We are pleased to introduce the collection Frontiers in Reproductive Health – Highlights in Reproductive Epidemiology 2021/22. This collection will welcome and showcase a selection of high impact articles authored by leaders in the field. The work presented here highlights the broad diversity of research performed across the Reproductive Epidemiology section, and aims to put a spotlight on the main areas of interest. This collection aims to further support Frontiers’ strong community by shining a spotlight on our authors' highly impactful research.

Karolinska Institutet (KI)

Aristotle University of Thessaloniki

Alfaisal University

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. Research on the effects of danger signs in pregnancy, oncofertility support, dioxins on male reproductive system, emergency contraceptives, and interferon on pregnancy outcomes have been studied: <ul> <li>Adequate prevalence of knowledge of danger signs in pregnancy among pregnant mothers in Hosanna Zuria Kebeles was found, with advanced maternal age, the respondent's level of education, and the number of live births being independent determining factors.</li> <li>Cancer patients of reproductive age in Saudi Arabia were aware of treatment-related infertility and fertility preservation, but not receiving adequate oncofertility support or fertility preservation procedures.</li> <li>Dioxins were found to cause irreversible abnormalities in the male reproductive system, including effects on sexual function and fertility.</li> <li>The pandemic had an immediate effect on the use of emergency contraceptives, with the number of users continuing to increase.</li> <li>Exposure to interferon (IFN) does not increase the risk of pregnancy outcomes or birth defects.</li> </ul>

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Frontiers in Reproductive Health

Reproductive Epidemiology

Highlights in Reproductive Epidemiology 2021/22

BackgroundDanger signs in pregnancy can warn of maternal health problems. In developing African countries, including Ethiopia, the rate of maternal mortality is high. There is little knowledge of danger signs during pregnancy and their associated factors at the community level in the study area.</sec>MethodsA community-based, cross-sectional study was conducted to assess knowledge about danger signs among pregnant women in Hosanna Zuria Kebeles between 30 June and 30 July 2021. A simple random sampling method was used to select eligible pregnant women. The sample size was proportionally allocated based on the number of pregnant women in each kebele. Data were collected in face-to-face interviews using a pretested questionnaire. The descriptive results were presented as proportions, whereas the analytic results were presented as adjusted odds ratios (AOR).</sec>ResultsThe prevalence of good knowledge of danger signs in pregnancy was 259/410 (63.2%, 95% confidence interval (CI) 58.3–67.8). The most common known danger signs during pregnancy were severe vaginal bleeding (n = 227, 55.4%), followed by blurred vision (n = 224, 54.6%). In the multivariable analysis, the age of the respondent (AOR = 3.29, 95% CI 1.15–9.38), the tertiary education of the mother (AOR = 5.40, 95% CI 2.56–11.34), and the number of live births (AOR = 3.95, 95% CI 2.08–7.48) were statistically significant factors.</sec>ConclusionThere was an adequate prevalence of knowledge of danger signs in pregnancy among pregnant mothers compared with different studies in Ethiopia and different countries. Advanced maternal age, the respondent's level of education, and the number of live births were found to be independent determining factors for the level of knowledge on danger signs in pregnancy among pregnant mothers. Health facilities and healthcare providers should focus on antenatal care and the age and parity of the mother when giving information about danger signs in pregnancy. The Ministry of Health should provide reproductive health services in rural areas and encourage education for women. Further studies need to be conducted and include danger signs in the three trimesters using a qualitative study design.</sec>

Background: Danger signs in pregnancy can warn of maternal health problems. In developing African countries, including Ethiopia, the rate of maternal mortality is high. There is little knowledge of danger signs during pregnancy and their associated factors at the community level in the study area.Methods: A community-based, cross-sectional study was conducted to assess knowledge about danger signs among pregnant women in Hosanna Zuria Kebeles between 30 June and 30 July 2021. A simple random sampling method was used to select eligible pregnant women. The sample size was proportionally allocated based on the number of pregnant women in each kebele. Data were collected in face-to-face interviews using a pretested questionnaire. The descriptive results were presented as proportions, whereas the analytic results were presented as adjusted odds ratios (AOR).Results: The prevalence of good knowledge of danger signs in pregnancy was 259/410 (63.2%, 95% confidence interval (CI) 58.3–67.8). The most common known danger signs during pregnancy were severe vaginal bleeding (n = 227, 55.4%), followed by blurred vision (n = 224, 54.6%). In the multivariable analysis, the age of the respondent (AOR = 3.29, 95% CI 1.15–9.38), the tertiary education of the mother (AOR = 5.40, 95% CI 2.56–11.34), and the number of live births (AOR = 3.95, 95% CI 2.08–7.48) were statistically significant factors.Conclusion: There was an adequate prevalence of knowledge of danger signs in pregnancy among pregnant mothers compared with different studies in Ethiopia and different countries. Advanced maternal age, the respondent's level of education, and the number of live births were found to be independent determining factors for the level of knowledge on danger signs in pregnancy among pregnant mothers. Health facilities and healthcare providers should focus on antenatal care and the age and parity of the mother when giving information about danger signs in pregnancy. The Ministry of Health should provide reproductive health services in rural areas and encourage education for women. Further studies need to be conducted and include danger signs in the three trimesters using a qualitative study design.

Knowledge of danger signs in pregnancy and their associated factors among pregnant women in Hosanna Town, Hadiya Zone, southern Ethiopia

BackgroundMore cancer survivors and a greater burden of long-term side effects have resulted from rising cancer incidence, improved treatment modalities, and younger age at cancer diagnosis. Treatment- related Infertility (TRI) is a well-known sequelae. This study looked at current oncofertility support and fertility preservation (FP) in men and women of reproductive age with cancer in Saudi Arabia, where there is little knowledge on the subject.</sec>MethodsA cross-sectional study included oncology patients of reproductive age from an academic hospital was conducted. Patients' characteristics, cancer type, treatment modalities and assessment of oncofertility support data were collected and examined to assess oncofertility support and potentially influencing factors.</sec>ResultsOur study included 135 patients (39.3% males and 60.7% females). Although 66.7% believed they were fertile at the time of diagnosis, and more than half planned to have children in the future, Unfortunately, only 37.8% have received fertility counseling, and only 17% have seen a fertility specialist. In male patients, the most common FP method was sperm cryopreservation (6.7%), while the majority of both genders (87.4%) did not use any FP method. Two-thirds of the patients are knowledgeable about TRI and FP methods. About half of the female patients (57.3%) were advised about the possibility of post-treatment amenorrhea while only 8.1% of the whole cohort received psychological support.</sec>ConclusionsDespite patients' satisfactory knowledge of TRI and FP, oncologists infrequently referred their patients to a specialized fertility service. More than half of our patients expressed a desire to have children in the future, but this desire was impeded by limited oncofertility care and FP procedures. Several factors influenced the knowledge of TRI, fertility counseling and FP. It is critical to incorporate oncofertility into management planning as it has a significant impact on patients' quality of life.</sec>

Background: More cancer survivors and a greater burden of long-term side effects have resulted from rising cancer incidence, improved treatment modalities, and younger age at cancer diagnosis. Treatment- related Infertility (TRI) is a well-known sequelae. This study looked at current oncofertility support and fertility preservation (FP) in men and women of reproductive age with cancer in Saudi Arabia, where there is little knowledge on the subject.Methods: A cross-sectional study included oncology patients of reproductive age from an academic hospital was conducted. Patients' characteristics, cancer type, treatment modalities and assessment of oncofertility support data were collected and examined to assess oncofertility support and potentially influencing factors.Results: Our study included 135 patients (39.3% males and 60.7% females). Although 66.7% believed they were fertile at the time of diagnosis, and more than half planned to have children in the future, Unfortunately, only 37.8% have received fertility counseling, and only 17% have seen a fertility specialist. In male patients, the most common FP method was sperm cryopreservation (6.7%), while the majority of both genders (87.4%) did not use any FP method. Two-thirds of the patients are knowledgeable about TRI and FP methods. About half of the female patients (57.3%) were advised about the possibility of post-treatment amenorrhea while only 8.1% of the whole cohort received psychological support.Conclusions: Despite patients' satisfactory knowledge of TRI and FP, oncologists infrequently referred their patients to a specialized fertility service. More than half of our patients expressed a desire to have children in the future, but this desire was impeded by limited oncofertility care and FP procedures. Several factors influenced the knowledge of TRI, fertility counseling and FP. It is critical to incorporate oncofertility into management planning as it has a significant impact on patients' quality of life.

Oncofertility care and influencing factors among cancer patients of reproductive age from Saudi Arabia

The male reproductive system is especially affected by dioxins, a group of persistent environmental pollutants, resulting in irreversible abnormalities including effects on sexual function and fertility in adult males and possibly on the development of male offspring. The reproductive toxicity caused by dioxins is mostly mediated by an aryl hydrocarbon receptor (AhR). In animals, spermatogenesis is a highly sensitive and dynamic process that includes proliferation and maturation of germ cells. Spermatogenesis is subject to multiple endogenous and exogenous regulatory factors, including a wide range of environmental toxicants such as dioxins. This review discusses the toxicological effects of dioxins on spermatogenesis and their relevance to male infertility. After a detailed categorization of the environmental contaminants affecting the spermatogenesis, the exposure pathways and bioavailability of dioxins in animals was briefly reviewed. The effects of dioxins on spermatogenesis are then outlined in detail. The endocrine-disrupting effects of dioxins in animals and humans are discussed with a particular focus on their effects on the expression of spermatogenesis-related genes. Finally, the impacts of dioxins on the ratio of X and Y chromosomes, the status of serum sex hormones, the quality and fertility of sperm, and the transgenerational effects of dioxins on male reproduction are reviewed.

The male reproductive system is especially affected by dioxins, a group of persistent environmental pollutants, resulting in irreversible abnormalities including effects on sexual function and fertility in adult males and possibly on the development of male offspring. The reproductive toxicity caused by dioxins is mostly mediated by an aryl hydrocarbon receptor (AhR). In animals, spermatogenesis is a highly sensitive and dynamic process that includes proliferation and maturation of germ cells. Spermatogenesis is subject to multiple endogenous and exogenous regulatory factors, including a wide range of environmental toxicants such as dioxins. This review discusses the toxicological effects of dioxins on spermatogenesis and their relevance to male infertility. After a detailed categorization of the environmental contaminants affecting the spermatogenesis, the exposure pathways and bioavailability of dioxins in animals was briefly reviewed. The effects of dioxins on spermatogenesis are then outlined in detail. The endocrine-disrupting effects of dioxins in animals and humans are discussed with a particular focus on their effects on the expression of spermatogenesis-related genes. Finally, the impacts of dioxins on the ratio of X and Y chromosomes, the status of serum sex hormones, the quality and fertility of sperm, and the transgenerational effects of dioxins on male reproduction are reviewed.

Effects of dioxins on animal spermatogenesis: A state-of-the-art review

The Coronavirus disease pandemic has disrupted reproductive health services including decline in the use of pre-coital contraceptives. However, evidence of its impact on the use of emergency contraceptives, often, post-coital methods, is limited in the emerging literature, hence this study. Data on total number of emergency contraceptive users from January 2018 to February 2020 (pre-pandemic) and March to December 2020 (during the pandemic) were extracted from the Ghana Health Service District Health Information Management System. Interrupted Time Series analysis was used to estimate the impact of the pandemic on the trend of emergency contraceptive use, adjusting for serial autocorrelation and seasonality. The results showed a gradual upward trend in emergency contraceptive use before the pandemic, increasing at a rate of about 67 (95% CI 37.6–96.8; p = 0.001) users per month. However, the pandemic caused a sudden spike in the use of emergency contraceptives. The pandemic and its related restrictions had an immediate effect on the use of emergency contraceptives, increasing significantly by about 1939 users (95% CI 1096.6–2781.2; p = 0.001) in March 2020. Following March 2020, the number of emergency contraceptive users continued to increase by about 385 users per month (95% CI 272.9–496.4; p = 0.001). The evidence shows that use of emergency contraceptives, often used as post-coital methods for unprotected sex was not negatively impacted by the pandemic. In fact, it is the opposite. Hence, in planning for similar situations attention should be given to the distribution of post-coital contraceptive methods.

The Coronavirus disease pandemic has disrupted reproductive health services including decline in the use of pre-coital contraceptives. However, evidence of its impact on the use of emergency contraceptives, often, post-coital methods, is limited in the emerging literature, hence this study. Data on total number of emergency contraceptive users from January 2018 to February 2020 (pre-pandemic) and March to December 2020 (during the pandemic) were extracted from the Ghana Health Service District Health Information Management System. Interrupted Time Series analysis was used to estimate the impact of the pandemic on the trend of emergency contraceptive use, adjusting for serial autocorrelation and seasonality. The results showed a gradual upward trend in emergency contraceptive use before the pandemic, increasing at a rate of about 67 (95% CI 37.6–96.8; p = 0.001) users per month. However, the pandemic caused a sudden spike in the use of emergency contraceptives. The pandemic and its related restrictions had an immediate effect on the use of emergency contraceptives, increasing significantly by about 1939 users (95% CI 1096.6–2781.2; p = 0.001) in March 2020. Following March 2020, the number of emergency contraceptive users continued to increase by about 385 users per month (95% CI 272.9–496.4; p = 0.001). The evidence shows that use of emergency contraceptives, often used as post-coital methods for unprotected sex was not negatively impacted by the pandemic. In fact, it is the opposite. Hence, in planning for similar situations attention should be given to the distribution of post-coital contraceptive methods.

Impact of COVID-19 on the Use of Emergency Contraceptives in Ghana: An Interrupted Time Series Analysis

Interferon (IFN) treatment is widely applied in viral hepatitis and multiple myeloproliferative diseases. However, there is considerable controversy on how to deal with unintended pregnancy during IFN treatment, even selective termination is suggested by hepatologists. To settle this clinical dilemma, we conducted a systematic review to retrieve all published articles involving IFN exposure during pregnancy up until March 31, 2021. Only 8 case reports that were relevant with outcomes of pregnant women with viral hepatitis exposed to IFN-α were retrieved, and 17 studies reporting pregnancy outcomes after exposure to type I IFNs involving 3,543 pregnancies were eligible for meta-analysis. No birth defect was reported in the case reports of pregnant women with viral hepatitis. The meta-analysis showed that risks of pregnancy outcomes and birth defects were not increased after exposure to IFN-α. Further comprehensive meta-analysis concerning the IFN-α and IFN-β exposure demonstrated that the risks of live birth (OR 0.89, 95% CI: 0.62–1.27), spontaneous abortion (OR 1.09, 95% CI: 0.73–1.63), stillbirth (OR 1.38, 95% CI: 0.51–3.72), preterm delivery (OR 1.24, 95% CI: 0.85–1.81), and maternal complications (OR 0.72, 95% CI: 0.38–1.38) were not increased in patients exposed to IFNs. The pooled estimates of live birth, spontaneous abortion, stillbirth, preterm delivery, and maternal complications were 85.2, 9.4, 0, 7.5, and 6.5%, respectively. Importantly, the risk of birth defects was not increased (OR 0.68, 95% CI: 0.39–1.20) after IFN exposure, with a pooled rate of 0.51%. Therefore, IFN exposure does not increase the prevalence of spontaneous abortion, stillbirth, preterm delivery, and birth defects. Clinical decision should be made after weighing up all the evidence.

Interferon (IFN) treatment is widely applied in viral hepatitis and multiple myeloproliferative diseases. However, there is considerable controversy on how to deal with unintended pregnancy during IFN treatment, even selective termination is suggested by hepatologists. To settle this clinical dilemma, we conducted a systematic review to retrieve all published articles involving IFN exposure during pregnancy up until March 31, 2021. Only 8 case reports that were relevant with outcomes of pregnant women with viral hepatitis exposed to IFN-&#x3b1; were retrieved, and 17 studies reporting pregnancy outcomes after exposure to type I IFNs involving 3,543 pregnancies were eligible for meta-analysis. No birth defect was reported in the case reports of pregnant women with viral hepatitis. The meta-analysis showed that risks of pregnancy outcomes and birth defects were not increased after exposure to IFN-&#x3b1;. Further comprehensive meta-analysis concerning the IFN-&#x3b1; and IFN-&#x3b2; exposure demonstrated that the risks of live birth (OR 0.89, 95% CI: 0.62&#x2013;1.27), spontaneous abortion (OR 1.09, 95% CI: 0.73&#x2013;1.63), stillbirth (OR 1.38, 95% CI: 0.51&#x2013;3.72), preterm delivery (OR 1.24, 95% CI: 0.85&#x2013;1.81), and maternal complications (OR 0.72, 95% CI: 0.38&#x2013;1.38) were not increased in patients exposed to IFNs. The pooled estimates of live birth, spontaneous abortion, stillbirth, preterm delivery, and maternal complications were 85.2, 9.4, 0, 7.5, and 6.5%, respectively. Importantly, the risk of birth defects was not increased (OR 0.68, 95% CI: 0.39&#x2013;1.20) after IFN exposure, with a pooled rate of 0.51%. Therefore, IFN exposure does not increase the prevalence of spontaneous abortion, stillbirth, preterm delivery, and birth defects. Clinical decision should be made after weighing up all the evidence.