The preterm prediction study: Fetal fibronectin testing and spontaneous preterm birth*
Objective
To evaluate the presence of fetal fibronectin in the cervix and vagina as a screening test for spontaneous pretenn birth.
Methods
Two thousand nine hundred twenty-nine women at ten centers were routinely screened every 2 weeks from 22–24 to 30 weeks for cervical and vaginal fetal fibronectin. A positive test was defined as a value equal to or greater than 50 ng/mL. The relation between a positive test at four gestational ages and spontaneous preterm birth at various intervals after the test was determined.
Results
In each testing period, 3–4% of the fetal fibronectin tests were positive. The correlation between cervical and vaginal fetal fibronectin at the same visit was always approximately 0.7 (P < .001), and that between cervical or vaginal fetal fibronectin in consecutive visits was between 0.17 and 0.25 (P < .001). The sensitivity of fetal fibronectin at 22–24 weeks to predict spontaneous preterm birth at less than 28 weeks was 0.63, and the relative risk for a positive versus negative test was 59. The specificity was always 96–98%, whereas the positive predictive value rose from 13% to 36% as the upper limit of the definition of preterm birth was increased from less than 28 to less than 37 weeks. The relative risk for spontaneous preterm birth after a positive fetal fibronectin test compared with a negative fetal fibronectin test varied substantially by testing period and by the definition of spontaneous preterm birth, but always remained greater than 4 and statistically significant.
Conclusion
A positive cervical or vaginal fetal fibronectin test at 22–24 weeks predicted more than half of the spontaneous preterm births at less than 28 weeks (sensitivity 0.63). As the definition of spontaneous preterm birth was extended to include later gestational ages or when the fetal fibronectin test was performed later in pregnancy, the level of association between a positive fetal fibronectin test and spontaneous preterm birth, while remaining highly significant, tended to decrease. Although fetal fibronectin is an excellent test for predicting spontaneous preterm birth, we present no evidence that the use of this test will result in a reduction in spontaneous preterm birth.
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Accelerated epigenetic clock aging in maternal peripheral blood and preterm birth
2024, American Journal of Obstetrics and GynecologyEpigenetic clocks use CpG DNA methylation to estimate biological age. Acceleration is associated with cancer, heart disease, and shorter life span. Few studies evaluate DNA methylation age and pregnancy outcomes. AgeAccelGrim is a novel epigenetic clock that combines 7 DNA methylation components.
This study aimed to determine whether maternal biological aging (via AgeAccelGrim) is associated with early preterm birth.
A prospective cohort of patients with singleton pregnancies and at high risk of spontaneous preterm birth delivering at a tertiary university hospital were included in this study. Genome-wide CpG methylation was measured using the Illumina EPIC BeadChip (Illumina, Inc, San Diego, CA) from maternal blood samples obtained at <28 weeks of gestation. AgeAccelGrim and its 7 DNA methylation components were estimated by the Horvath DNA methylation age online tool. Positive values are associated with accelerated biological aging, whereas negative values are associated with slower biological aging relative to each subject’s age. The primary outcome was preterm birth at <34 weeks of gestation (any indication). The secondary outcomes were preterm birth at <37 and <28 weeks of gestation. AgeAccelGrim was analyzed as a continuous variable and in quartiles. Exploratory analyses evaluated each of the 7 DNA methylation components included in the composite AgeAccelGrim. Data were analyzed by chi-square test, t test, rank-sum test, logistic regression (controlling a priori for maternal age, cell counts, low socioeconomic status, and gestational age at the time of sample collection), and Kaplan-Meier survival analyses. The log-rank test was used to test the equality of the survival functions.
Overall, 163 patients met the inclusion criteria. Of the patients, 48%, 39%, and 21% delivered at <37, <34, and <28 weeks of gestation, respectively. The median AgeAccelGrim was −0.35 years (interquartile range, −2.24 to 1.31) for those delivering at term. Those delivering preterm had higher AgeAccelGrim values that were inversely proportional to delivery gestational age (preterm birth at <37 weeks of gestation: +0.40 years [interquartile range: −1.21 to +2.28]; preterm birth at <34 weeks of gestation: +0.51 years [interquartile range: −1.05 to +2.67]; preterm birth at <28 weeks of gestation: +1.05 years [interquartile range: −0.72 to +2.72]). Estimated DNA methylation of the 7 epigenetic clock component values was increased among those with preterm birth at <34 weeks of gestation, although the differences were only significant for DNA methylation of plasminogen activation inhibitor 1. In regression models, AgeAcccelGrim was associated with an elevated risk of preterm birth with increasing magnitude for increasing severity of preterm birth. For each 1-year increase in the AgeAccelGrim value (ie, each 1-year increase in biological age compared with chronologic age), the adjusted odds of preterm birth were 11% (adjusted odds ratio, 1.11; 95% confidence interval, 1.00–1.24), 13% (adjusted odds ratio, 1.13; 95% confidence interval, 1.01–1.26), and 18% (adjusted odds ratio, 1.18; 95% confidence interval, 1.04–1.35) higher for preterm birth at <37, <34, and <28 weeks of gestation, respectively. Similarly, individuals with accelerated biological aging (≥75th percentile AgeAccelGrim) had more than double the odds of preterm birth at <34 weeks of gestation (adjusted odds ratio, 2.36; 95% confidence interval, 1.10–5.08) and more than triple the odds of preterm birth at <28 weeks of gestation (adjusted odds ratio, 3.89; 95% confidence interval, 1.61–9.38). The adjusted odds ratio for preterm birth at <37 weeks of gestation was 1.73 but spanned the null (adjusted odds ratio, 1.73; 95% confidence interval, 0.81–3.69). In Kaplan-Meier survival analyses, those in the highest AgeAccelGrim quartile delivered the earliest (log-rank P value of <.001).
Accelerated biological aging was associated with preterm birth among high-risk patients. Future research confirming these findings and elucidating factors that slow biological aging may improve birth outcomes.
Giants in Obstetrics and Gynecology Series: a profile of Robert L. Goldenberg, MD
2021, American Journal of Obstetrics and GynecologyCompliance with Fetal Fibronectin Testing at a Canadian Tertiary Care Perinatal Centre
2021, Journal of Obstetrics and Gynaecology CanadaThe purpose of this study was to assess compliance with fetal fibronectin (fFN) testing recommendations at a single tertiary care perinatal centre. The secondary objective was to identify factors associated with compliance with these recommendations.
A retrospective cohort study was conducted from January 1, 2016 to December 31, 2016 of all patients who presented to the IWK Health Centre with suspected preterm labour. Inclusion criteria included symptoms of preterm labour prior to 370 weeks gestation, singleton or multiple pregnancy, and established fetal wellbeing. Exclusion criteria included severe fetal anomaly, contraindications to tocolysis, transfer from community hospital, or inadequate documentation. Provider compliance was evaluated to determine: 1) whether the test was performed for appropriate indications according to provincial fFN guidelines; 2) whether fFN results were appropriately being used to inform patient care. Logistic regression was used to determine factors associated with compliance.
A total of 528 patients presented with symptoms of preterm labour. The overall compliance with testing recommendations was 76.1%. Compliance for patients who met criteria for fFN testing was 73%, and compliance for those not meeting criteria was 76.4%. Of patients with a negative fFN result, 85.3% were appropriately discharged home without intervention. Gestational age, time of day, and non-obstetrician provider type were found to be associated with compliance.
Despite regional and national guidelines, this study demonstrates a compliance rate of 76% in our centre, indicating a gap in provider knowledge regarding proper use and interpretation of fFN. Non-obstetrician provider type was associated with decreased compliance.
L'objectif de cette étude était d’évaluer la conformité aux recommandations en matière de détection de la fibronectine fœtale (FNf) dans un seul centre de soins périnataux tertiaires. L'objectif secondaire était de déterminer les facteurs associés à la conformité aux recommandations.
Une étude de cohorte rétrospective a été menée du 1er janvier au 31 décembre 2016 chez toutes les patientes manifestant un travail avant terme présumé à l'IWK Health Centre. Les critères d'inclusion étaient la présence de symptômes de travail avant terme à moins de 37 SA + 0 j; une grossesse monofœtale, gémellaire ou multiple; et un bien-être fœtal établi. Les critères d'exclusion étaient les anomalies fœtales graves, les contre-indications à la tocolyse, le transfert en provenance d'un hôpital communautaire ou un dossier médical inadéquat. La conformité du fournisseur de soins a été évaluée afin de déterminer : 1) si le test de détection a été effectué pour des indications appropriées conformément aux lignes directrices provinciales relativement à la FNf ; 2) si les résultats de détection de la FNf étaient adéquatement utilisés pour orienter la prestation de soins. Une régression logistique a été utilisée pour déterminer les facteurs associés à la conformité.
Au total, 528 patientes présentaient des symptômes de travail avant terme. La conformité globale aux recommandations en matière de détection de la FNf était de 76,1 %. La conformité aux recommandations était de 73 % pour les patientes répondant aux critères de détection de la FNf et de 76,4 % pour celles qui n'y répondaient pas. Parmi les patientes ayant obtenu un résultat de détection de la FNf négatif, 85,3 % ont reçu un congé adéquat sans intervention. L’âge gestationnel, l'heure de la journée et le type de fournisseur de soins non-obstétricien ont été associés à la conformité.
Malgré les lignes directrices régionales et nationales, cette étude révèle un taux de conformité de 76 % dans notre centre, ce qui indique une lacune dans les connaissances des fournisseurs de soins en ce qui concerne l'utilisation et l'interprétation appropriées de la détection de la FNf. Le type de fournisseur de soins non-obstétricien était associé à une diminution de la conformité.
Comparison of Fetal Fibronectin and Phosphorylated Insulin-Like Growth Factor Binding Protein-1 Testing to Predict Preterm Delivery in Symptomatic Women: A 10-Year Retrospective Study
2020, Journal of Obstetrics and Gynaecology CanadaTo assess the diagnostic accuracy and cost-effectiveness of fetal fibronectin (fFN) and cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) tests, individually and in combination, to predict preterm delivery within 48 hours, 7 days and 14 days in symptomatic women.
We selected women in Victoria, British Columbia, who presented between January 2008 and December 2017 at <34 weeks gestation at intermediate risk for labour (intact membrane, cervical dilatation <3 cm, and >6 contractions per hour). We calculated sensitivity, specificity, and positive and negative predictive values (PPV, NPV) for independent and concurrent testing and conducted a cost-effectiveness analysis to ensure appropriate test utilization.
We identified 2911 cases. Both fFN and phIGFBP-1 tests showed high and comparable NPV in predicting risk of delivery within 48 hours, 7 days and 14 days (fFN: 99.3%, 98.5% and 97.3%; phIGFBP-1: 98.8%, 97.9% and 96.1%). In 1976 cases, samples for fFN and phIGFBP-1 tests were collected and analyzed concurrently. Concurrent analysis increased specificity (90.8%, 91.4%, and 91.8%) and PPV (11.8%, 19.8% and 24.2%). Independently, both tests had comparable sensitivity, while the fFN test had higher specificity. Concurrent testing offered the highest PPV. The net gain in PPV comes with a clinically insignificant net loss (<1%) in NPV when compared with either of the tests individually.
Clinical usefulness of PPV for either test is limited. Routine concurrent testing comes with additional costs, and fFN has additional collection requirements. Point-of-care phIGFBP-1 testing has proven to be cheaper, simpler, and equally effective. Ordering physicians should be provided with education on how to interpret test results and should have protocols to guide clinical decision making.
Évaluer l'exactitude et le rapport coût-efficacité des tests de détection de la fibronectine fœtale (FNf) de l’insulin-like growth factor binding protein-1 phosphorylée (IGFBP-1ph) cervicale, indépendamment ou en association, utilisés pour prédire l'accouchement prématuré dans les 48 heures, les 7 jours et les 14 jours chez les femmes symptomatiques.
Nous avons sélectionné des femmes à Victoria, en Colombie-Britannique, à <34 SA qui manifestaient un risque intermédiaire de travail prématuré (membranes intactes, dilatation du col <3 cm et >6 contractions par heure), dans la période de janvier 2008 à décembre 2017. Nous avons calculé la sensibilité, la spécificité ainsi que les valeurs prédictives positives et négatives (VPP et VPN) pour les tests de détection utilisés indépendamment ou en association, puis effectué une analyse coût-efficacité pour veiller à l'utilisation appropriée des tests.
Nous avons recensé 2 911 cas. Les deux tests de détection (FNf et IGFBP-1ph) ont obtenu des VPN élevées et comparables pour la prédiction du risque d'accouchement dans les 48 heures, les 7 jours et les 14 jours (FNf : 99,3 %, 98,5 % et 97,3 %; IGFBP-1ph : 98,8 %, 97,9 % et 96,1 %). Dans 1 976 cas, les échantillons ont été prélevés pour les tests de détection de la FNf et de l'IGFBP-1ph puis analysés simultanément. L'analyse simultanée a augmenté la spécificité (90,8 %, 91,4 % et 91,8 %) et la VPP (11,8 %, 19,8 % et 24,2 %). Individuellement, les deux tests de détection ont eu une sensibilité comparable, tandis que le test de détection de la FNf a obtenu une meilleure spécificité. Les tests de détection réalisés simultanément ont obtenu la meilleure VPP. Le gain net en VPP s'accompagne d'une perte nette cliniquement négligeable (<1 %) en VPN par comparaison à chacun des tests utilisés individuellement.
L'utilité clinique de la VPP pour un ou l'autre des deux tests de détection est limitée. La détection simultanée systématique entraîne des coûts supplémentaires, et la détection de la FNf comporte des exigences de prélèvement supplémentaires. Le test de détection de l'IGFBP-1ph au point de service s'est révélé plus économique, plus simple et aussi efficace que le test de détection de la FNf. Il y a lieu de fournir aux médecins qui demandent les tests la formation nécessaire sur la façon d'interpréter les résultats; de même, il y a lieu d’établir des protocoles pour orienter le processus décisionnel clinique.
Endocrine Diseases of Pregnancy
2019, Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management: Eighth EditionPhysiological and endocrine adaptations occur in the mother in response to the demands of pregnancy. These demands include support of the fetus (volume support, nutritional and oxygen supply, and clearance of fetal waste), protection of the fetus (from starvation, drugs, toxins), preparation of the uterus for labor, and protection of the mother from potential cardiovascular injury at delivery. The presence of a preexisting endocrine disorder is likely to affect the ability of the mother to adapt to the demands of pregnancy and, as a result, may influence fetal growth and development. Drugs used to treat such disorders may also affect perinatal outcome. The most common preexisting endocrine disorders that can complicate pregnancy are diabetes mellitus, thyroid dysfunction, and obesity. Less common preexisting maternal endocrine disorders include pituitary tumors, diabetes insipidus, and hyperparathyroidism.
The physiological and endocrine adaptations that characterize pregnancy can also lead to the development of pregnancy-specific diseases in previously healthy women, the most common of which are gestational diabetes and disorders of the endocrine and sympathetic nervous systems associated with preeclampsia and preterm labor. This chapter is designed to review in detail the underlying pathophysiology of these pregnancy-specific diseases, as well as the effects of pregnancy on preexisting endocrine disorders. A better understanding of these conditions will improve the ability of clinicians to optimize maternal and perinatal outcome in such pregnancies.
Predicting preterm birth: Cervical length and fetal fibronectin
2017, Seminars in PerinatologySpontaneous preterm birth remains the leading cause of neonatal morbidity and mortality worldwide, and accounts for a significant global health burden. Several obstetric strategies to screen for spontaneous preterm delivery, such as cervical length and fetal fibronectin measurement, have emerged. However, the effectiveness of these strategies relies on their ability to accurately predict those pregnancies at increased risk for spontaneous preterm birth (SPTB). Transvaginal cervical shortening is predictive of preterm birth and when coupled with appropriate preterm birth prevention strategies, has been associated with reductions in SPTB in asymptomatic women with a singleton gestation. The use of qualitative fetal fibronectin may be useful in conjunction with cervical length assessment in women with acute preterm labor symptoms, but data supporting its clinical utility remain limited. As both cervical length and qualitative fetal fibronectin have limited capacity to predict preterm birth, further studies are needed to investigate other potential screening modalities.
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Funded by NICHD grants HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27889, HD27905, HD27915, and HD19897.