, zip)}

Data Availability

"All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study was supported by funding from the National Natural Science Foundation of China (81300484) and the Natural Science Foundation of Guangdong Province, China (2022A1515010849). The funders is responsible for the publication costs of this manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0312003.r001

Decision Letter 0

Tamara Sljivancanin Jakovljevic

7 Jun 2024

PONE-D-24-09843The effect of fresh embryo transfer and frozen-thawed embryo transfer on the perinatal outcomes of single fetuses from mothers with PCOSPLOS ONE

Dear Dr. ma,

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Reviewer #2: No

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Reviewer #1: Dear authors, thank you for submitting your manuscript for consideration for publication in PLOS ONE. I find some issues that have to be address in order to improve the quality of the manuscript. You have written "The inclusion criteria for the PCOS group were as follows: less than 35 years of age; retrieval of more than 5 eggs; selection of a long protocol". Could you please explain (justify) the selection of those inclusion criteria, having in mind:

1) "retrieval of more than 5 eggs" in PCOS is considered as poor ovarian response in PCOS and it is happening commonly, especially in women with severe PCOS (very high AMH)

2) "selection of a long protocol" is usually not considered for women with PCOS

3) "less than 35 years of age" – significant proportion of women with PCOS undergoing IVF belongs to the population older than 35 years of age

Please rewrite the sentence “According to the transplantation method”, since the "transplantation method" could be replaced with more suitable word. The same is for the “the embryo was thawed and transplanted 3 days later" and it could be better written as “the embryo was thawed and transferred 3 days later". Furthermore, I believe you should find better word / expression for "intima thickness".

I cannot understand in row one in Table 1 "Female sex". What kind of f patient characteristic of women undergoing IVF is "Female sex". Furthermore, in order to simplify the Table 1, you could leave out row with "Secondary infertility". Moreover, in footnote of the table you could indicate the statistical tests used to evaluate the differences between study groups. The same should be done for Table 2, 3 and 4 (indicate the statistical tests used to evaluate the differences between study groups).

In Table 2, please "Total Gn" replace with "Total gonadotropin dose", "Gn Total days" with "stimulation duration", "HCG testing day E2/(pg/ml)" with "E2 at trigger day", "Endometrial thickness on HCG testing day/(mm)" with "Endometrial thickness on trigger day/(mm)", "Proportion of embryo transfers" with "Day of embryotransfer".

How do you explain impossible results in your study presented in Table 3: Clinical pregnancy rates being higher than Biochemical pregnancy rates (68 pregnant out of 104 in Group A, 112 pregnant out of 212 in Group B…. Biochemical pregnancy (9 pregnant out 104 in Group A, 21 pregnant out of 212 in Group B, etc)…

Discussion is poorly written. The beginning of Discussion: "The use of assisted reproductive technology has increased steadily in the past 30 years, helping many infertile families. However, the abnormal internal environment during ART treatment may increase the risk of health problems in future generations. Among them, higher maternal E2 levels are notable. Due to the use of COH technology, an increased E2 level in supraphysiological growth hormone during IVF/ICSI cycles is inevitable. However, with the advancement of embryo cryopreservation technology, especially in vitrification, FET enables women receiving COH to maintain their initial hormone levels before embryo transfer, but whether this can improve adverse pregnancy and perinatal outcomes remains unclear" belong more to Introduction section or to some book chapter, not to Introduction. At the beginning instead of your first sentences summarize key results with reference to study objectives. Then, give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence.

Reviewer #2: Numerous changes needed to be made:

1.Table 1 needs more data such as patient age, gravity, parity, history of prior c-section - these are ALL factors that are crucial to understanding perinatal risk. Without this data, the conclusions of the study remain faulty.

2. The above factors need to be assessed. if significant differences are seen, then they need to be included in a multivariable logistic regression to assess their influence on embryo transfer type on obstetrical outcomes.

Without the above, the paper should not be published.

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2024 Oct 28;19(10):e0312003. doi: 10.1371/journal.pone.0312003.r002

Author response to Decision Letter 0

12 Jul 2024

Dear Editors and Reviewers：

Thank you for your letter and for the reviewers' comments concerning our manuscript entitled “The effect of fresh embryo transfer and frozen-thawed embryo transfer on the perinatal outcomes of single fetuses from mothers with PCOS” (ID: PONE-D-24-09843）. Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked in yellow in the paper. The main corrections in the paper and the responds to the reviewer’s comments are as flowing：

Responds to the reviewer's comments:

Reviewer #1:

1)"retrieval of more than 5 eggs" in PCOS is considered as poor ovarian response in PCOS and it is happening commonly, especially in women with severe PCOS (very high AMH).

Response："retrieval of more than 5 eggs" is the inclusion criteria for this study, in order to exclude patients with severe poor ovarian function. If patients with PCOS had less than 5 eggs extracted after superovulation, these patients were not included in our study.

2)"selection of a long protocol" is usually not considered for women with PCOS.

Response：This study is a retrospective study. The initial development of the center is mainly based on the use of long-term regimen, and it is gradually converted to antagonist regimen after the treatment technology is mature. Therefore, the long scheme is selected as the research entry point.

3)"less than 35 years of age" – significant proportion of women with PCOS undergoing IVF belongs to the population older than 35 years of age.

Response：China 's national conditions define age ≥ 35 years old as elderly patients. In order to avoid the influence of elderly factors, this study screened patients younger than 35 years old.

4)Please rewrite the sentence“According to the transplantation method”, since the "transplantation method" could be replaced with more suitable word. The same is for the “the embryo was thawed and transplanted 3 days later" and it could be better written as “the embryo was thawed and transferred 3 days later". Furthermore, I believe you should find better word / expression for "intima thickness".

Response：We modified ' according to the method of transplantation ' to ' according to whether the fresh embryo transfer patients were divided into fresh embryo transfer group and frozen-thawed embryo transfer group ' ; revise ' the embryo was thawed and transplanted 3 days later ' to ' the embryo was thawed and transferred 3 days later' ; the ' intima thickness ' was modified to ' endometrial thickness '.

5)I cannot understand in row one in Table 1 "Female sex". What kind of f patient characteristic of women undergoing IVF is "Female sex". Furthermore, in order to simplify the Table 1, you could leave out row with "Secondary infertility". Moreover, in footnote of the table you could indicate the statistical tests used to evaluate the differences between study groups. The same should be done for Table 2, 3 and 4 (indicate the statistical tests used to evaluate the differences between study groups).

Response：I am very sorry for such a low-level error.I changed ' Female sex ' to ' Female age '.Secondary infertility data were omitted in accordance with expert opinion and statistical tests used to to evaluate the differences between study groups were indicated under the table.

6)In Table 2, please "Total Gn" replace with "Total gonadotropin dose", "Gn Total days" with "stimulation duration", "HCG testing day E2/(pg/ml)" with "E2 at trigger day", "Endometrial thickness on HCG testing day/(mm)" with "Endometrial thickness on trigger day/(mm)", "Proportion of embryo transfers" with "Day of embryotransfer".

Response：According to the reviewer 's opinion, we modified ' Total Gn ' to ' Total gonadotropin dose ' ; the ' Gn Total days ' was modified to ' Gn stimulation duration ', and the ' HCG testing day E2 / ( pg / ml ) ' was modified to ' E2 at trigger day '. The ' Endometrial thickness on HCG testing day / ( mm ) ' was modified to ' Endometrial thickness on trigger day / ( mm ) ', and the ' Proportion of embryo transfers ' was modified to ' Day embryo of embryo transfer '.

7)How do you explain impossible results in your study presented in Table 3: Clinical pregnancy rates being higher than Biochemical pregnancy rates (68 pregnant out of 104 in Group A, 112 pregnant out of 212 in Group B…. Biochemical pregnancy (9 pregnant out 104 in Group A, 21 pregnant out of 212 in Group B, etc)

Response：The Biochemical pregnancy in this study is defined as the number of pregnancies diagnosed only by beta-HCG detection without a gestational sac visualized by vaginal ultrasound at the fifth week of pregnancy, per number of pregnancies.

8)Discussion is poorly written. The beginning of Discussion: "The use of assisted reproductive technology has increased steadily in the past 30 years, helping many infertile families. However, the abnormal internal environment during ART treatment may increase the risk of health problems in future generations. Among them, higher maternal E2 levels are notable. Due to the use of COH technology, an increased E2 level in supraphysiological growth hormone during IVF/ICSI cycles is inevitable. However, with the advancement of embryo cryopreservation technology, especially in vitrification, FET enables women receiving COH to maintain their initial hormone levels before embryo transfer, but whether this can improve adverse pregnancy and perinatal outcomes remains unclear" belong more to Introductio

Response：We are very sorry for our negligence in the writing of the discussion section. We rewrite the discussion section according to the suggestions of the reviewers, and thank the reviewers for their hard work again.

Reviewer #2：

1)Table 1 needs more data such as patient age, gravity, parity, history of prior c-section - these are ALL factors that are crucial to understanding perinatal risk. Without this data, the conclusions of the study remain faulty.

Response：In this study, patients with a history of uterine surgery were excluded before data analysis. The age of female infertility was calculated in Table 1, and BMI was calculated in Table 2.

2)The above factors need to be assessed. if significant differences are seen, then they need to be included in a multivariable logistic regression to assess their influence on embryo transfer type on obstetrical outcomes

Response：Based on the opinions of the reviewers, single factor and multi-factor analysis were carried out. The content has been added to the text to thank the experts for their suggestions.

We tried our best to improve the manuscript and made some changes in the manuscript.These changes will not influence the content and framework of the paper.And here we did not list the changes but marked in yellow in revised paper.

We appreciate for Editors/Reviewers’ warm work earnestly, and hope that the correction will meet with approval.

Once again， thank you very much for your comments and suggestions.

Sincerely,

Tianzhong Ma and Huizhen Li

Attachment

Submitted filename: R20240708-eview comments reply letter.docx

pone.0312003.s002.docx^{(16.3KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0312003.r003

Decision Letter 1

Tamara Sljivancanin Jakovljevic

6 Aug 2024

PONE-D-24-09843R1The effect of fresh embryo transfer and frozen-thawed embryo transfer on the perinatal outcomes of single fetuses from mothers with PCOSPLOS ONE

Dear Dr. ma,

Please submit your revised manuscript by Sep 20 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Reviewers' comments:

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Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #2: Yes

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6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: Gravity and Parity are still missing - these are certainly factors that could influence the conclusions of this paper. It is concerning that the authors did not incorporate this despite requesting this after review of their original manuscript.

Also, antral follicle counts and/or AMH levels should also be compared between all of the groups.

**********

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Reviewer #2: No

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PLoS One. 2024 Oct 28;19(10):e0312003. doi: 10.1371/journal.pone.0312003.r004

Author response to Decision Letter 1

26 Aug 2024

Dear Reviewers：

Thank you for your letter and for the reviewers' comments concerning our manuscript entitled “The effect of fresh embryo transfer and frozen-thawed embryo transfer on the perinatal outcomes of single fetuses from mothers with PCOS” (ID: PONE-D-24-09843R2）. Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked in yellow in the paper. The main corrections in the paper and the responds to the reviewer’s comments are as flowing：

Responds to the reviewer's comments:

Reviewer#2:

1.Gravity and Parity are still missing - these are certainly factors that could influence the conclusions of this paper. It is concerning that the authors did not incorporate this despite requesting this after review of their original manuscript.

Response：Thank you for the insightful and constructive feedback provided by the reviewers. In response, we have enriched our manuscript with pertinent supplementary data（AFC, Gravity and Parity）, which are distinctly highlighted in yellow for ease of reference within the revised article.

We appreciate for Editors/Reviewers’ warm work earnestly, and hope that the correction will meet with approval.

Once again， thank you very much for your comments and suggestions.

Sincerely,

Tianzhong Ma and Huizhen Li

Attachment

Submitted filename: 20240826-review comments reply letter.docx

pone.0312003.s003.docx^{(12.9KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0312003.r005

Decision Letter 2

Tamara Sljivancanin Jakovljevic

30 Sep 2024

The effect of fresh embryo transfer and frozen-thawed embryo transfer on the perinatal outcomes of single fetuses from mothers with PCOS

PONE-D-24-09843R2

Dear Dr. Tianzhong Ma,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Tamara Sljivancanin Jakovljevic

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #2: Thank you for making the previously-mentioned correction. The incorporation of gravity and parity greatly increase the robustness of your conclusions relating to perinatal outcomes.

**********

PLoS One. doi: 10.1371/journal.pone.0312003.r006

Acceptance letter

Tamara Sljivancanin Jakovljevic

16 Oct 2024

PONE-D-24-09843R2

PLOS ONE

Dear Dr. ma,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

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on behalf of

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Data. Datasets used in the research.

(ZIP)

pone.0312003.s001.zip^{(145.6KB, zip)}

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pone.0312003.s002.docx^{(16.3KB, docx)}

Attachment

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Data Availability Statement

"All relevant data are within the paper and its Supporting Information files.

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PERMALINK

The effects of fresh embryo transfer and frozen-thawed embryo transfer on the perinatal outcomes of single fetuses from mothers with PCOS

Huizhen Li

Lihua Xu

Yanru Niu

Xia Zhu

Xiaomei Gao

Tianzhong Ma

Roles

Abstract

Purpose

Method

Results

Conclusion

Introduction

Materials and methods

Study design and participants

Treatment protocol

Statistical analysis

Results

Patient characteristics

Table 1. General comparison of patient characteristics [M (P25, P75), %].

Outcome of ART treatment

Table 2. Comparison of ovulation induction, fertilization and embryo transfer [M (P25, P75), %].

Clinical pregnancy outcomes

Table 3. Comparison of clinical pregnancy outcomes.

Perinatal outcomes

Table 4. Comparison of perinatal data [M (P25, P75), X±SD, %].

Perinatal complications of pregnant women

Table 5. Perinatal complications of pregnant women [%].

Perinatal outcomes of newborns

Table 6. Perinatal outcomes of neonates [%].

Regression analysis of related factors affecting the clinical pregnancy rate

Table 7. Logistic regression analysis of factors affecting the clinical pregnancy rate.

Regression analysis of related factors affecting lowering of the placenta

Table 8. Logistic regression analysis of factors affecting low placental position.

Regression analysis of related factors affecting fetal distress

Table 9. Logistic regression analysis of the influence on fetal distress.

Regression analysis of related factors affecting neonatal jaundice

Table 10. Logistic regression analysis of the incidence of neonatal jaundice.

Discussion

Conclusions

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Tamara Sljivancanin Jakovljevic

Roles

Author response to Decision Letter 0

Decision Letter 1

Tamara Sljivancanin Jakovljevic

Roles

Author response to Decision Letter 1

Decision Letter 2

Tamara Sljivancanin Jakovljevic

Roles

Acceptance letter

Tamara Sljivancanin Jakovljevic

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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