Abstract
Polycystic ovary syndrome (PCOS) is a common female reproductive endocrine disease, which increases the long-term health risks of the offspring. Chinese herbal medicine (CHM) has demonstrated significantly positive effects in treating PCOS. However, the effects of preconception administration of CHM on the offspring of the women with PCOS need to be elucidated. This study aimed to investigate the effects of a patented CHM (Bu-Shen-Tian-Jing Formula) on the offspring of women with PCOS. This study was designed as a retrospective cohort study. A total of 75 PCOS women, who achieved successful pregnancy through letrozole-induced ovulation and delivered successfully, were divided into CHM group (n = 38, treated with Bu-Shen-Tian-Jing Formula before the treatment of letrozole) and non-CHM group (n = 37, without CHM treatment). The information of the women with PCOS and their children (at birth) was collected from the Hangzhou City Community Health Service Information System. The included mothers were invited to complete the Ages and Stages Questionnaire, Third Edition to China and the Chinese version of Ages and Stages Questionnaire Social-Emotional, Second Edition to screen the developmental delays of the offspring. The total incidence rate of pregnancy complications was significantly higher in non-CHM group compared with CHM group (P = .001). The height of the children in CHM group was significantly lower than non-CHM group at 6 months old (P = .038). The head circumference of children in CHM group was significantly larger than the non-CHM group respectively at 24 and 36 months old (P = .047 and P = .030). The proportions of “above cutoff value” in fine motor and problem-solving domains of the children in the CHM group were significantly higher than non-CHM group (P = .003 and P = .022) and the proportions of “below cutoff value” in the CHM group were significantly smaller than the non-CHM group (P = .024). Preconception administration of CHM significantly decreased the incidence of pregnancy complications in the women with PCOS undergoing letrozole-induced ovulation and improved the development of the offspring. However, it may be limited by the relatively small sample size and the simple evaluation indicators.
Keywords: Chinese herbal medicine, offspring, polycystic ovary syndrome, retrospective cohort study
1. Introduction
Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine conditions in women of reproductive age. Maternal PCOS had long-term effects on the offspring growth and development,[1,2] neuropsychiatric system,[3] endocrine system,[4,5] cardiovascular system,[6] and reproductive system.[7,8] Additionally, women with PCOS are at higher risk for pregnancy complications.[9]
Letrozole is the preferred first-line pharmacological treatment for ovulation induction in infertile anovulatory women with PCOS, and there is no evidence for increased teratogenicity compared to other ovulation induction agents.[10] However, the use of letrozole for ovulation induction is off-label and may cause side effects such as nausea, headache, bone pain, hot flash, and weight gain.[11]
Chinese herbal medicine (CHM) has demonstrated significantly positive effects in treating PCOS, which is widely used in daily clinical practice.[12] However, the effects of CHM on the offspring of women with PCOS need to be elucidated. Bu-Shen-Tian-Jing Formula (BSTJF) is a patented CHM created by the authors’ group (International patent PCT: Publication No. WO2012/100471). BSTJF could effectively improve the pregnancy outcomes of PCOS women undergoing in vitro fertilization,[13] and the effects were found to be obtained via mitochondrial SIRT3 and the subsequent insulin signaling pathway.[14] More importantly, BSTJF had positive effects in recovering the pubertal neurobehavioral alterations in the female offspring by reversing dendritic spine density, the ultrastructure of neurons and synapses, and the Gabrb1 and Grin2b protein expression levels in the hippocampus, thereby producing a positive intergenerational effect on the offspring.[15] However, the clinical evidence is limited. This study aimed to investigate the effects of preconception administration of BSTJF on the offspring of women with PCOS.
2. Methods
2.1. Participants
This study was designed as a retrospective cohort study. A total of 75 PCOS women, who achieved successful pregnancy through letrozole-induced ovulation and delivered successfully from November 2019 to November 2022, were divided into CHM group (n = 38, treated with BSTJF before the treatment of letrozole) and non-CHM group (n = 37, without CHM treatment). The participants were diagnosed as PCOS if they met 2 or 3 of the Rotterdam criteria: oligo or anovulation, clinical or biochemical signs of hyperandrogenism and polycystic ovaries by ultrasonography.[16] The ethical approval for this study was obtained from the Ethics Committee of the First People’s Hospital of Yuhang District (The Linping Campus of the Second Affiliated Hospital, School of Medicine, Zhejiang University), Hangzhou, China (No. 2019-Lunshenyan-015). The PCOS women with obvious and severe organic lesions in the reproductive organs, pituitary tumors and empty sella syndrome, congenital ovarian developmental abnormalities, thyroid or adrenal diseases, or infertility caused by male factors were excluded.
2.2. Interventions
All the included women with PCOS were directly treated with the letrozole (Hengrui, China) to stimulate ovulation. Briefly, from the 2nd to 6th day of menstruation, the starting dose of letrozole was 2.5 mg/d and continuously used for 5 days after a withdrawal bleeding as recommended. If the ovulation failed, the dose would gradually increase in the second cycle (increasing by 2.5 mg/d), with a maximum dose of 7.5 mg/d.[17] As shown in Table S1, Supplemental Digital Content, https://links.lww.com/MD/Q29 BSTJF consists of 7 herbs, including H. glutinosa Libosch. (Dihuang), 20 g; Ligustrum lucidum Ait. (Nvzhenzi), 20 g; Rubus chingii Hu (Fupenzi), 10 g; Cwscwia australis R. Br. (Tusizi), 15 g; Psoralea corylifolia L. (Buguzhi), 15 g; Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (Huangqi), 10 g; and Salvia miltiorrhiza Bge. (Danshen), 10 g. These herbs were purchased and from Kailun Medicine, Co., Ltd. (Hangzhou, China), with authentication, quality inspection, and preparation strictly conforming to the standards specified in the Pharmacopoeia of the People’s Republic of China (2020 edition).[18] BSTJF was decocted by the hospital’s TCM Pharmacy via standard protocol, and 1 dose was taken per day, separately in the morning and evening. The women with PCOS in the CHM group were treated with BSTJF for 12 weeks with weekly follow-ups before the letrozole-induced ovulation.[13]
During ovulation induction, follicle growth is monitored via ultrasound with adjusted intervals based on size. Serum levels of estradiol, luteinizing hormone, follicle-stimulating hormone, and progesterone (P) were measured to assess maturity and determine the timing of human chorionic gonadotropin (HCG) triggering (10,000 units i.m. Guanlong Biopharmaceutical Co., Ltd, CN). After HCG administration, timed intercourse is advised, and ovulation success is confirmed 2 days later by follow-up ultrasound showing follicle resolution with corpus luteum formation (or serum P measurement if inconclusive). Post-ovulation, routine luteal phase support with dydrogesterone (10 mg twice daily, Abbott, NL) is initiated, continuing until the pregnancy test day (12 days post-HCG triggering).[19] Successful pregnancy is defined by rising serum HCG and ultrasound-confirmed intrauterine gestational structures.[20,21] In case of successful pregnancy, the continuation of luteal support is determined based on measured P levels.[22]
2.3. Data collection and outcome measures
Prior to data acquisition, all participants were contacted via telephone to provide explicit informed consent, with full explanation of data usage purpose, collection scope, and confidentiality measures. The baseline characteristics and clinical data of PCOS patients and their children (at birth) were collected from the Hangzhou City Community Health Service Information System and Hangzhou Residents’ Health Records. All the anthropometric data of the offspring was collected by trained professionals, including nutrition status and timing of deciduous tooth eruption. The information of feeding patterns was offered by the participants.
The included mothers were invited to complete the Ages and Stages Questionnaire, third edition to China (ASQ-C) and the Chinese version of Ages and Stages Questionnaire Social-Emotional, Second Edition (ASQ: SE-2) to screen the developmental delays of the children.[23–26] In ASQ-C and ASQ: SE-2, the results are respectively divided into 3 zones: above cutoff (normal development); close to cutoff (score between 1 and 2 standard deviations (SDs) below the mean); and below cutoff (score fewer than 2 SDs below the mean). The results of questionnaires were provided by the Zhangyuan, Co., Ltd. (Shanghai, China).
2.4. Statistical analysis
All the analyses were conducted with SPSS version 26.0 (SPSS, Chicago). Firstly, the Shapiro–Wilk test was specifically employed to evaluate the normality of continuous variables. For the approximately normally distributed continuous variables, the single t tests were used, and the data was displayed as mean ± SDs. If the variables did not conform to the normal distribution, Mann–Whitney U tests were applied and expressed as median and interquartile range. The Chi-square test was used to compare categorical variables and displayed as frequency (%). Rank variables were analyzed using Wilcoxon rank sum test and displayed as frequency (%). Multiple logistic regression analysis was carried out to correct the baseline data in order to determine the correlation between the outcome measures and the CHM intervention. If there is a significant difference in covariates, an interactive method is used to determine whether the covariate is an independent confounding factor.[27] P-value < .05 was regarded as significant.
3. Results
3.1. The baseline characteristics of the participants
During the 12-week preconception CHM treatment, no severe adverse events were reported. As shown in Table 1, there were no significant differences between the CHM and non-CHM groups on the baseline characteristics of the participants (all P > .05). In CHM group, 1 participant delivered twins and another 1 delivered twice, with 1 daughter each time. In the non-CHM group, 2 women delivered twins.
Table 1.
Baseline characteristics of the mothers with polycystic ovary syndrome.
| Items | CHM group (n = 38) | Non-CHM group (n = 37) | P-value |
|---|---|---|---|
| Age (yr) | 30.55 ± 3.86 | 29.59 ± 3.76 | .280 |
| Height (cm) | 160.0 (157.0, 163.0) | 160.0 (158.0, 163.0) | .422 |
| Preconception weight (kg) | 60.0 (50.0, 69.2) | 59.5 (52.5, 70.0) | .668 |
| Preconception BMI (kg/m2) | 22.6 (19.3, 26.7) | 23.0 (20.4, 26.4) | .807 |
| Pre-delivery weight (kg) | 73.93 ± 12.11 | 74.74 ± 12.84 | .778 |
| Pre-delivery BMI (kg/m2) | 28.88 ± 4.45 | 28.75 ± 4.37 | .896 |
| Maternal weight gain during gestation (kg) | 13.53 ± 3.93 | 13.09 ± 3.71 | .621 |
| Current employment status [n (%)] | .356 | ||
| Full-time employment | 31/38 (81.6%) | 27/37 (73.0%) | |
| Part-time employment | 1/38 (2.6%) | 4/27 (10.8%) | |
| Registered unemployed | 6/38 (15.8%) | 6/27 (16.2%) | |
| Educational level [n (%)] | .150 | ||
| Lower than high school | 6/38 (15.8%) | 1/37 (2.7%) | |
| High school | 8/38 (21.0%) | 9/37 (24.3%) | |
| Higher than high school | 24/38 (63.2%) | 27/37 (73.0%) | |
| Mode of delivery [n (%)] | .720 | ||
| Vaginal delivery | 18/38 (47.4%) | 16/37 (43.2%) | |
| Caesarean section delivery | 20/38 (52.6%) | 21/37 (56.8%) | |
| Age of spouse (yr) | 32 (30, 34) | 31 (29, 33) | .784 |
| Current employment status of spouse [n (%)] | .915 | ||
| Full-time employment | 8/38 (21.0%) | 8/37 (21.6%) | |
| Part-time employment | 26/38 (60.5%) | 24/37 (64.9%) | |
| Others | 4/38 (10.5%) | 5/37 (13.5%) | |
| Educational level of spouse [n (%)] | .283 | ||
| Lower than high school | 8/38 (21.0%) | 3/37 (8.1%) | |
| High school | 2/38 (5.3%) | 2/37 (5.4%) | |
| Higher than high school | 28/38 (73.7%) | 32/37 (84.5%) | |
BMI = body mass index, CHM = Chinese herbal medicine.
3.2. The incidence rate of the pregnancy complications
The total incidence rate of the pregnancy complications in the non-CHM group (81.09%) was significantly higher than the CHM group (42.11%) (P = .001). As shown in Table S2, Supplemental Digital Content, https://links.lww.com/MD/Q29, the incidence rate of gestational diabetes mellitus (GDM) was significantly higher in the non-CHM group (P = .011), and no significant difference existed on the other complications between the 2 groups (all P > .05).
3.3. The anthropometric measurement outcomes of the offspring under 1 year old
As shown in Table 2 and Figure 1, the height of the children under 1 year old in CHM group were significantly lower than those of the non-CHM group at 6 months old (P = .038). There were no significant differences on the weight, body mass index (BMI), head circumference and teething number between the 2 groups (all P > .05). For feeding patterns, the proportion of artificial feeding in CHM group was significantly higher than the non-CHM group at 6 and 8 months old (P = .009 and P = .040, respectively), while the non-CHM group had a higher proportion of mix feeding (P = .009 and P = .040, respectively). The head circumference of the sons in CHM group was significantly larger than the non-CHM group at 12 months old (P = .001, Figure S1, Supplemental Digital Content, https://links.lww.com/MD/Q28). For the daughters, the proportion of artificial feeding rate was significantly higher in CHM group than the non-CHM group at 6 and 8 months old (P = .016 and P = .009, Figure S2, Supplemental Digital Content, https://links.lww.com/MD/Q28). All the anthropometric measurement outcomes of the sons and daughters were in line with the “Growth standard for children under 7 years of age in China,”[28] as shown in Figure 2.
Table 2.
The anthropometric measurement outcomes of the offspring under 1 year old.
| Items | Overall (n = 78) | Sons (n = 36) | Daughters (n = 42) | P-values | |||||
|---|---|---|---|---|---|---|---|---|---|
| CHM group (n = 39) |
Non-CHM group (n = 39) | CHM group (n = 19) | Non-CHM group (n = 17) | CHM group (n = 20) | Non-CHM group (n = 22) | CHM vs non-CHM | CHMs vs non-CHMs | CHMd vs non-CHMd | |
| At birth | |||||||||
| Gestational age (wk) | 38.00 (37.00, 39.00) | 39.00 (37.00, 40.00) | 39.00 (37.00, 39.00) | 38.00 (34.50, 39.00) | 38.00 (37.00, 39.00) | 39.00 (38.00, 40.00) | .442 | .549 | .105 |
| Body length (m) | 0.50 (0.49, 0.50) | 0.50 (0.50, 0.50) | 0.50 (0.49, 0.50) | 0.50 (0.50, 0.50) | 0.50 (0.50, 0.50) | 0.50 (0.50, 0.50) | .075 | .080 | .555 |
| Birth weight (kg) | 3.22 (2.89, 3.47) | 3.33 (3.00, 3.52) | 3.10 (2.76, 3.52) | 3.38 (3.24, 3.61) | 3.26 (2.91, 3.45) | 3.28 (2.94, 3.43) | .393 | .281 | .873 |
| BMI (kg/m2) | 13.40 (11.98, 14.38) | 13.32 (12.00, 14.08) | 13.40 (11.98, 14.08) | 13.52 (12.94, 14.20) | 12.89 ± 1.71 | 12.95 ± 1.41 | .810 | .516 | .417 |
| At 1 month | |||||||||
| Height (m) | 0.55 (0.52, 0.57) | 0.55 (0.53, 0.56) | 0.54 ± 0.04 | 0.55 ± 0.03 | 0.54 ± 0.02 | 0.55 ± 0.02 | .519 | .351 | .682 |
| Weight (kg) | 4.53 (4.00, 5.00) | 4.40 (4.00, 5.00) | 4.44 ± 0.78 | 4.72 ± 0.97 | 4.44 ± 0.57 | 4.28 ± 0.64 | .896 | .342 | .406 |
| BMI (kg/m2) | 15.23 ± 1.91 | 14.84 ± 1.57 | 15.42 ± 2.20 | 15.55 ± 1.62 | 15.03 ± 1.62 | 14.30 ± 1.33 | .341 | .842 | .112 |
| Head circumference (cm) | 36.92 ± 1.26 | 36.86 ± 1.45 | 37.13 ± 1.28 | 37.18 ± 1.72 | 36.73 ± 1.25 | 36.61 ± 1.18 | .829 | .929 | .759 |
| Feeding patterns | .792 | .604 | .196 | ||||||
| Breast feeding [n (%)] | 29 (74.4%) | 31 (79.5%) | 15/19 (78.9%) | 11/17 (64.7%) | 14/20 (70.0%) | 20/22 (90.9%) | |||
| Artificial feeding [n (%)] | 2 (5.1%) | 1 (2.6%) | 1/19 (5.3%) | 1/17 (5.9%) | 1/20 (5.0%) | 0/22 (0%) | |||
| Mix feeding [n (%)] | 8 (20.5%) | 7 (17.9%) | 3/19 (15.8%) | 5/17 (29.4%) | 5/20 (25.0%) | 2/22 (9.1%) | |||
| At 3 mo | |||||||||
| Height (cm) | 0.61 ± 0.03 | 0.62 ± 0.03 | 0.60 ± 0.04 | 0.62 ± 0.03 | 0.61 ± 0.02 | 0.61 ± 0.02 | .061 | .130 | .283 |
| Weight (kg) | 6.32 ± 0.83 | 6.63 ± 0.84 | 6.45 ± 0.94 | 6.81 ± 0.94 | 6.20 ± 0.72 | 6.49 ± 0.76 | .116 | .278 | .208 |
| BMI (kg/m2) | 16.71 (15.61, 18.32) | 17.20 (16.15, 18.19) | 17.79 ± 2.67 | 17.51 ± 1.79 | 16.79 ± 2.14 | 17.12 ± 1.25 | .408 | .740 | .553 |
| Head circumference (cm) | 40.10 ± 1.38 | 39.92 ± 1.12 | 40.51 ± 1.19 | 40.27 ± 1.30 | 39.72 ± 1.46 | 39.67 ± 0.93 | .552 | .577 | .899 |
| Feeding patterns | .500 | .636 | .092 | ||||||
| Breast feeding [n (%)] | 18/37 (48.6%) | 22/36 (61.1%) | 8/19 (42.1%) | 5/17 (29.4%) | 10/20 (50.0%) | 17/21 (81.0%) | |||
| Artificial feeding [n (%)] | 4/37 (10.8%) | 4/36 (11.1%) | 1/19 (5.3%) | 2/17 (11.8%) | 3/20 (15.0%) | 2/21 (9.5%) | |||
| Mix feeding [n (%)] | 15/37 (40.5%) | 10/36 (27.8%) | 8/19 (42.1%) | 8/17 (47.1%) | 7/20 (35.0%) | 2/21 (9.5%) | |||
| At 6 mo | |||||||||
| Height (cm) | 0.67 (0.65, 0.69) | 0.68 (0.67, 0.71) | 0.66 ± 0.04 | 0.68 ± 0.03 | 0.67 ± 0.03 | 0.68 ± 0.02 | .038* | .111 | .234 |
| Weight (kg) | 7.98 ± 0.97 | 8.33 ± 0.96 | 8.15 ± 1.06 | 8.38 ± 0.90 | 7.84 ± 0.88 | 8.29 ± 1.03 | .148 | .539 | .156 |
| BMI (kg/m2) | 17.78 (16.55, 18.82) | 18.02 (16.78, 18.37) | 18.31 (16.68, 19.59) | 17.86 (16.78, 18.48) | 17.32 ± 2.15 | 17.71 ± 1.50 | .902 | .818 | .527 |
| Head circumference (cm) | 42.65 ± 1.49 | 42.79 ± 1.26 | 42.95 ± 1.25 | 42.85 ± 0.94 | 42.39 ± 1.66 | 42.74 ± 1.47 | .679 | .810 | .493 |
| Teething (n) | 0 (0, 0) | 0 (0, 0) | 0 (0, 0) | 0 (0, 0) | 0 (0, 0) | 0 (0, 0) | .637 | .933 | .594 |
| Feeding patterns | .009* | .201 | .016* | ||||||
| Breast feeding [n (%)] | 9/37 (24.3%) | 11/35 (31.4%) | 3/19 (15.7%) | 1/17 (5.9%) | 6/20 (30.0%) | 10/21 (47.6%) | |||
| Artificial feeding [n (%)] | 16/37 (43.2%) | 4/35 (11.4%) | 6/19 (31.6%) | 2/17 (11.8%) | 10/20 (50.0%) | 2/21 (9.5%) | |||
| Mix feeding [n (%)] | 12/37 (32.4%) | 20/35 (57.1%) | 8/19 (42.1%) | 11/17 (64.7%) | 4/20 (20.0%) | 9/21 (42.9%) | |||
| At 8 mo | |||||||||
| Height (cm) | 0.83 ± 0.03 | 0.83 ± 0.03 | 0.72 ± 0.04 | 0.72 ± 0.03 | 0.72 ± 0.03 | 0.71 ± 0.02 | .840 | .858 | .775 |
| Weight (kg) | 8.94 ± 1.10 | 9.07 ± 0.97 | 9.11 ± 1.12 | 9.12 ± 1.07 | 8.79 ± 1.09 | 9.04 ± 0.93 | .621 | .978 | .467 |
| BMI (kg/m2) | 17.31 ± 2.11 | 17.65 ± 1.28 | 17.54 ± 2.64 | 17.54 ± 1.25 | 17.10 ± 1.53 | 17.72 ± 1.33 | .455 | .999 | .208 |
| Head circumference (cm) | 44.65 (43.55, 45.50) | 44.40 (43.50, 45.00) | 44.98 ± 1.02 | 44.22 ± 0.96 | 44.12 ± 1.48 | 44.25 ± 0.99 | .314 | .062 | .758 |
| Teething (n) | 2 (2, 2) | 2 (2, 2) | 2 (2, 2) | 2 (2, 2) | 2 (2, 2) | 2 (2, 2) | .912 | .912 | .981 |
| Feeding patterns | .040* | .960 | .009* | ||||||
| Breast feeding [n (%)] | 5/35 (14.3%) | 3/28 (10.7%) | 2/19 (10.5%) | 1/17 (5.9%) | 3/19 (15.8%) | 2/17 (11.8%) | |||
| Artificial feeding [n (%)] | 22/35 (62.9%) | 10/28 (35.7%) | 10/19 (52.6%) | 7/17 (41.2%) | 12/19 (63.2%) | 3/17 (17.6%) | |||
| Mix feeding [n (%)] | 8/35 (22.9%) | 15/28 (53.6%) | 4/19 (21.1%) | 3/17 (17.6%) | 4/19 (21.1%) | 12/17 (70.6%) | |||
| At 12 mo | |||||||||
| Height (cm) | 0.77 (0.75, 0.81) | 0.77 (0.74, 0.79) | 0.78 ± 0.03 | 0.77 ± 0.04 | 0.77 ± 0.04 | 0.76 ± 0.02 | .530 | .875 | .582 |
| Weight (kg) | 10.30 (9.60, 10.90) | 10.40 (9.30, 11.00) | 10.42 (9.75, 11.08) | 10.30 (9.28, 10.78) | 10.13 ± 1.32 | 10.17 ± 1.07 | .881 | .833 | .931 |
| BMI (kg/m2) | 17.11 ± 1.88 | 17.45 ± 1.46 | 17.20 ± 2.19 | 17.58 ± 1.82 | 17.03 ± 1.62 | 17.37 ± 1.23 | .455 | .649 | .522 |
| Head circumference (cm) | 46.31 ± 1.17 | 45.78 ± 1.00 | 46.69 ± 0.88 | 45.52 ± 0.65 | 45.95 ± 1.32 | 45.95 ± 1.16 | .075 | .001* | .865 |
| Teething (n) | 6 (5.5, 6) | 6 (6, 6) | 6 (6, 7) | 6 (6, 7) | 6 (6, 6) | 6 (6, 6) | .727 | 1.000 | .486 |
| Feeding patterns | .693 | .593 | .583 | ||||||
| Breast feeding [n (%)] | 3/32 (9.4%) | 1/25 (4.0%) | 2/19 (10.5%) | 1/17 (5.9%) | 1/17 (5.9%) | 0/15 (0.0%) | |||
| Artificial feeding [n (%)] | 24/32 (75.0%) | 19/25 (76.0%) | 11/19 (57.9%) | 6/17 (35.3%) | 13/17 (76.5%) | 13/15 (86.7%) | |||
| Mix feeding [n (%)] | 5/32 (15.6%) | 5/25 (25.0%) | 2/19 (10.5%) | 3/17 (17.6%) | 3/17 (17.6%) | 2/15 (13.3%) | |||
BMI = body mass index, CHM = Chinese herbal medicine, CHMd = daughters of CHM group, CHMs = sons of CHM group, non-CHMd = daughters of non-CHM group, non-CHMs = sons of non-CHM group.
*P < .05, significant difference.
Figure 1.
The anthropometric measurement outcomes of the offspring under 1 year old. (A) The comparison of the height in two groups; (B) the comparison of the weight in two groups; (C) the comparison of the BMI in two groups; (D) the comparison of the head circumference in two groups; (E) the comparison of the teething in two groups. BMI = body mass index, CHM = Chinese herbal medicine. *P < .05, significant difference.
Figure 2.
The consistency of the anthropometric measurement outcomes of the children with the “Growth standard for children under 7 years of age in China.” (A) The consistency of the height of the sons with the growth standard; (B) the consistency of the weight of the sons with the growth standard; (C) the consistency of the head circumference of the sons with the growth standard; (D) the consistency of the height of the daughters with the growth standard; (E) the consistency of the weight of the daughters with the growth standard; (F) the consistency of the head circumference of the daughters with the growth standard. BMI = body mass index, CHM = Chinese herbal medicine, D = daughters, S = sons, SD = standard deviation. *P < .05, significant difference between 2 groups.
3.4. The anthropometric measurement outcomes of the offspring aged 2 to 3 years
As shown in Table 3, the head circumference of the children in CHM group was significantly larger than the non-CHM group at 24 and 36 months old (P = .047 and P = .030). For the sons, the head circumference of the CHM group was significantly larger than the non-CHM group from 18 months to 36 months (P = .030, P = .006, P = .003, P = .018, respectively). However, for the daughters, there were no significant differences between the 2 groups on all the anthropometric measurement outcomes aged 2 to 3 years old (all P > .05).
Table 3.
The anthropometric measurement outcomes of the offspring aged 2 to 3 years.
| Items | Overall (n = 78) | Sons (n = 36) | Daughters (n = 42) | P-values | |||||
|---|---|---|---|---|---|---|---|---|---|
| CHM group (n = 39) | Non-CHM group (n = 39) | CHM group (n = 19) | Non-CHM group (n = 17) | CHM group (n = 20) | Non-CHM group (n = 22) | CHM vs non-CHM | CHMs vs non-CHMs | CHMd vs non-CHMd | |
| At 18 mo | |||||||||
| Height (cm) | 0.83 ± 0.03 | 0.83 ± 0.03 | 0.83 (0.82, 0.85) | 0.81 (0.78, 0.85) | 0.83 ± 0.04 | 0.84 ± 0.02 | .840 | .162 | .632 |
| Weight (kg) | 11.43 ± 1.15 | 11.24 ± 1.26 | 11.53 ± 1.21 | 11.24 ± 1.26 | 11.35 ± 1.13 | 11.24 ± 1.31 | .595 | .626 | .821 |
| BMI (kg/m2) | 16.36 (15.70, 17.30) | 16.49 (15.50, 16.97) | 16.82 ± 2.02 | 17.06 ± 1.34 | 16.04 (15.70, 16.92) | 16.38 (15.38, 16.70) | .795 | .783 | .631 |
| Head circumference (cm) | 47.66 ± 1.19 | 47.16 ± 1.04 | 47.89 ± 0.92 | 46.99 ± 0.51 | 47.47 ± 1.38 | 47.25 ± 1.23 | .140 | .030* | .659 |
| Teething (n) | 12 (12, 15.5) | 12 (12, 16) | 13 (12, 16) | 15 (12, 16) | 14 (12,16) | 16 (12,16) | .237 | .431 | .381 |
| At 24 mo | |||||||||
| Height (cm) | 0.89 (0.87, 0.91) | 0.90 (0.87, 0.91) | 0.89 (0.87, 0.91) | 0.86 (0.85, 0.93) | 0.89 ± 0.02 | 0.90 ± 0.01 | .782 | .713 | .297 |
| Weight (kg) | 13.10 (12.05, 13.70) | 12.75 (12.15, 14.00) | 12.87 ± 1.18 | 13.50 ± 1.54 | 12.83 ± 1.09 | 12.86 ± 1.24 | .897 | .392 | .966 |
| BMI (kg/m2) | 16.21 (15.49, 16.89) | 16.57 (14.90, 17.36) | 15.89 (15.22, 17.53) | 17.24 (15.80, 18.60) | 16.32 ± 0.97 | 16.02 ± 1.28 | .783 | .270 | .552 |
| Head circumference (cm) | 49.00 (48.00, 50.03) | 48.00 (47.40, 48.75) | 49.00 (48.40, 49.80) | 48.00 (47.75, 48.05) | 48.60 ± 1.59 | 48.29 ± 1.27 | .047* | .006* | .635 |
| Teething (n) | 16 (16, 16) | 16 (16, 16) | 16 (16, 16) | 16 (15, 16) | 16 (16, 18) | 16 (16, 18) | .755 | .430 | .936 |
| At 30 mo | |||||||||
| Height (cm) | 0.89 (0.87, 0.91) | 0.90 (0.87, 0.91) | 0.95 (0.92, 0.96) | 0.93 (0.91, 1.00) | 0.92 ± 0.02 | 0.94 ± 0.11 | .455 | .807 | .067 |
| Weight (kg) | 13.10 (12.05, 13.70) | 12.75 (12.15, 14.00) | 14.77 ± 1.74 | 15.04 ± 1.78 | 13.23 ± 1.22 | 13.99 ± 0.76 | .679 | .800 | .188 |
| BMI (kg/m2) | 16.01 (15.49, 16.90) | 16.57 (14.90, 17.36) | 17.11 ± 3.47 | 16.69 ± 1.47 | 15.47 ± 1.38 | 15.81 ± 0.69 | .877 | .802 | .572 |
| Head circumference (cm) | 49.41 ± 1.03 | 48.93 ± 1.03 | 49.90 ± 0.55 | 48.76 ± 0.40 | 48.85 ± 1.22 | 49.04 ± 1.33 | .246 | .003* | .792 |
| Teething (n) | 20 (20, 20) | 20 (20, 20) | 20 (20, 20) | 20 (19, 20) | 20 (20, 20) | 20 (19.5, 20) | .642 | .726 | .765 |
| At 36 mo | |||||||||
| Height (cm) | 0.98 (0.98, 0.99) | 0.99 (0.96, 1.03) | 0.99 (0.95, 0.99) | 1.00 (0.95, 1.03) | 0.98 ± 0.00 | 0.99 ± 0.03 | .479 | .624 | .465 |
| Weight (kg) | 15.86 ± 1.85 | 15.72 ± 1.23 | 16.22 ± 1.73 | 16.03 ± 1.35 | 15.40 ± 2.15 | 15.48 ± 1.22 | .859 | .859 | .945 |
| BMI (kg/m2) | 16.65 ± 2.45 | 15.99 ± 0.96 | 17.13 ± 2.72 | 16.30 ± 0.99 | 16.05 ± 2.29 | 15.74 ± 0.97 | .461 | .583 | .791 |
| Head circumference (cm) | 50.34 ± 0.56 | 49.50 ± 0.90 | 50.48 ± 0.53 | 49.28 ± 0.66 | 50.18 ± 0.62 | 49.68 ± 1.10 | .030* | .018* | .452 |
BMI = body mass index, CHM = Chinese herbal medicine, CHMd = daughters of CHM group, CHMs = sons of CHM group, non-CHMd = daughters of non-CHM group, non-CHMs = sons of non-CHM group.
*P < .05, significant difference.
3.5. Screening the developmental delays of the offspring
Only part of the participants completed the study questionnaires. As shown in Table 4, the proportions of “above cutoff value” in fine motor and problem-solving domains of the children in the CHM group were significantly higher than non-CHM group with ASQ-C (P = .003 and P = .022, respectively); and the proportions of “below cutoff value” of the CHM group was significantly larger than the non-CHM group using ASQ: SE-2 (P = .024). After adjusting for confounding factors, including age, preconception BMI, educational level, employment status, and mode of delivery, further multiple regression analysis revealed that there was a significant correlation between CHM intervention and the results of offspring ASQ: SE-2 close to the below of cutoff value (P = .038, Table S3, Supplemental Digital Content, https://links.lww.com/MD/Q29).
Table 4.
The results of screening the developmental delays of the offspring.
| Items | Non-CHM group (n = 21) | CHM group (n = 31) | Z-score | P-values |
|---|---|---|---|---|
| ASQ-3 | ||||
| Fine motor | −2.959 | .003 * | ||
| Below cutoff value [n (%)] | 3/21 (14.3%) | 0/31 (0.0%) | ||
| Close to the cutoff value [n (%)] | 4/21 (19.0%) | 1/31 (3.2%) | ||
| Above cutoff value [n (%)] | 14/21 (66.7%) | 30/31 (96.8%) | ||
| Gross motor | −0.193 | .847 | ||
| Below cutoff value [n (%)] | 1/21 (4.8%) | 2/31 (6.5%) | ||
| Close to the cutoff value [n (%)] | 2/21 (9.5%) | 3/31 (9.7%) | ||
| Above cutoff value [n (%)] | 18/21 (85.7%) | 26/31 (83.9%) | ||
| Communication | −1.195 | .232 | ||
| Below cutoff value [n (%)] | 6/21 (28.6%) | 4/31 (12.9%) | ||
| Close to the cutoff value [n (%)] | 3/21 (14.3%) | 5/31 (16.1%) | ||
| Above cutoff value [n (%)] | 12/21 (57.1%) | 22/31 (71.0%) | ||
| Personal-social | −1.414 | .157 | ||
| Below cutoff value [n (%)] | 2/21 (9.5%) | 1/31 (3.2%) | ||
| Close to the cutoff value [n (%)] | 4/21 (19.0%) | 3/31 (9.7%) | ||
| Above cutoff value [n (%)] | 15/21 (71.4%) | 27/31 (87.1%) | ||
| Problem solving | −2.291 | .022 * | ||
| Below cutoff value [n (%)] | 2/21 (9.5%) | 2/31 (6.5%) | ||
| Close to the cutoff value [n (%)] | 6/21 (28.6%) | 1/31 (3.2%) | ||
| Above cutoff value [n (%)] | 13/21 (61.9%) | 28/31 (90.3%) | ||
| ASQ:SE-2 | ||||
| Total number | −2.254 | .024 * | ||
| Below cutoff value [n (%)] | 9/19 (47.4%) | 23/31 (74.2%) | ||
| Close to the cutoff value [n (%)] | 2/19 (10.5%) | 5/31 (16.1%) | ||
| Above cutoff value [n (%)] | 8/19 (42.1%) | 3/31 (9.7%) | ||
Statistically significant values (P < .05) are indicated in bold.
ASQ-C = Ages and Stages Questionnaire, third edition to China, ASQ: SE-2 = Ages and Stages Questionnaire Social-Emotional, Second Edition, CHM = Chinese herbal medicine, SD = standard deviation, Z = Z-score.
P < .05, significant difference.
4. Discussion
In the present study, we found BSTJF could significantly decrease the incidence rate of pregnant complications, especially for GDM, which is one of the major pregnant complications among women with PCOS and tightly related to the increased incidence rate of excess body mass of the offspring.[29] However, the weight of the offspring in both of the 2 groups conformed to the “Growth standard for children under 7 years of age” in China and no significant differences existed on the weight and BMI during the first 3 years between the 2 groups. Therefore, the positive effects of BSTJF on the children’s growth and development may not rely on changing the incidence rate of GDM. In the rat models with PCOS, we found BSTJF significantly decreased the levels of inflammation as well as oxidative stress, and activated the insulin pathway to improve the insulin resistance conditions, which may be the underlying mechanism of BSTJF in reducing the pregnancy complication rate.[14]
As the genetic and environmental factors, maternal weight gain and the mode of delivery have impacts on the development of offspring,[30,31] we investigated the differences on the maternal height, weight, BMI before delivery, weight gain and mode of delivery, even the employment status and educational levels of the participants and their spouse, between the 2 groups. There were no significant differences on all of these items. When we continued to evaluate the anthropometric measurement outcomes from the offspring aged 1 to 36 months in CHM group and non-CHM group, we found that the height of offspring in the CHM group was significantly lower than the non-CHM group at 6 months old. The proportion of artificial feeding was significantly higher in CHM group at 6 months, while the proportion of mix feeding was higher in non-CHM group. There may exist an association between the significant difference on the height of the offspring aged 6 months and the different proportion of the feeding pattern. “Below the cutoff value” in ASQ: SE-2 means the child’s current social-emotional development is at a normal level.[25,26] Therefore, the results of multiple regression analysis revealed the CHM intervention has a better effects for the offspring of PCOS.
Maternal PCOS has complex and multi-factorial impacts on the offspring, including the embryo quality, placental development, fetal growth and development, and increasing the risk of offspring suffering from metabolic diseases, neuropsychiatric diseases, cardiovascular diseases, and other diseases.[15] CHM has been found to help the women with PCOS obtain more oocytes and fertilized oocytes by reducing anti-Müllerian hormone levels in the follicular fluids, which significantly improved the pregnancy outcomes of in vitro fertilization.[13] CHM had significantly positive effects on the model rats with PCOS and the female offspring of the PCOS.[15] However, the effects of preconception administration of CHM on the offspring of the women with PCOS needs to be elucidated. A new theory titled Reproductive Genetics of Traditional Chinese Medicine has been created by the authors, which is strongly supported by findings that preconception administration of CHM significantly decreased the incidence of pregnancy complications of the women with PCOS undergoing letrozole-induced ovulation and improved the development of the offspring. Further studies need to be conducted on the mechanism underlying the intergenerational and transgenerational effects of preconception administration of CHM on the offspring of the women with PCOS.
There are several limitations to our study. Firstly, the sample size is relatively small; thus, the conclusion drawn requires validation through future studies with larger sample size. Secondly, we could not compare the effects of CHM on the offspring of PCOS mothers with different phenotype due to the small sample. Thirdly, although most of the information was obtained from the databases, some of the information provided by the participants might have potential bias. To eliminate the bias, a well-planned prospective study should be conducted in the future. Fourthly, a more detailed tool should be used to screen the developmental delays of the offspring.
5. Conclusion
Preconception administration of CHM significantly decreased the incidence of pregnancy complications of the women with PCOS undergoing letrozole-induced ovulation and improved the development of the offspring. However, it may be limited by the relatively small sample size and the simple evaluating indicators.
Author contributions
Conceptualization: Fan Qu.
Data curation: Lifang You, Weihuan Hu, Xinyin Hu, Wenxuan Xu, Hairong Huang.
Formal analysis: Lifang You, Weihuan Hu, Xinyin Hu.
Supervision: Fan Qu.
Writing – original draft: Lifang You, Weihuan Hu, Xinyin Hu.
Writing – review & editing: Fangfang Wang, Fan Qu.
Supplementary Material
Abbreviations:
- ASQ:SE-2
- Chinese version of Ages and Stages Questionnaire Social-Emotional, Second Edition
- ASQ-C
- Ages and Stages Questionnaire, third edition to China
- BMI
- body mass index
- BSTJF
- Bu-Shen-Tian-Jing Formula
- CHM
- Chinese herbal medicine
- GDM
- gestational diabetes mellitus
- HCG
- human chorionic gonadotropin
- P
- progesterone
- PCOS
- polycystic ovary syndrome
- SDs
- standard deviations
This research was supported by National Natural Science Foundation of China under Grant No. 82274564 and Yuhang District Medical and Health Research Project under Grant No. Yu 2019007.
The ethical approval for this study was obtained from the Ethics Committee of the First People’s Hospital of Yuhang District (The Linping Campus of the Second Affiliated Hospital, School of Medicine, Zhejiang University), Hangzhou, China (No. 2019-Lunshenyan-015).
The authors have no conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Supplemental Digital Content is available for this article.
How to cite this article: You L, Hu W, Hu X, Xu W, Huang H, Wang F, Qu F. Chinese herbal medicine on the offspring of women with polycystic ovary syndrome: A retrospective cohort study. Medicine 2025;104:39(e44677).
Contributor Information
Lifang You, Email: y20042668@sina.com.
Weihuan Hu, Email: 5524019@zju.edu.cn.
Xinyin Hu, Email: 5524019@zju.edu.cn.
Wenxuan Xu, Email: yawei.yu@outlook.com.
Hairong Huang, Email: Hhr112530036@163.com.
Fangfang Wang, Email: Drwangfangfang@zju.edu.cn.
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