Towards Optimal Fertility, Fathering and Fatherhood studY (TOFFFY)

Investigating Male Factors and Their Relationships With Reproductive Health Outcomes in Singapore: Towards Optimal Fertility, Fathering and Fatherhood studY

This case-control study involving fertile and subfertile couples aims to identify male factors related to pregnancy likelihood, create a fertility index measure combining male and female factors to predict pregnancy likelihood, and examine how male factors relate to the semen physical and biological characteristics.

Study Overview

• Status: Recruiting
• Conditions: Fertility Issues; Reproductive Issues
• Intervention / Treatment: Other: Lifestyle and metabolic indicators

Detailed Description

Paternal contributions to fertility and reproductive health outcomes have been understudied, despite promising evidence from animal studies. This study aims to investigate the male contribution to pregnancy likelihood and explore the underlying biological mechanisms. Specifically, the investigators aim to (1) identify male factors associated with pregnancy rate; (2) develop a fertility index combining modifiable factors for both males and females to predict pregnancy rate; and (3) explore the relationship of male modifiable factors with semen physical and molecular characteristics. This is a case-control study with 480 fertile and subfertile males (along with their female partners), recruited from KK Women's and Children's Hospital. The investigators will use questionnaires to collect data on socio-demographic characteristics, clinical, lifestyle, and environmental factors; analyze metabolic and stress biomarkers from blood samples; and measure semen parameters including sperm motility, density, morphology, volume, DNA fragmentation, DNA methylation, gene expression, and seminal plasma oxidative status. Findings from this proposed study will pave the way for developing lifestyle-based or medical interventions to enhance male and couple reproductive health, and potentially benefiting future offspring health.

• Study Type: Observational
• Enrollment (Estimated): 960

Contacts and Locations

• Study Contact: Name: Benjarat Oh; Phone Number: 65 63948105; Email: benjarat.oh@kkh.com.sg

Study Locations

• Singapore
  • Singapore, Singapore, 229899
    • Recruiting
    • KK Women's and Children's Hospital
    • Contact: Benjarat Oh; Phone Number: +6583684641; Email: benjarat.oh@kkh.com.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The subfertile couples will be recruited from the infertility clinics, while the fertile couples will be recruited from the antenatal clinics. Both groups will also be recruited from on-going preconception and pregnancy programs in the hospital.

Description

Inclusion Criteria:

Subfertile couples:

• men aged ≥21-49 years
• men with a female partner aged 21-39 years
• couples who are not able to conceive for at least 12 months
• couples who are Singapore citizen or permanent resident

Fertile couples:

• men aged 21-49 years
• men with a female partner aged 21-39 years
• men with proven fertility defined as those female partners who are currently pregnant and with viable intrauterine pregnancy at gestational weeks of less or equal to 16 at the time of the study
• couples with attempted time to conceive within 12 months to achieve this pregnancy or with unplanned pregnancy
• couples who are Singapore citizen or permanent resident

Exclusion Criteria:

Subfertile couples:

• male infertility of a known aetiology including azoospermia, retrograde ejaculation, genetic disorders, cancer treatment, or testes trauma
• female infertility diagnosis as confirmed by diagnostic imaging or having severe endometriosis
• female partners with irregular menstrual cycle >35 days
• couples with known chromosomal abnormalities

Fertile couples:

• couples who achieve pregnancy after oocyte or spermatozoa donation
• couples with known chromosomal abnormalities
• female partners with known uterine abnormalities

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Subfertile couples; Couples who are not able to conceive for at least 12 months with female partners without infertility diagnosis.	Other: Lifestyle and metabolic indicators; Socio-demographics, health history, behavioural characteristics, environmental exposures, anthropometric measurements, body fat composition, metabolic and stress biomarkers, semen physical and molecular characteristics.; Other Names: Semen quality and characteristics
Fertile couples; Couples with attempted time to conceive within 12 months to achieve this pregnancy or with unplanned pregnancy, with female partners who are currently pregnant with viable intrauterine pregnancy.	Other: Lifestyle and metabolic indicators; Socio-demographics, health history, behavioural characteristics, environmental exposures, anthropometric measurements, body fat composition, metabolic and stress biomarkers, semen physical and molecular characteristics.; Other Names: Semen quality and characteristics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pregnancy rate	Defined by viable intrauterine pregnancy at gestational weeks of less or equal to 16 at the time of the study	Up to 16 weeks of gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fertility index	Defined by a composite index score derived from both male and female predictive factors	Through study completion, an average of 3 years
Oxidative stress	Defined by oxidative status measured from blood and semen samples using the micro-NMR	Through study completion, an average of 3 years
Semen volume	Assessed by semen analysis in ml	Up to 2 years
Sperm concentration	Assessed by semen analysis in million/ml	Up to 2 years
Sperm total motility	Assessed by semen analysis in percent	Up to 2 years
Sperm progressive motility	Assessed by semen analysis in percent	Up to 2 years
Total progressive motile sperm count	measured by multiplying the semen volume (ml) by sperm concentration (million/ml) and the percentage of progressively motile sperm	Up to 2 years
Single strand sperm DNA fragmentation	Measured by the AI-powered semen analyzer	Up to 2 years
Double strand sperm DNA fragmentation	Measured by the AI-powered semen analyzer	Up to 2 years
mRNA level	From blood and semen samples through transcriptomics analysis	Through study completion, an average of 3 years
sncRNA level	From blood and semen samples through transcriptomics analysis	Through study completion, an average of 3 years
DNA methylation	From blood and semen samples through bisulfite sequencing	Through study completion, an average of 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sperm morphology	Assessed by semen analysis	Up to 2 years

Collaborators and Investigators

• Sponsor: KK Women's and Children's Hospital
• Investigators: Principal Investigator: See Ling Loy, PhD, KK Women's and Children's Hospital

Publications and helpful links

General Publications

• Ku CW, Pek JW, Cheung YB, Tharmalingam Durgahshree MD, Chan M, Lee YH, Godfrey K, Yap F, Chan JKY, Loy SL. Investigating male factors and their relationships with reproductive health outcomes: a case-control study protocol for Towards Optimal Fertility, Fathering, and Fatherhood studY (TOFFFY) in Singapore. BMJ Open. 2025 Jan 15;15(1):e088143. doi: 10.1136/bmjopen-2024-088143.

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: February 20, 2024
• First Submitted That Met QC Criteria: February 27, 2024
• First Posted (Actual): March 5, 2024

Study Record Updates

• Last Update Posted (Actual): March 20, 2026
• Last Update Submitted That Met QC Criteria: March 17, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Oxidative stress; Male; Lifestyle; Epigenetic; DNA fragmentation; Risk factor; Semen analysis
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Infertility; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Molecular Structure; Biochemical Phenomena; Chemical Phenomena; Protein Structural Elements; Protein Conformation; Molecular Conformation; Protein Structure, Secondary; Semen Analysis; Amino Acid Motifs
• Other Study ID Numbers: MOH-001530-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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