Lihua Huang1,2, See Ling Loy3,4, Wei-Qing Chen2,5, Johan G Eriksson6,7,8,9,10, Yap Seng Chong6, Zhongwei Huang6,11, Jerry Kok Yen Chan3, Tien Yin Wong4,12, Michael Kramer6,13, Cuilin Zhang14, Ling-Jun Li6,9,12. 1. Administration Department of Nosocomial Infection, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China. 2. Department of Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, China. 3. Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, Singapore. 4. Duke-NUS Medical School, National University of Singapore, Singapore, Singapore. 5. Department of Information Management, Xinhua College, Sun Yat-sen University, Guangzhou, Guangdong, China. 6. Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, Singapore, Singapore. 7. Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 8. Folkhälsan Research Center, Helsinki, Finland. 9. Department of Obstetrics and Gynecology and Human Potential Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 10. Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. 11. Institute of Molecular and Cell Biology, Agency of Science, Technology & Research, Singapore, Singapore. 12. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore. 13. Department of Pediatrics and of Epidemiology, Biostatistics and Occupational Health, McGill University Faculty of Medicine, Montreal, Canada. 14. Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Abstract
STUDY QUESTION: Can abnormalities in retinal microvasculature representing adverse microcirculatory perfusion and inflammation shed light on the pathophysiology of female fecundability? SUMMARY ANSWER: In our prospective study, abnormalities in retinal vascular geometric morphology (i.e. sparser arteriolar fractal and larger venular bifurcation) during pre-conception phase are temporarily associated with a prolonged time-to-pregnancy (TTP). WHAT IS KNOWN ALREADY: Suboptimal retinal microcirculatory morphology has been associated with obesity, psychological stress and hypertension, all of which are known risk factors for reduced female fecundability. STUDY DESIGN, SIZE, DURATION: A total of 652 women of Chinese, Malay or Indian ethnicity 18-45 years of age and planning to conceive spontaneously within the next 12 months were recruited during the pre-conception period into the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO), from February 2015 to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: During recruitment, we collected information on socio-demographic factors, menstrual characteristics and lifestyle behaviors and made anthropometric measurements. We assessed the following retinal microvascular features: caliber, branching angle and fractal dimension. We conducted follow-up telephone surveys to track each participant's pregnancy status at 6, 9 and 12 months after enrolment. We ascertained clinical pregnancies via ultrasonography, with TTP measured by the number of menstrual cycles required to achieve a clinical pregnancy over a 1-year follow-up. Then, we performed discrete-time proportional hazards models to estimate the fecundability odds ratio (FOR) and 95% CI for each retinal microvascular feature in association with TTP, after adjusting for major confounders, including body mass index and fasting glycemic level at study entry. MAIN RESULTS AND THE ROLE OF THE CHANCE: Among 652 recruited women, 276 (42.3%) successfully conceived within 1 year of follow-up. The mean (and SD) was 1.24 (0.05) Df for retinal arteriolar dimension fraction and 78.45 (9.79) degrees for retinal venular branching angle, respectively. Non-linear relationship testing was performed before multiple adjustment in all associations and a non-monotonic association was detected between retinal venular branching angle and TTP. Compared with women in the highest tertile of retinal arteriolar fractal dimension, women in the second tertile had a prolonged TTP (FOR: 0.68; 95% CI: 0.51-0.92), as did women in the lowest tertile (FOR: 0.73; 95% CI: 0.55-0.98). Compared with women in the middle tertile of retinal venular branching angle, women in the highest tertile had a borderline prolonged TTP (FOR: 0.75; 95% CI: 0.56-1.02). No other retinal vascular features were significantly associated with TTP. LIMITATIONS, REASONS FOR CAUTION: We were unable to adjust for other potential confounding factors such as female sexual function (e.g. frequency of sexual intercourse), which might introduce a residual bias. Moreover, even though this is a prospective cohort design, our findings can identify the temporal relationship but not necessarily infer a causal relationship between maternal microvasculature and TTP. Lastly, our study involving mainly Chinese, Malay and Indian ethnicities might not be generalizable to other races or ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Suboptimal microcirculation may lead to reduced female fecundability. In the future, in addition to conventional ultrasonographic evaluation of ovarian and uterine physiological function, assessing the retinal microvasculature might be useful for assessment of ovarian age, fertility prediction and endometrial evaluation before assisted reproductive techniques for fertility treatments. STUDY FUNDING/COMPETING INTEREST(S): This research is supported by the Singapore National Research Foundation (NRF) under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC) (Singapore-NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014) and Singapore National Medical Research Council Transition Award (NMRC TA/0027/2014). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03531658.
STUDY QUESTION: Can abnormalities in retinal microvasculature representing adverse microcirculatory perfusion and inflammation shed light on the pathophysiology of female fecundability? SUMMARY ANSWER: In our prospective study, abnormalities in retinal vascular geometric morphology (i.e. sparser arteriolar fractal and larger venular bifurcation) during pre-conception phase are temporarily associated with a prolonged time-to-pregnancy (TTP). WHAT IS KNOWN ALREADY: Suboptimal retinal microcirculatory morphology has been associated with obesity, psychological stress and hypertension, all of which are known risk factors for reduced female fecundability. STUDY DESIGN, SIZE, DURATION: A total of 652 women of Chinese, Malay or Indian ethnicity 18-45 years of age and planning to conceive spontaneously within the next 12 months were recruited during the pre-conception period into the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO), from February 2015 to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: During recruitment, we collected information on socio-demographic factors, menstrual characteristics and lifestyle behaviors and made anthropometric measurements. We assessed the following retinal microvascular features: caliber, branching angle and fractal dimension. We conducted follow-up telephone surveys to track each participant's pregnancy status at 6, 9 and 12 months after enrolment. We ascertained clinical pregnancies via ultrasonography, with TTP measured by the number of menstrual cycles required to achieve a clinical pregnancy over a 1-year follow-up. Then, we performed discrete-time proportional hazards models to estimate the fecundability odds ratio (FOR) and 95% CI for each retinal microvascular feature in association with TTP, after adjusting for major confounders, including body mass index and fasting glycemic level at study entry. MAIN RESULTS AND THE ROLE OF THE CHANCE: Among 652 recruited women, 276 (42.3%) successfully conceived within 1 year of follow-up. The mean (and SD) was 1.24 (0.05) Df for retinal arteriolar dimension fraction and 78.45 (9.79) degrees for retinal venular branching angle, respectively. Non-linear relationship testing was performed before multiple adjustment in all associations and a non-monotonic association was detected between retinal venular branching angle and TTP. Compared with women in the highest tertile of retinal arteriolar fractal dimension, women in the second tertile had a prolonged TTP (FOR: 0.68; 95% CI: 0.51-0.92), as did women in the lowest tertile (FOR: 0.73; 95% CI: 0.55-0.98). Compared with women in the middle tertile of retinal venular branching angle, women in the highest tertile had a borderline prolonged TTP (FOR: 0.75; 95% CI: 0.56-1.02). No other retinal vascular features were significantly associated with TTP. LIMITATIONS, REASONS FOR CAUTION: We were unable to adjust for other potential confounding factors such as female sexual function (e.g. frequency of sexual intercourse), which might introduce a residual bias. Moreover, even though this is a prospective cohort design, our findings can identify the temporal relationship but not necessarily infer a causal relationship between maternal microvasculature and TTP. Lastly, our study involving mainly Chinese, Malay and Indian ethnicities might not be generalizable to other races or ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Suboptimal microcirculation may lead to reduced female fecundability. In the future, in addition to conventional ultrasonographic evaluation of ovarian and uterine physiological function, assessing the retinal microvasculature might be useful for assessment of ovarian age, fertility prediction and endometrial evaluation before assisted reproductive techniques for fertility treatments. STUDY FUNDING/COMPETING INTEREST(S): This research is supported by the Singapore National Research Foundation (NRF) under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC) (Singapore-NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014) and Singapore National Medical Research Council Transition Award (NMRC TA/0027/2014). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03531658.
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