Vitamin D and Pregnancy Outcome in PCOS Patients

Vitamin D Supplementation Prior to in Vitro Fertilization in Women With Polycystic Ovary Syndrome: a Protocol of a Multicenter Randomised Double-blind Placebo-controlled Clinical Trial

This multicenter double-blinded placebo-controlled randomised trial aims to evaluate the effectiveness of vitamin D supplementation prior to IVF on the live birth rate in women with PCOS. Women with PCOS scheduled for IVF will be enrolled. Eligible participants will be randomised 1:1 to receive oral capsules of 4000IU vitamin D per day or placebo for around 12 weeks until the day of triggering.

Study Overview

• Status: Completed
• Conditions: Polycystic Ovary Syndrome; in Vitro Fertilization
• Intervention / Treatment: Drug: vitamin D; Other: Placebo

Detailed Description

Polycystic ovary syndrome (PCOS) is one of the leading causes of female infertility, affecting around 5% of women with a child-bearing age in China. Vitamin D insufficiency is common in women with PCOS and is associated with lower live birth rates in these women. However, evidence regarding the effectiveness of vitamin D treatment in women with PCOS is inconclusive. This multicenter double-blinded placebo-controlled randomised trial aims to evaluate the effectiveness of vitamin D supplementation prior to IVF on the live birth rate in women with PCOS.

The investigators plan to enroll women with PCOS scheduled for IVF. Eligible participants will be randomised 1:1 to receive oral capsules of 4000IU vitamin D per day or placebo for around 12 weeks until the day of triggering. All IVF procedures will be carried out following a routine method in each center. Women will be followed up until six months after randomisation for those who fail to get pregnant after the completion of the first embryo transfer or delivery for those who get pregnant after the first embryo transfer. The primary outcome is live birth after the first embryo transfer. Primary analysis will be by intention-to-treat analysis. The investigators plan to recruit 860 women to demonstrate women treated with vitamin D have a higher live birth rate than those treated with placebo (48% versus 38%), accounting for 10% loss to follow-up with a significance level at 0.05 and a power of 80%.

• Study Type: Interventional
• Enrollment (Actual): 876
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Peking University Third Hospital
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Women's Hospital, Zhejiang University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 42 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

1. Women aged 20 to 42 years old;
2. Diagnosed with PCOS (Rotterdam Criteria);
3. Scheduled for IVF;
4. Written informed consent.

Exclusion criteria

1. Women who had three or more failed IVF cycles;
2. Women scheduled for preimplantation genetic testing;
3. Known Vitamin D allergy;
4. Women with a history of chronic absorption syndrome or bile dysplasia, or parathyroid dysfunction, or kidney stones, or blood Calcium ion concentration greater than 2.6mmol/L (normal value 2.25 - 2.75mmol/L (9 to 11mg/dl), or hyperphosphataemia (1.61mmol/L), or metabolic-related bone disease, or chronic diseases that may cause bone abnormalities (liver and kidney insufficiency);
5. Women receiving treatments for tuberculosis, convulsions, and epilepsy because medications treating these diseases may affect the metabolism of vitamin D.
6. Women undergoing an IVF treatment with donor oocytes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vitamin D; Participants in the intervention group will be treated with vitamin D 4000IU (800IU per pill, take five pills once each day) per day for around 12 weeks (till the triggering day).	Drug: vitamin D; 4000IU per day; Other Names: non
Placebo Comparator: Placebo; Participants in the control group will be treated with equal amount of placebo tablets per day for the same duration.	Other: Placebo; The same doses with vitamin D

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with live birth	The primary outcome is live birth after the first embryo transfer. Live birth is defined as the delivery of at least one baby after 24 weeks of gestation that exhibits any sign of life.	1 day after delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Cumulative live birth	Cumulative live birth: defined as live birth resulting from pregnancies that occur within 6 months after randomization.	6 months after randomization of the last participant
Number of Participants with Clinical pregnancy	Clinical pregnancy: defined as at least one gestational sac on ultrasound at around 7 weeks' gestation with the detection of heart beat activity after the completion of the first embryo transfer;	4 weeks after embryo transfer
birth weight	Weight of newborns at delivery.	The day of delivery
Number of Participants with miscarriage	miscarriage was defined as a positive pregnancy test but no detectable heart rate before 24 weeks' gestation after the completion of the first transfer;	24 gestational weeks in maximum
Number of Participants with Ongoing pregnancy	defined as pregnancy with detectable heart rate at 12 weeks' gestation or beyond after the completion of the first transfer	at 12 weeks' gestation
Number of Participants with Biochemical pregnancy	defined with a positive pregnancy test	2 weeks after embryo transfer
Number of Participants with Ectopic pregnancy	defined as embryo implanted at any site other than the endometrial lining of the uterus cavity after the completion of the first transfer	4 weeks after embryo transfer
Number of Participants with Ovarian hyperstimulation syndrome	defined according to the Golan criteria. Moderate OHSS is diagnosed by the presence of ascites on ultrasonography in addition to abdominal distension and discomfort with or without nausea, vomiting and/or diarrhea. Severe OHSS is diagnosed when there is clinical evidence of ascites and/or hydrothorax or breathing difficulties with or without hemoconcentration, coagulation abnormalities and diminished renal function.	From the day of oocyte retrieval to two weeks after embryo transfer
Number of available embryos for transfer	non	5 days after oocyte retrieval
Number of Participants with Pre-eclampsia	defined as the development of gestational hypertension with proteinuria (≥300 mg/24-hour urine collection or 30 mg/dL in single urine sample) of new onset after 20 weeks of gestation after the completion of the first transfer	20 weeks of gestation till delivery
Number of Participants with Gestational hypertension	defined as the development of blood pressure greater than 140/90 mmHg after pregnancy without proteinuria or other signs of preeclampsia after the completion of the first transfer;	20 weeks of gestation till delivery
Number of Participants with Premature rupture of membrane	PROM was defined as rupture of the amniotic membranes before the onset of labor including PROM at term and preterm PROM.	The day of delivery
Number of Participants with Postpartum hemorrhage	defined as the loss of 500 ml of blood or more after completion of the third stage of labor after the completion of the first transfer	1 day after delivery
Number of Participants with Preterm delivery	Defined as delivery of a fetus at less than 37 and more than 28 weeks' gestational age after the completion of the first transfer	1 day after delivery
Number of Participants with Gestational diabetes mellitus	defined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy as determined from the diagnosis in the obstetrical medical record	Up to ten months once the participants get pregnancy
Number of Participants with Placenta previa	defined as a placenta that is implanted over or very close to the internal cervical orifice	after 24 weeks of gestation
Number of Participants with Stillbirth	defined as the absence of signs of life at or after birth after the completion of the first transfer	1 day after delivery
Apgar score	non	1 minute or 5 minutes after delivery
Serum Vitamin D binding protein, glucose, insulin, Calcium ion concentration	non	The day of oocyte retrieval
Serum vitamin levels	Serum vitamin levels at the triggering day	One day before oocyte retrieval

Collaborators and Investigators

• Sponsor: Women's Hospital School Of Medicine Zhejiang University
• Investigators: Principal Investigator: Dan Zhang, M.D. Ph.D., Women's Hospital School of Medicine Zhejiang University

Publications and helpful links

General Publications

• Hu KL, Gan K, Wang R, Li W, Wu Q, Zheng B, Zou L, Zhang S, Liu Y, Wu Y, Chen R, Cao W, Yang S, Liu FT, Tian L, Zeng H, Xu H, Qiu S, Yang L, Chen X, Pan X, Wu X, Mol BW, Li R, Zhang D. Vitamin D supplementation prior to in vitro fertilisation in women with polycystic ovary syndrome: a protocol of a multicentre randomised, double-blind, placebo-controlled clinical trial. BMJ Open. 2020 Dec 8;10(12):e041409. doi: 10.1136/bmjopen-2020-041409.

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2020
• Primary Completion (Actual): May 23, 2024
• Study Completion (Actual): January 27, 2025

Study Registration Dates

• First Submitted: September 4, 2019
• First Submitted That Met QC Criteria: September 6, 2019
• First Posted (Actual): September 9, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 28, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Vitamin D; randomized trial; Polycystic Ovary Syndrome; in vitro fertilization
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Pathologic Processes; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease; Genital Diseases, Female; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Ovarian Cysts; Cysts; Syndrome; Polycystic Ovary Syndrome; Physiological Effects of Drugs; Bone Density Conservation Agents; Micronutrients; Vitamins; Vitamin D
• Other Study ID Numbers: VDPI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: All data relevant to the study will be generated in the article or uploaded as supplementary information. Deidentified participant data will be available from Dr. Dan Zhang (zhangdan@zju.edu.cn) on a reasonable request. Protocols and statistical analysis plans will be included as supplementary information.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No