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Game-Changing Concepts in Reproductive Health

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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Clinical Diagnosis and Prognosis".

Deadline for manuscript submissions: 31 August 2026 | Viewed by 17008

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Editors

Prof. Dr. Mark I. Evans

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Lancaster Maternal Fetal Medicine, Lancaster PA and School of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Interests: CVS; fetal reduction; prenatal diagnosis; amniocentesis; ultrasound; nuchal translucency screening; fetal therapy
Special Issues, Collections and Topics in MDPI journals

Dr. Christian R. Macedonia

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Guest Editor

Lancaster Maternal Fetal Medicine, Lancaster PA and School of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Interests: obstetrics; gynecology; maternal and fetal medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The published research juggernaut is largely occupied by relatively incremental studies building upon an existing foundation which flood the literature and only advance the field in small increments. Such studies often predominate for several years. Periodically, however, there are game-changing discoveries that advance our understanding onto a new playing field, often with new rules, and which force everyone to think differently to how they did the day before. It is these sentinel discoveries that make careers and can have highly leveraged implications for both individual patients and public health. In women’s reproductive medicine, the logarithmic growth of molecular techniques and accompanying bioinformatics has translated into rapid changes in our appreciation of fetal, neonatal, childhood, and adult diagnoses and set the stage for new therapies. This Special Issue seeks research articles and reviews exploring such game-changing discoveries and how they are presented, argued, resisted, and ultimately translated and implemented into actual patient care.

You may choose our Joint Special Issue in Reproductive Medicine.

Prof. Dr. Mark I. Evans
Dr. Christian R. Macedonia
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

pregnancy
artificial intelligence
prenatal diagnosis
genetic sequencing
diagnostic tests
screening tests
public policy
electronic fetal monitoring
introducing new technologies

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Published Papers (8 papers)

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Research

Jump to: Review

19 pages, 769 KB

Open AccessArticle

Plasma RNA-Based Dual Screening for Early/Extreme Spontaneous Preterm Birth and Early Onset Preeclampsia to Enable Prevention

by Carl P. Weiner, Susan E. Carlson and Hamutal Meiri

Diagnostics 2026, 16(5), 660; https://doi.org/10.3390/diagnostics16050660 - 25 Feb 2026

Cited by 1 | Viewed by 729

Abstract

Background/Objectives: Preterm birth (PTB) at <33 wks’ gestation annually accounts for more than 60,000 births in the United States and 2 million births worldwide. Of these, spontaneous PTB (sPTB) at <33 wks’ gestation complicates about 1.8% of US births, while early onset preeclampsia (EOP), necessitating delivery at ≤33 wks’ gestation, complicates an additional 0.8% of US births. Current screening is based on medical and pregnancy history and biophysical variables with the goal of sensitizing patients and caregivers to early symptom identification. There is no individual patient risk prediction for sPTB at ≤33 wks’ gestation. We now have preventative therapies for women at high risk for EOP with delivery at <33 wks’ gestation (aspirin) and sPTB at ≤33 wks’ gestation (+/− preterm premature rupture of membranes (PPROMs)) (docosahexaenoic acid (DHA). Both require initiation of therapy by ~16 wks’ gestation for optimal effect, a requirement that current screening options cannot satisfy except for the FMF Combined Test for EOP. Neither do we have either an effective first-trimester screen for sPTB nor a dual screen for both of these major obstetric disorders. FutureBIRTH^® is a maternal five-plasma RNA panel supported by multiple external validation studies to provide effective dual screening for sPTB at <33 wks’ gestation and EOP with delivery at ≤33 wks’ gestation. Herein, we present the second external validation study for EOP with delivery at ≤33 wks with maternal sampling 12–13 wks 6 d combined with a review of the potential clinical impact of FutureBIRTH^® on the prevention of sPTB and EOP. Methods: Two NIH cohorts totaling 494 women were sampled from 12 to 20 wks. FutureBIRTH^® marker expression was quantified by polymerase chain reaction (PCR) as in the four preceding external validation studies. Results: After appropriate exclusions, there were nine cases (2.4%) of EOP with delivery at ≤33 wks gestation and 370 controls. Of this cohort, 79 (21%) were sampled at <14 wks’ gestation. Two of the nine cases were sampled at <14 wks’ gestation. NAMPT expression at 12–20 wks’ gestation was significantly increased in women destined for EOP with delivery at ≤33 wks’ gestation. Only the addition of diastolic blood pressure improved the predictive accuracy of NAMPT, yielding an AUC of 0.89 with a DR of 89% (8/9). Two cases sampled at <14 wks’ gestation who developed EOP with delivery at ≤33 wks’ gestation were screen positive, and two subjects placed on aspirin before 14 wks’ gestation were screen false positives. Conclusions: FutureBIRTH^® offers dual screening for EOP and sPTB with a sampling window extending down to 12 wks’ gestation, thus enabling the widespread use of preventative therapy. Full article

(This article belongs to the Special Issue Game-Changing Concepts in Reproductive Health)

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10 pages, 225 KB

Open AccessArticle

A Critical Assessment of Antenatal Monitoring for Fetal Well-Being in Down Syndrome Pregnancies

by Juliet C. Bishop, Angie C. Jelin, Ahizechukwu C. Eke, Christine B. Hertenstein, Amanda Jones, Clark T. Johnson and Karin Blakemore

Diagnostics 2026, 16(1), 39; https://doi.org/10.3390/diagnostics16010039 - 22 Dec 2025

Viewed by 903

Abstract

Background/Objectives: The antenatal management of Down syndrome (DS) is difficult as it is associated with a high risk for in utero fetal demise (IUFD) with a paucity of literature to guide antenatal surveillance. Avoidance of preterm delivery in the DS fetus, so commonly affected by anomalies, compounds the dichotomy of achieving term delivery while balancing against the risk for IUFD as gestational age advances. Higher-performing tests are needed to predict, and, thus, hopefully prevent, both preterm delivery and fetal mortality. Our study was undertaken to evaluate the performance metrics of current antenatal surveillance parameters that might suggest an increased risk for IUFD. Methods: We studied a retrospective cohort of all continuing pregnancies with a cytogenetically confirmed DS fetus between 2009 and 2019 at a single institution. Cases were investigated for abnormalities in fetal growth, anatomy, UA Doppler, and amniotic fluid volume to analyze their interrelationships and their association with the primary outcome, IUFD. Nonstress testing (NST) and biophysical profile data as available were also reviewed for analysis on each case. Maternal demographic data were also collected. Results: A total of 41 DS pregnancies at >20 weeks gestation were included. Eight (19.5%) resulted in IUFD, while thirty-three (80.5%) resulted in live birth. Between these groups, there was no significant difference in the incidence of fetal structural anomalies. FGR was present in 8/41 fetuses or 19.5% of all cases. FGR was present in 1 of 8 (12.5%) IUFD cases and 7 of 33 (21.2%) live births (p = 0.50). Thus, notably, 87.5% (7/8) of the IUFDs occurred in the absence of FGR. Furthermore, 1/8 (12.5%) FGR cases resulted in IUFD vs. 7/33 (21.2%) of non-FGR cases (p = 0.50). In DS fetuses after 24 weeks gestation, UA Doppler abnormalities developed in 75% of FGR cases (6/8) and in 64.5% of normally grown cases (20/31) (p = 0.33). Abnormal UA Dopplers were noted in 83.3% of IUFD and in 84.8% of liveborn cases (p = 0.34). Eleven of thirty-three live births, however, underwent iatrogenic delivery secondary to worsening fetal surveillance, including ten with worsening UA Doppler indices. There was an increased frequency of abnormal NST in the IUFD group (66.7% vs. 23.8%), although this difference did not reach statistical significance. Polyhydramnios was more frequent in the IUFD group (62.5% vs. 16.1%, p = 0.04). Conclusions: Aside from polyhydramnios, no fetal surveillance parameter demonstrated an association with IUFD that reached statistical significance. A majority of fetuses with DS are normally grown and demonstrate abnormal UA Doppler indices in the absence of FGR. Within our cohort, a substantial number of liveborn deliveries were prompted following worsening UA Dopplers. Both polyhydramnios and UA Doppler indices are worthy of further investigation to inform clinically useful fetal surveillance strategies in DS. Full article

(This article belongs to the Special Issue Game-Changing Concepts in Reproductive Health)

Review

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18 pages, 1191 KB

Open AccessReview

Preeclampsia Screening

by Yunyu Chen and Liona C. Poon

Diagnostics 2026, 16(13), 2074; https://doi.org/10.3390/diagnostics16132074 - 2 Jul 2026

Viewed by 169

Abstract

Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality worldwide. This significant burden necessitates effective early identification of pregnancies at high-risk for preeclampsia. Accurate prediction is essential in order to develop and optimize preventive strategies. The evolution of preeclampsia screening has progressed from a traditional checklist-based approach to individualized, multivariable models. The first-trimester triple test, which was developed by the Fetal Medicine Foundation (FMF), represents this advancement. It utilizes Bayes’ theorem to calculate patient-specific risks by integrating maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor. This model, called “first trimester FMF triple test”, has undergone successful internal and external validation for the prediction of preterm preeclampsia. To ensure the reliability of biomarker measurements and achieve an optimal screening performance, it is essential to implement standardized measurement protocols and rigorous quality control processes in biomarker testing. The triple test could also be utilized in the 2nd and 3rd trimester, and the addition of biomarkers such as soluble fms-like tyrosine kinase-1 further improves risk stratification assessment and continued surveillance of high-risk pregnancies. Full article

(This article belongs to the Special Issue Game-Changing Concepts in Reproductive Health)

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13 pages, 1160 KB

Open AccessReview

Prenatal Use of Exome Sequencing and Chromosomal Microarray Analysis: Indications, Interpretation, and Gene Selection Strategies

by Laia Rodriguez-Revenga, Victoria Ardiles-Ruesjas and Antoni Borrell

Diagnostics 2026, 16(2), 185; https://doi.org/10.3390/diagnostics16020185 - 7 Jan 2026

Viewed by 1208

Abstract

As genomic technologies continue to evolve, understanding the scope and limitations of available prenatal testing methods is essential for accurate diagnosis and counseling. Chromosomal microarray analysis (CMA) and exome sequencing (ES) have emerged as key complementary tools in this setting. This review aims to outline the technical principles underlying CMA and ES and to compare their diagnostic capabilities and limitations in the prenatal context. This narrative review includes a literature search, with additional relevant articles identified through manual screening of reference lists from key publications and review articles. Due to the narrative nature of this review, no formal inclusion or exclusion criteria or quantitative synthesis were applied. Special focus was placed on clinical indications, variant interpretation challenges—particularly uncertain and incidental findings—gene selection strategies, and implications for prenatal counseling. Indications for both tests have increased over time but differ substantially. CMA is becoming the standard prenatal genetic test, particularly in the evaluation of fetal structural anomalies, whereas ES remains restricted to selected fetal structural anomalies. Interpretation of molecular results remains a major challenge, especially for variants of uncertain significance and incidental findings with unclear or unexpected implications for pregnancy management. For ES, agnostic gene selection strategies showed superior diagnostic yield compared with phenotype-driven approaches, likely reflecting the limited characterization of prenatal phenotypes. Continuous refinement of clinical indications, bioinformatic pipelines, variant classification criteria, and gene curation strategies is critical to ensure that prenatal results are accurate and clinically meaningful. Together, ongoing improvements in technology, interpretation, and clinical integration have the potential to transform prenatal genomics into a more precise, informed, and ethically responsible field. Full article

(This article belongs to the Special Issue Game-Changing Concepts in Reproductive Health)

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9 pages, 231 KB

Open AccessReview

AI-Driven Advances in Women’s Health Diagnostics: Current Applications and Future Directions

by Christian Macedonia

Diagnostics 2025, 15(23), 3076; https://doi.org/10.3390/diagnostics15233076 - 3 Dec 2025

Cited by 2 | Viewed by 2189

Abstract

Background: Women’s health has historically served as an incubator for major medical innovations yet often faces relative neglect in sustained funding and implementation. The rise of artificial intelligence (AI) and machine learning (ML) presents both opportunities and risks for diagnostics in obstetrics and gynecology (OB/GYN). Methods: A narrative review (January 2018–August 2025) integrating peer-reviewed literature and clinical exemplars was conducted. OB/GYN relevance, clinical validation/scale, near-term outcome impact, and domain diversity were prioritized in selection. Results: We highlight ten promising AI applications across imaging, laboratory diagnostics, patient monitoring/digital biomarkers, and decision support, including AI-enhanced fetal ultrasound, cervical screening, preeclampsia prediction with cell-free RNA, noninvasive endometriosis testing, remote maternal–fetal monitoring, and reinforcement-learning decision support in gynecologic oncology. Conclusions: AI shows transformative potential for women’s health diagnostics but requires attention to bias, privacy, regulatory evolution, reimbursement, and workflow integration. Equity-focused development and diverse datasets are essential to ensure benefits accrue broadly. Full article

(This article belongs to the Special Issue Game-Changing Concepts in Reproductive Health)

16 pages, 939 KB

Open AccessReview

Maternal–Fetal Implications of Chikungunya Virus Infection: An Updated Review

by Luisa Scomparim, Gustavo Yano Callado, Livian Cássia De Melo, Marina Macruz Rugna, Stefany Silva Pereira, Liris Naomi Noguchi, Camilla Martins dos Santos Maia, Evelyn Traina, Geraldo Duarte, Antonio Braga and Edward Araujo Júnior

Diagnostics 2025, 15(22), 2843; https://doi.org/10.3390/diagnostics15222843 - 10 Nov 2025

Viewed by 1953

Abstract

Chikungunya virus (CHIKV) infection during pregnancy represents an increasing public health concern, especially in endemic and epidemic regions. The main concern is vertical transmission, particularly during the peripartum period, which can lead to severe neonatal outcomes such as encephalopathy, hematologic abnormalities, and long-term neurodevelopmental impairment. This review synthesizes current knowledge on pathophysiology, clinical manifestations, diagnosis, maternal and neonatal outcomes, and management of CHIKV infection in pregnancy. Diagnosis relies on clinical evaluation supported by laboratory confirmation, RT-PCR in the acute phase and IgM serology thereafter. Treatment is supportive, using acetaminophen as first-line therapy and corticosteroids for selected refractory cases. No antivirals or vaccines are approved for use in pregnancy as of 2025. Prevention is centered on vector control, personal protection, and epidemiological surveillance. Delivery planning and neonatal monitoring are essential when infection occurs close to term due to the high risk of peripartum transmission. Despite growing recognition of CHIKV’s maternal–fetal impact, significant gaps remain regarding long-term outcomes and optimal management strategies. Strengthening prenatal care, neonatal preparedness, and surveillance systems is crucial to mitigate adverse outcomes and inform future clinical and public health policies. Full article

(This article belongs to the Special Issue Game-Changing Concepts in Reproductive Health)

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19 pages, 846 KB

Open AccessReview

Advancements in Prenatal Genetic Screening and Testing: Emerging Technologies and Evolving Applications

by Mona M. Makhamreh, Mei Ling Chong and Ignatia B. Van den Veyver

Diagnostics 2025, 15(20), 2579; https://doi.org/10.3390/diagnostics15202579 - 13 Oct 2025

Cited by 5 | Viewed by 7474

Abstract

Advancements in genomic technologies have transformed prenatal genetic testing, offering more accurate, comprehensive, and noninvasive approaches to reproductive care. This review provides an in-depth overview of current methodologies and emerging innovations, including expanded carrier screening (ECS), cell-free DNA (cfDNA) testing, chromosomal microarray analysis (CMA), and sequencing-based diagnostics. We highlight how next-generation sequencing (NGS) technologies have revolutionized carrier screening and fetal genome analysis, enabling detection of a broad spectrum of genetic conditions. The clinical implementation of cfDNA has expanded from common aneuploidies to include copy number variants (CNVs), and single-gene disorders. Diagnostic testing has similarly evolved, with genome sequencing outperforming traditional CMA and exome sequencing through its ability to detect both sequence and structural variants in a single assay. Emerging tools such as optical genome mapping, RNA sequencing, and long-read sequencing further enhance diagnostic yield and variant interpretation. This review summarizes major technological advancements, assesses their clinical utility and limitations, and outlines future directions in prenatal genomics. Full article

(This article belongs to the Special Issue Game-Changing Concepts in Reproductive Health)

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19 pages, 3282 KB

Open AccessReview

Generational Leaps in Intrapartum Fetal Surveillance

by Lawrence D. Devoe

Diagnostics 2025, 15(19), 2482; https://doi.org/10.3390/diagnostics15192482 - 28 Sep 2025

Viewed by 1685

Abstract

Background/Objectives: Electronic fetal monitoring (EFM) has been used for intrapartum fetal surveillance for over 50 years. Despite numerous trials comparing EFM with standard fetal heart rate (FHR) auscultation, it remains contentious whether continuous monitoring with standard interpretation has reliably improved perinatal outcomes, specifically lower rates of perinatal morbidity and mortality. This review examines previous attempts to improve fetal monitoring and presents future directions for novel intrapartum fetal surveillance systems. Methods: We conducted a chronological review of EFM developments, including ancillary methods such as fetal ECG analysis, automated systems for FHR analysis, and artificial intelligence applications. We analyzed the evolution from visual interpretation to intelligent systems and evaluated the performance of various automated monitoring platforms. Results: Various ancillary methods developed to improve EFM accuracy for predicting fetal compromise have shown limited success. Only a limited number of studies demonstrated that adding fetal ECG analysis to visual FHR pattern interpretation resulted in better fetal outcomes. Automated systems for FHR analysis have not consistently enhanced intrapartum fetal surveillance. However, novel approaches such as the Fetal Reserve Index (FRI) show promise by incorporating clinical risk factors with traditional FHR patterns to provide higher-level risk assessment and prognosis. Conclusions: The shortcomings of visual interpretation of FHR patterns persist despite technological advances. Future intelligent intrapartum surveillance systems must combine conventional fetal monitoring with comprehensive risk assessment that incorporates maternal, fetal, and obstetric factors. The integration of artificial intelligence with contextualized metrics like the FRI represents the most promising direction for improving intrapartum fetal surveillance and clinical outcomes. Full article

(This article belongs to the Special Issue Game-Changing Concepts in Reproductive Health)

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