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Nature Jul 2023Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large,...
Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR). However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells.
Topics: Female; Humans; Pregnancy; Arteries; Decidua; Pregnancy Trimester, First; Trophoblasts; Uterus; Maternal-Fetal Exchange; Time Factors; Proteomics; Gene Expression Profiling; Datasets as Topic; Gestational Age
PubMed: 37468587
DOI: 10.1038/s41586-023-06298-9 -
Human Reproduction Update Nov 2023Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks... (Review)
Review
The pathophysiological role of estrogens in the initial stages of pregnancy: molecular mechanisms and clinical implications for pregnancy outcome from the periconceptional period to end of the first trimester.
BACKGROUND
Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks of pregnancy failure and complications, including hypertensive disorders and low birthweight babies. However, the role of estrogens in the periconceptional period and early pregnancy is still understudied.
OBJECTIVE AND RATIONALE
This review aims to summarize the current evidence on the role of maternal estrogens during the periconceptional period and the first trimester of pregnancies conceived naturally and following ART. Detailed molecular mechanisms and related clinical impacts are extensively described.
SEARCH METHODS
Data for this narrative review were independently identified by seven researchers on Pubmed and Embase databases. The following keywords were selected: 'estrogens' OR 'estrogen level(s)' OR 'serum estradiol' OR 'estradiol/estrogen concentration', AND 'early pregnancy' OR 'first trimester of pregnancy' OR 'preconceptional period' OR 'ART' OR 'In Vitro Fertilization (IVF)' OR 'Embryo Transfer' OR 'Frozen Embryo Transfer' OR 'oocyte donation' OR 'egg donation' OR 'miscarriage' OR 'pregnancy outcome' OR 'endometrium'.
OUTCOMES
During the periconceptional period (defined here as the critical time window starting 1 month before conception), estrogens play a crucial role in endometrial receptivity, through the activation of paracrine/autocrine signaling. A derailed estrogenic milieu within this period seems to be detrimental both in natural and ART-conceived pregnancies. Low estrogen levels are associated with non-conception cycles in natural pregnancies. On the other hand, excessive supraphysiologic estrogen concentrations at time of the LH peak correlate with lower live birth rates and higher risks of pregnancy complications. In early pregnancy, estrogen plays a massive role in placentation mainly by modulating angiogenic factor expression-and in the development of an immune-tolerant uterine micro-environment by remodeling the function of uterine natural killer and T-helper cells. Lower estrogen levels are thought to trigger abnormal placentation in naturally conceived pregnancies, whereas an estrogen excess seems to worsen pregnancy development and outcomes.
WIDER IMPLICATIONS
Most current evidence available endorses a relation between periconceptional and first trimester estrogen levels and pregnancy outcomes, further depicting an optimal concentration range to optimize pregnancy success. However, how estrogens co-operate with other factors in order to maintain a fine balance between local tolerance towards the developing fetus and immune responses to pathogens remains elusive. Further studies are highly warranted, also aiming to identify the determinants of estrogen response and biomarkers for personalized estrogen administration regimens in ART.
Topics: Pregnancy; Female; Humans; Pregnancy Outcome; Estrogens; Pregnancy Trimester, First; Placentation; Fertilization in Vitro; Estradiol
PubMed: 37353909
DOI: 10.1093/humupd/dmad016 -
JAMA Sep 2023While population-level data suggest Rh immunoglobulin is unnecessary before 12 weeks' gestation, clinical evidence is limited. Thus, guidelines vary, creating confusion... (Observational Study)
Observational Study
IMPORTANCE
While population-level data suggest Rh immunoglobulin is unnecessary before 12 weeks' gestation, clinical evidence is limited. Thus, guidelines vary, creating confusion surrounding risks and benefits of Rh testing and treatment. As abortion care in traditional clinical settings becomes harder to access, many people are choosing to self-manage and need to know if ancillary blood type testing is necessary.
OBJECTIVE
To determine how frequently maternal exposure to fetal red blood cells (fRBCs) exceeds the most conservative published threshold for Rh sensitization in induced first-trimester abortion.
DESIGN, SETTING, AND PARTICIPANTS
Multicenter, observational, prospective cohort study using high-throughput flow cytometry to detect circulating fRBCs in paired maternal blood samples before and after induced first-trimester abortion (medication or procedural). Individuals undergoing induced first-trimester abortion before 12 weeks 0 days' gestation were included. Paired blood samples were available from 506 participants who underwent either medical (n = 319 [63.0%]) or procedural (n = 187 [37.0%]) abortion.
EXPOSURE
Induced first-trimester abortion.
MAIN OUTCOMES AND MEASURES
The primary outcome was the proportion of participants with fRBC counts above the sensitization threshold (125 fRBCs/5 million total RBCs) after induced first-trimester abortion.
RESULTS
Among the 506 participants, the mean (SD) age was 27.4 (5.5) years, 313 (61.9%) were Black, and 123 (24.3%) were White. Three of the 506 participants had elevated fRBC counts at baseline; 1 of these patients had an elevated fRBC count following the abortion (0.2% [95% CI, 0%-0.93%]). No other participants had elevated fRBC counts above the sensitization threshold after induced first-trimester abortion. The median change from baseline was 0 fRBCs, with upper 95th and 99th percentiles of 24 and 35.6 fRBCs, respectively. Although there was a strong association between the preabortion and postabortion fRBC counts, no other baseline characteristic was significantly associated with postabortion fRBC count.
CONCLUSIONS AND RELEVANCE
Induced first-trimester abortion is not a risk factor for Rh sensitization, indicating that Rh testing and treatment are unnecessary before 12 weeks' gestation. This evidence may be used to inform international guidelines for Rh immunoglobulin administration following first-trimester induced abortion.
Topics: Adult; Female; Humans; Pregnancy; Abortion, Induced; Immunoglobulins; Prospective Studies; Rh Isoimmunization; Risk; Pregnancy Trimester, First; Erythrocytes; Young Adult; Black or African American; White
PubMed: 37750879
DOI: 10.1001/jama.2023.16953 -
Archives of Gynecology and Obstetrics Oct 2023To compare the efficacy of intravenous (IV) iron (ferric derisomaltose) with oral iron (ferrous fumarate) in women 14-21 weeks pregnant with persistent iron deficiency... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To compare the efficacy of intravenous (IV) iron (ferric derisomaltose) with oral iron (ferrous fumarate) in women 14-21 weeks pregnant with persistent iron deficiency (ferritin < 30 µg/L).
METHODS
In a single-centre, open-label, randomised controlled trial at a Danish hospital, women with persistent iron deficiency after routine oral iron treatment were allocated to receive 1000 mg IV iron (single-dose) or 100 mg elemental oral iron daily. Outcomes were assessed during an 18-week follow-up period. The primary endpoint was the proportion of non-anaemic (haemoglobin [Hb] ≥ 11 g/dL) women throughout follow-up. Other outcomes included changes in haematological parameters, patient-reported fatigue, and quality of life (QoL). Safety was assessed by recording adverse events.
RESULTS
From July 2017 to February 2020, 100 women were randomised to IV iron and 101 to oral iron. Throughout follow-up, 91% of women were non-anaemic in the IV iron group compared with 73% in the oral iron group (18% difference [95% confidence interval 0.10-0.25]; p < 0.001). The mean Hb increase was significantly greater with IV iron versus oral iron at Weeks 6 (0.4 versus - 0.2 g/dL; p < 0.001), 12 (0.5 versus 0.1 g/dL; p < 0.001), and 18 (0.8 versus 0.5 g/dL; p = 0.01). Improvements in fatigue and QoL were greater with IV iron versus oral iron at Weeks 3 and 6. The incidence of treatment-related adverse events was comparable between treatment groups.
CONCLUSION
IV iron was superior in preventing anaemia compared with oral iron in pregnant women with persistent iron deficiency; biochemical superiority was accompanied by improved fatigue and QoL.
CLINICAL TRIAL REGISTRATION
European Clinical Trials Database: EudraCT no.: 2017-000776-29 (3 May 2017); ClinicalTrials.gov: NCT03188445 (13 June 2017). The trial protocol has been published: https://dx.doi.org/10.1186%2Fs13063-020-04637-z .
Topics: Humans; Female; Pregnancy; Ferric Compounds; Anemia, Iron-Deficiency; Administration, Oral; Administration, Intravenous; Trace Elements; Pregnancy Trimester, Second; Denmark; Treatment Outcome; Adult
PubMed: 36107229
DOI: 10.1007/s00404-022-06768-x -
The Journal of Maternal-fetal &... Dec 2023Preliminary research suggests that maternal prenatal stress may alter the development of the fetal microbiome and resulting microbial composition after birth. However,...
OBJECTIVES
Preliminary research suggests that maternal prenatal stress may alter the development of the fetal microbiome and resulting microbial composition after birth. However, the findings of existing studies are mixed and inconclusive. The purpose of this exploratory study was to assess whether maternal stress during pregnancy is associated with the overall number and diversity of various microbial species in the infant gut microbiome or the abundance of specific bacterial taxa.
METHODS
Fifty-one women were recruited during their third trimester of pregnancy. The women completed a demographic questionnaire and Cohen's Perceived Stress Scale at recruitment. A stool sample was collected from their neonate at one month of age. Data on potential confounders, such as gestational age and mode of delivery, were extracted from medical records to control for their effects. 16s rRNA gene sequencing was used to identify the diversity and abundance of microbial species, along with multiple linear regression models to examine the effects of prenatal stress on microbial diversity. We employed negative binomial generalized linear models to test for differential expression of various microbial taxa among infants exposed to prenatal stress and those not exposed to prenatal stress.
RESULTS
More severe symptoms of prenatal stress were associated with a greater diversity of microbial species in the gut microbiome of neonates (β = .30, = .025). Certain microbial taxa, such as and were enriched among infants exposed to greater maternal stress in utero, while others, such as and , were depleted in contrast to infants exposed to less stress.
CONCLUSIONS
Findings suggest that mild to moderate stress exposure in utero could be associated with a microbial environment in early life that is more optimally prepared to thrive in a stressful postnatal environment. Adaptation of gut microbiota under conditions of stress may involve upregulation of bacterial species, including certain protective microorganisms (e.g. ), as well as downregulation of potential pathogens (e.g. ) epigenetic or other processes within the fetal/neonatal gut-brain axis. However, further research is needed to understand the trajectory of microbial diversity and composition as infant development proceeds and the ways in which both the structure and function of the neonatal microbiome may mediate the relationship between prenatal stress and health outcomes over time. These studies may eventually yield microbial markers and gene pathways that are biosignatures of risk or resilience and inform targets for probiotics or other therapies in utero or during the postnatal period.
Topics: Infant, Newborn; Infant; Pregnancy; Child; Humans; Female; Pregnancy Trimester, Third; RNA, Ribosomal, 16S; Bacteria; Fetus; Gastrointestinal Microbiome
PubMed: 37217447
DOI: 10.1080/14767058.2023.2214835 -
Epigenetics Dec 2023Most pregnancy complications originate with early placentation. MicroRNAs (miRNAs) may play an important role in placentation and function as biomarkers of future...
Most pregnancy complications originate with early placentation. MicroRNAs (miRNAs) may play an important role in placentation and function as biomarkers of future pregnancy complications. We summarized from the literature all first trimester circulating miRNAs associated with pregnancy complications of placental origin and further identified the miRNAs which have the most evidence as potential early biomarkers for pregnancy complications. We conducted a systematic review following PRISMA reporting guidelines (PROSPERO CRD42020183421). We identified all first trimester serum or plasma miRNAs associated with a pregnancy complication of placental origin (preeclampsia, intrauterine growth restriction (IUGR), gestational hypertension, preterm delivery) and the number of times those miRNAs were identified, as a measure of replication. Twenty-one studies examined 118 unique miRNAs, and 87 were associated with at least one pregnancy complication; preeclampsia was the most common. Seven miRNAs were significantly associated with a pregnancy complication in at least two studies: miR-125b, miR-518b, miR-628-3p, miR-365a-3p, miR-520h, miR-374a-5p, miR-191-5p. Few miRNAs were associated with more than one pregnancy complication: miR-518b and miR-520h with preeclampsia and gestational hypertension, miR-374a-5p and miR-191-5p with preterm birth and preeclampsia. Our systematic review suggests seven miRNAs as potential biomarkers of pregnancy complications. These complications are thought to originate with early placental defects and these miRNAs may also be biomarkers of placental pathology. First-trimester biomarkers of pregnancy complications can facilitate early detection and interventions.
Topics: Pregnancy; Humans; Infant, Newborn; Female; Pregnancy Trimester, First; Pre-Eclampsia; Hypertension, Pregnancy-Induced; Circulating MicroRNA; Placenta; Premature Birth; DNA Methylation; MicroRNAs; Pregnancy Complications; Placentation; Biomarkers
PubMed: 36503407
DOI: 10.1080/15592294.2022.2152615 -
American Journal of Human Genetics Sep 2023Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural...
Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.
Topics: Female; Pregnancy; Humans; Autism Spectrum Disorder; Pregnancy Trimester, First; Ultrasonography, Prenatal; Chromosome Mapping; Exome
PubMed: 37595579
DOI: 10.1016/j.ajhg.2023.07.010 -
Scandinavian Journal of Surgery : SJS :... Sep 2023Non-obstetric surgery is fairly common in pregnant women. We performed a systematic review to update data on non-obstetric surgery in pregnant women. The aim of this... (Review)
Review
BACKGROUND AND OBJECTIVE
Non-obstetric surgery is fairly common in pregnant women. We performed a systematic review to update data on non-obstetric surgery in pregnant women. The aim of this review was to evaluate the effects of non-obstetric surgery during pregnancy on pregnancy, fetal and maternal outcomes.
METHODS
A systematic literature search of MEDLINE and Scopus was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search span was from January 2000 to November 2022. Thirty-six studies matched the inclusion criteria, and 24 publications were identified through reference mining; 60 studies were included in this review. Outcome measures were miscarriage, stillbirth, preterm birth, low birth weight, low Apgar score, and infant and maternal morbidity and mortality rates.
RESULTS
We obtained data for 80,205 women who underwent non-obstetric surgery and data for 16,655,486 women who did not undergo surgery during pregnancy. Prevalence of non-obstetric surgery was between 0.23% and 0.74% (median 0.37%). Appendectomy was the most common procedure with median prevalence of 0.10%. Near half (43%) of the procedures were performed during the second trimester, 32% during the first trimester, and 25% during the third trimester. Half of surgeries were scheduled, and half were emergent. Laparoscopic and open techniques were used equally for abdominal cavity. Women who underwent non-obstetric surgery during pregnancy had increased rate of stillbirth (odds ratio (OR) 2.0) and preterm birth (OR 2.1) compared to women without surgery. Surgery during pregnancy did not increase rate of miscarriage (OR 1.1), low 5 min Apgar scores (OR 1.1), the fetus being small for gestational age (OR 1.1) or congenital anomalies (OR 1.0).
CONCLUSIONS
The prevalence of non-obstetric surgery has decreased during last decades, but still two out of 1000 pregnant women have scheduled surgery during pregnancy. Surgery during pregnancy increases the risk of stillbirth, and preterm birth. For abdominal cavity surgery, both laparoscopic and open approaches are feasible.
Topics: Infant; Pregnancy; Infant, Newborn; Female; Humans; Pregnancy Outcome; Premature Birth; Stillbirth; Abortion, Spontaneous; Fetus
PubMed: 37329286
DOI: 10.1177/14574969231175569 -
Journal of Translational Medicine Sep 2023Preeclampsia (PE) is a leading cause of maternal and perinatal mortality and morbidity worldwide, but effective early prediction remains a challenge due to the lack of...
BACKGROUND
Preeclampsia (PE) is a leading cause of maternal and perinatal mortality and morbidity worldwide, but effective early prediction remains a challenge due to the lack of reliable biomarkers.
METHODS
Based on the extensive human biobank of our large-scale assisted reproductive cohort platform, the first-trimester serum levels of 48 cytokines, total immunoglobulins (Igs), anti-phosphatidylserine (aPS) antibodies, and several previously reported PE biomarkers [including placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and activin A] were measured in 34 women diagnosed with PE and 34 matched normotensive controls.
RESULTS
The PE group has significantly higher first-trimester serum levels of interleukin (IL)-2Rα, IL-9, tumor necrosis factor-β (TNF-β), RANTES, hepatocyte growth factor (HGF), total IgM, and total IgG, and aPS IgG optical density (OD) value, as well as lower first-trimester serum levels of PlGF and total IgA and aPS-IgG immune complexes (IC) OD value than the control group. Combining top five first-trimester serum biomarkers (total IgM, total IgG, PlGF, aPS IgG, and total IgA) achieved superior predictive value [area under the curve (AUC) and 95% confidence interval (CI) 0.983 (0.952-1.000), with a sensitivity of 100% and a specificity of 94.1%] for PE development compared to PlGF and PlGF/sFlt-1 independently [AUC and 95% CI 0.825 (0.726-0.924) and 0.670 (0.539-0.800), respectively].
CONCLUSION
We identified novel first-trimester serum biomarkers and developed an effective first-trimester prediction model using immune-related factors and PlGF for PE, which could facilitate the development of early diagnostic strategies and provide immunological insight into the further mechanistic exploration of PE.
Topics: Pregnancy; Humans; Female; Pre-Eclampsia; Placenta Growth Factor; Pregnancy Trimester, First; Vascular Endothelial Growth Factor A; Biomarkers; Immunoglobulin G; Immunoglobulin A; Immunoglobulin M
PubMed: 37718445
DOI: 10.1186/s12967-023-04472-1 -
American Journal of Obstetrics &... May 2024In recent years, there has been a significant rise in cases of placenta accreta spectrum, a group of life-threatening placental disorders that can arise during... (Review)
Review
In recent years, there has been a significant rise in cases of placenta accreta spectrum, a group of life-threatening placental disorders that can arise during childbirth. Early detection plays a crucial role in facilitating meticulous delivery planning, ultimately leading to a reduction in mortality and morbidity rates and improved overall outcomes. Although third-trimester ultrasound has traditionally been the primary method for prenatal screening for placenta accreta spectrum, it often falls short in identifying cases or diagnosis is too late for optimal delivery planning. Emerging evidence has highlighted the option of early detection of placenta accreta spectrum indicators during the first trimester of pregnancy. This comprehensive review delves into our current knowledge of sonographic assessment of the uterine cervicoisthmic complex in the first trimester, examining the location and appearance of cesarean scars and exploring first-trimester screening strategies, ultimately paving the way for improved maternal and neonatal outcomes.
Topics: Humans; Placenta Accreta; Pregnancy; Female; Pregnancy Trimester, First; Ultrasonography, Prenatal; Cesarean Section; Cicatrix; Early Diagnosis; Cervix Uteri
PubMed: 38447672
DOI: 10.1016/j.ajogmf.2024.101329