This was a retrospective cohort study performed at the Assisted Reproduction Center of the Third Affiliated Hospital of Zhengzhou University. Two thousand three hundred and eighty-one overweight or obese infertile women who voluntarily underwent (intervention group, n=495) or rejected/discontinued a 60-day weight reduction intervention (control group, n=1,886) prior to IVF/ICSI from February 27, 2017 to November 11, 2020 and the 2,381 singletons delivered by these patients were included. Patients were randomly selected from the medical record system. The weight reduction intervention was defined as a 60-day weight reduction program that included a low-carbohydrate diet, diet structure adjustment, and an exercise program under the guidance of nutritionists. Nutritionists in the weight management department of the reproductive center instructed patients with a high BMI to purchase appropriate foods and consume a low-carbohydrate diet, to choose foods with a low glycemic index to induce fat breakdown, and to exercise appropriately so that their energy expenditure exceeded their intake. The inclusion criteria of the intervention group included: i) accepting the weight reduction intervention prior to IVF/ICSI, ii) a BMI ≥ 25 kg/m², iii) undergoing IVF/ICSI after the weight-loss intervention, and iv) delivering a single child. The inclusion criteria for the control group differed in that these patients either interrupted or rejected the weight reduction intervention. Patients were excluded from the study if they had a diagnosis of recurrent spontaneous abortion, repeated implantation failure, abnormal anatomical structure of the uterus, chromosomal abnormalities, or tumors. This study was approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (2021-077-01). Nutritionists supervised and recorded the implementation of weight reduction by providing substitute meals, telephone follow-up, and wechat interaction, guided and adjusted according to the patients’ feedback, and recorded various physical function indexes after weight reduction. All patients included in the study were pregnant after IVF/ICSI and delivered successfully. This study included embryo transfer (ET) and frozen-thawed embryo transfer (FET) cycles.

Based on the patients’ condition, a controlled ovarian hyperstimulation protocol (gonadotropin releasing hormone agonist (GnRH-a) long-protocols or GnRH-antagonist protocols) was formulated and follicular growth was monitored by transvaginal ultrasound. The specific methods of ovarian stimulation were described in previous publications by researchers at our center (17). When the diameter of at least one dominant follicle was more than 20 mm, or the diameters of three follicles were more than 18 mm, the ovarian hyperstimulation program was stopped and recombinant human chorionic gonadotropin (Ezer, Merck, Germany) was used to trigger ovulation. Thirty-six hours later, the oocytes were removed under transvaginal ultrasound monitoring. Routine luteal support was given after oocyte retrieval, and IVF or ICSI was performed depending on the patients’ condition. Fresh embryo transfer was performed 3 days after oocyte retrieval or with blastocyst transplantation 5 days after oocyte retrieval. An endometrial preparation protocol for frozen-thawed embryo transfer, including natural cycles, artificial cycles, GnRH-a pre-treatment in hormone replacement therapy (HRT), and induced ovulation cycles, was devised based on the patients’ condition. Natural cycles were applied to patients with regular menstruation, and they usually induces ovulation with or without minimum human chorionic gonadotropin (HCG) that results in the least risk of adverse effects and cost. For convenience, patients with or without normal menstrual cycles all can be treated with artificial cycles which were performed using estrogen and progesterone (18). Artificial cycles can optimize endometrial receptivity with a more consistent interval, duration, and concentration of estrogen and progesterone compared to natural cycles. GnRH-a pre-treatment in HRT cycles were commonly used in patients with polycystic ovary syndrome to downregulate any hormones produced by the ovaries in subsequent therapy when using HRTs (19). Induced ovulation cycles were applied to patients with abnormal ovulation. Either cleavage-stage embryos were transferred on the third day after ovulation or blastocysts were transferred on the fifth day after ovulation. Vaginal ultrasound was used to monitor the presence of a gestational sac, an embryo, and a fetal heart rate on day 30 after transplantation. Basic clinical data and hormone levels were obtained from the case system. Patients were followed up with telephone calls until the end of their pregnancy, and any pregnancy complications and neonatal outcomes were obtained from the medical record system.

Data related to pregnancy complications and neonatal outcomes were obtained from a review of the patients’ medical charts or through follow-up telephone calls. Hypertensive disorders of pregnancy include the following four categories: chronic hypertension, gestational hypertension, preeclampsia–eclampsia, and chronic hypertension with superimposed preeclampsia (20, 21). Chronic hypertension during pregnancy is defined as the presence of hypertension before conception, the development of elevated blood pressure before a gestational age of 20 weeks, or the persistence of hypertension beyond 12 weeks after delivery. Gestational hypertension, formerly known as pregnancy-induced hypertension, is defined as the development of essential hypertension after 20 weeks of gestation, in the absence of diagnostic criteria for preeclampsia. Preeclampsia is defined as new-onset hypertension that develops after 20 weeks of gestation and is accompanied by proteinuria or evidence of end-organ dysfunction. Eclampsia is defined as seizures in a pregnant woman with preeclampsia with no other identifiable cause. Gestational diabetes, defined as diabetes diagnosed during pregnancy, is a condition in which women without a previous diagnosis of diabetes exhibit abnormal blood glucose concentrations during pregnancy (22, 23). The incidences of placenta praevia (24), premature membrane rupture (25), and stillbirth (26) were also determined. A live birth was defined as an infant born alive after at least 28 weeks of gestation who survived more than 28 days, and a postterm pregnancy was defined as a gestational age > 42 weeks (27, 28). The WHO defines preterm birth as birth before 37 gestational weeks. Birth weights < 2500 g were classified as low birth weight, and birth weights < 1500 g were classified as very low birth weight (27, 29).

Continuous variables are presented as means ± standard deviations and categorical variables are presented as frequencies and corresponding percentages. The differences between two groups were assessed using a Student’s t-test for continuous variables and a Pearson’s chi-square test or Fisher’s exact probability method for categorical variables. Logistic and linear regression analyses were used to assess perinatal outcomes. Linear regression analysis was used to identify the factors influencing neonatal birth weight. All statistical analyses were performed using SPSS 22.0 software (IBM, Armonk, NY, USA). Two-tailed P values < 0.05 were considered statistically significant.

Four hundred and ninety-five singletons from mothers who underwent a weight reduction intervention prior to IVF/ICSI and 1,886 singletons from mothers who directly entered the ovulation induction cycle without a weight reduction intervention were included in this study. The basic characteristics of the intervention group and the control group are presented in Table 1 . Anti-Müllerian hormone (AMH) concentration and antral follicle count (AFC) were significantly higher in the intervention group than the control group. There were no significant differences in age; infertility duration; cause of infertility; embryo transfer period; endometrial thickness on the day of embryo transfer; basal follicle-stimulating hormone (bFSH) dose; or free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) concentrations between the two groups.

Insulin resistance test and oral glucose tolerance test (OGTT) results were compared after weight loss ( Table 2 ). The BMI of the intervention group decreased significantly after the intervention (P < 0.001), while the BMI of the control group decreased slightly. Fasting glucose, 1-hour blood glucose, fasting insulin, 1-hour insulin, 2-hour insulin concentrations, and HOMA-IR values were lower after the intervention than before the intervention. The OGTT and insulin resistance test results did not change significantly in the control group after the change in BMI.

The comparison of perinatal outcomes between the the intervention group and the control group after adjusting for confounding factors (age, infertility duration, AMH concentration, AFC) is shown in Table 3 . The incidences of hypertensive disorders of pregnancy, gestational diabetes, placenta praevia, premature membrane rupture, premature delivery, postterm delivery, stillbirth, low birth weight, very low birth weight, birth defect, and neonatal asphyxia were not significantly different between two groups. Birth weight was significantly higher in the intervention group (3519.6 ± 484.8) g than the control group (3406.8 ± 554.2) g after adjusting for confounding factors (P < 0.001).

As shown in Table 4 , a linear regression analysis found that a weight reduction intervention prior to IVF/ICSI and lower HOMA-IR at ovulation induction were associated with increased neonatal birth weight. Maternal age, infertility duration, endometrial thickness at that day on embryo transfer, AMH concentration, AFC, bFSH dose, TSH concentration and initial HOMA-IR had no effect on birth weight.

Figure 1 demonstrates the influence of different weight loss ratios on perinatal outcomes. We divided the entire cohort into four weight loss ratio groups (≤0%, 0%-5%, 5%-10%, and ≥10%). With an increase in the weight loss ratio, the incidences of hypertensive disorders of pregnancy, premature membrane rupture, premature delivery, stillbirth and low birth weight gradually decreased. However, the incidences of gestational diabetes and very low birth weight reached their lowest levels at a weight loss ratio of 5%-10%.