(Abstracted from Am J Obstet Gynecol 2024;231:244.e1–244.e18) Noninvasive prenatal testing (NIPT) for Down, Edwards, and Patau syndromes is widely available. Its accuracy depends on a sufficient amount of fetal cell-free DNA (cfDNA) in maternal plasma.

BACKGROUND:Noninvasive prenatal testing by cell-free DNA analysis is offered to pregnant women worldwide to screen for fetal aneuploidies. In noninvasive prenatal testing, the fetal fraction of cell-free DNA in the maternal circulation is measured as a quality control parameter. Given that fetal cell-free DNA originates from the placenta, the fetal fraction might also reflect placental health and maternal pregnancy adaptation. OBJECTIVE:This study aimed to assess the association between the fetal fraction and adverse pregnancy outcomes. STUDY DESIGN:We performed a retrospective cohort study of women with singleton pregnancies opting for noninvasive prenatal testing between June 2018 and June 2019 within the Dutch nationwide implementation study (Trial by Dutch Laboratories for Evaluation of Non-Invasive Prenatal Testing [TRIDENT]-2). Multivariable logistic regression analysis was used to assess associations between fetal fraction and adverse pregnancy outcomes. Fetal fraction was assessed as a continuous variable and as <10th percentile, corresponding to a fetal fraction <2.5%. RESULTS:The cohort comprised 56,110 pregnancies. In the analysis of fetal fraction as a continuous variable, a decrease in fetal fraction was associated with increased risk of hypertensive disorders of pregnancy (adjusted odds ratio, 2.27 [95% confidence interval, 1.89-2.78]), small for gestational age neonates <10th percentile (adjusted odds ratio, 1.37 [1.28-1.45]) and <2.3rd percentile (adjusted odds ratio, 2.63 [1.96-3.57]), and spontaneous preterm birth from 24 to 37 weeks of gestation (adjusted odds ratio, 1.02 [1.01-1.03]). No association was found for fetal congenital anomalies (adjusted odds ratio, 1.02 [1.00-1.04]), stillbirth (adjusted odds ratio, 1.02 [0.96-1.08]), or neonatal death (adjusted odds ratio, 1.02 [0.96-1.08]). Similar associations were found for adverse pregnancy outcomes when fetal fraction was <10th percentile. CONCLUSION:In early pregnancy, a low fetal fraction is associated with increased risk of adverse pregnancy outcomes. These findings can be used to expand the potential of noninvasive prenatal testing in the future, enabling the prediction of pregnancy complications and facilitating tailored pregnancy management through intensified monitoring or preventive measures.

OBJECTIVE:To explore the perspectives of pregnant women on broadening the scope of noninvasive prenatal testing (NIPT) from screening for foetal aneuploidies to prediction of adverse pregnancy outcomes. METHODS:Four online focus groups (n = 23 participants) and 14 individual semi-structured interviews were conducted. Participants included pregnant women with and without a history of adverse pregnancy outcomes. RESULTS:Both women at low and high risk of adverse pregnancy outcomes had a positive attitude towards using NIPT to predict adverse pregnancy outcomes. Perceived benefits included the possibility to potentially improve maternal and foetal outcomes by taking risk-reducing measures and/or intensified monitoring during pregnancy and the ability to mentally prepare for the potential adverse outcome. Perceived concerns included anxiety and stress caused by a high-risk test result, a false sense of control over pregnancy, and potential false reassurance. Additionally, women reasoned that broadening the scope of NIPT could increase the complexity of prenatal screening and raised concerns on the combined screening aims in one test (prediction of adverse pregnancy outcomes to improve foetal and maternal health vs. screening for foetal aneuploidies to increase reproductive autonomy). On a societal level, considerations on the risk of medicalising pregnancy and overall pressure to opt for NIPT were mentioned. CONCLUSION:In general, pregnant women have a positive attitude towards broadening the scope of NIPT to the prediction of pregnancy outcomes, although some concerns are acknowledged.

Objective To assess the added value of fetal fraction of cell-free DNA in the maternal circulation in the prediction of adverse pregnancy outcomes. DesignRetrospective cohort study. SettingNationwide implementation study on non-invasive prenatal testing (NIPT; TRIDENT-2 study). PopulationPregnant women in the Netherlands opting for NIPT between June 2018 and June 2019. MethodsTwo logistic regression prediction models were constructed for each adverse pregnancy outcome. The first model (base model) included prognostic clinical parameters that were selected from existing first-trimester prediction models for adverse pregnancy outcomes. The second model (fetal fraction model) included fetal fraction as a predictor on top of the prognostic clinical parameters included in the base model. The added prognostic value of fetal fraction was assessed by comparing the base and fetal fraction models in terms of goodness of fit and predictive performance. Main Outcome MeasuresLikelihood ratio test (LRT), area under the curve (AUC) and Integrated Discrimination Improvement (IDI) index. ResultsThe study cohort consisted of 56 110 pregnancies. The incidence of adverse pregnancy outcomes was 5.7% for hypertensive disorders of pregnancy (HDP; n = 3207), 10.2% for birthweight < p10 (n = 5726), 3.2% for birthweight < p2.3 (n = 1796), 3.4% for spontaneous preterm birth (sPTB; n = 1891), 3.4% for diabetes (n = 1902) and 1.3% for congenital anomalies (n = 741). Adding fetal fraction to the base model improved model fit for HDP, birthweight < p10, birthweight < p2.3, all sPTB, and diabetes, but not for congenital anomalies (LRT p < 0.05). For HDP, the AUC improved from 0.67 to 0.68 by adding fetal fraction to the base model (p = 0.14) with an IDI of 0.0018 (p < 0.0001). For birthweight < p10, the AUC improved from 0.65 to 0.66 (p < 0.0001) with an IDI of 0.0023 (p < 0.0001). For birthweight < p2.3, the AUC improved from 0.67 to 0.69 (p < 0.0001) with an IDI of 0.0011 (p < 0.0001). For all sPTB, the AUC was similar for both models (AUC 0.63, p = 0.021) with an IDI of 0.00028 (p = 0.0023). For diabetes, the AUC was similar (AUC 0.72, p = 0.35) with an IDI of 0.00055 (p = 0.00015). ConclusionsFetal fraction has statistically significant but limited prognostic value in the prediction of adverse pregnancy outcomes in addition to known prognostic clinical parameters.

From an ethical point of view, there is an important distinction between two types of prenatal screening. The first of these targets maternal or foetal conditions (e.g., infectious diseases, blood group sensitization) where early detection allows for interventions that improve the chances of a healthy pregnancy outcome. The second screens for foetal conditions such as Down syndrome, where a timely diagnosis in most cases only allows for a choice between preparation for a child with special needs or termination of the pregnancy. Whereas the former makes an easy fit with the prevention aim of most other population screening programmes, the latter does not. In order to steer clear from a possible eugenic reading of its aim, a wide international consensus has emerged for the view that prenatal screening of this type should have the atypical aim of helping women (couples) to make autonomous reproductive choices, rather than reducing the birth prevalence of the relevant disorders. However, keeping these types of prenatal screening apart may become increasingly difficult given the development of tests, such as the Non-Invasive Prenatal Test, which cannot only be used for both types of screening but may also lead to interconnected findings on both sides of the divide. This makes it an urgent question: What the aim or aims of this new hybrid screening should be? As neither 'prevention' nor 'autonomy' will do, we argue for a normative framework that gives both aims their due, while recognizing the tensions between them.

BACKGROUND:Early risk stratification can facilitate timely interventions for adverse pregnancy outcomes, including preeclampsia (PE), small-for-gestational-age neonates (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). OBJECTIVES:To perform a systematic review and meta-analysis of first-trimester prediction models for adverse pregnancy outcomes. SEARCH STRATEGY:The PubMed database was searched until 6 June 2024. SELECTION CRITERIA:First-trimester prediction models based on maternal characteristics were included. Articles reporting on prediction models that comprised biochemical or ultrasound markers were excluded. DATA COLLECTION AND ANALYSIS:Two authors identified articles, extracted data and assessed risk of bias and applicability using PROBAST. MAIN RESULTS:A total of 77 articles were included, comprising 30 developed models for PE, 15 for SGA, 11 for sPTB and 35 for GDM. Discriminatory performance in terms of median area under the curve (AUC) of these models was 0.75 [IQR 0.69-0.78] for PE models, 0.62 [0.60-0.71] for SGA models of nulliparous women, 0.74 [0.72-0.74] for SGA models of multiparous women, 0.65 [0.61-0.67] for sPTB models of nulliparous women, 0.71 [0.68-0.74] for sPTB models of multiparous women and 0.71 [0.67-0.76] for GDM models. Internal validation was performed in 40/91 (43.9%) of the models. Model calibration was reported in 21/91 (23.1%) models. External validation was performed a total of 96 times in 45/91 (49.5%) of the models. High risk of bias was observed in 94.5% of the developed models and in 58.3% of the external validations. CONCLUSIONS:Multiple first-trimester prediction models are available, but almost all suffer from high risk of bias, and internal and external validations were often not performed. Hence, methodological quality improvement and assessment of the clinical utility are needed.

Thiopurine treatment is regularly complicated by drug-induced liver injury. It has been suggested that oxidative stress may play a synergistic role. To assess whether thiopurine-induced liver injury coincides with increased oxidative stress and whether co-administration with N-acetylcysteine is protective, we performed a randomized open label crossover pilot study in inflammatory bowel disease patients with thiopurine-induced increased serum liver tests. The study comprised four stages of 4 weeks. Patients received no additional therapy followed by N-acetylcysteine 1200 mg twice a day, or the other way around, alongside ongoing thiopurine treatment. The third and fourth stages comprised a washout period and thiopurine reintroduction period. Nine patients completed the study, and the addition of N-acetylcysteine decreased myeloperoxidase concentrations (33.6-24.5 pmol/L, p = 0.038). The other biomarkers remained unchanged, including thiopurine metabolites, xanthine oxidase activity, thiopurine S-methyltransferase activity and serum liver enzyme activity tests. Reintroduction of thiopurines led to an increase of F2-isoprostanes (101-157 ng/mmol, p = 0.038), but not of serum liver enzyme activity tests. Results suggests that thiopurines may increase oxidative stress and although the addition of N-acetylcysteine led to a decrease in plasma myeloperoxidase concentrations, it does not protect from thiopurine-induced increase of serum liver tests.

Background Fetal fraction (FF) measurement is considered important for reliable noninvasive prenatal testing (NIPT). Using minimal FF threshold as a quality parameter is under debate. We evaluated the variability in reported FFs of individual samples between providers and laboratories and within a single laboratory. Methods Genomic quality assessment and European Molecular Genetics Quality Network provide joint proficiency testing for NIPT. We compared reported FFs across all laboratories and stratified according to test methodologies. A single sample was sequenced repeatedly and FF estimated by 2 bioinformatics methods: Veriseq2 and SeqFF. Finally, we compared FFs by Veriseq and SeqFF in 87 351 NIPT samples. Results For each proficiency test sample we observed a large variability in reported FF, SDs and CVs ranging from 1.7 to 3.6 and 17.0 to 35.8, respectively. FF measurements reported by single nucleotide polymorphism-based methods had smaller SDs (0.5 to 2.4) compared to whole genome sequencing-based methods (1.8 to 2.9). In the internal quality assessment, SDs were similar between SeqFF (SD 1.0) and Veriseq v2 (SD 0.9), but mean FF by Veriseq v2 was higher compared to SeqFF (9.0 vs 6.4, P 0.001). In patient samples, reported FFs were on average 1.12-points higher in Veriseq than in SeqFF (P 0.001). Conclusions Current methods do not allow for a reliable and consistent FF estimation. Our data show estimated FF should be regarded as a laboratory-specific range, rather than a precise number. Applying strict universal minimum thresholds might result in unnecessary test failures and should be used with caution.

Objectives To assess the association between low fetal fraction (FF) in prenatal cell-free DNA (cfDNA) testing and adverse pregnancy outcomes. Methods We conducted a retrospective cohort study of participants of the TRIDENT-2 study (Dutch nationwide government-supported study offering cfDNA screening for fetal aneuploidies) who received a failed test result due to low FF (<4%) between April 2017 until February 2018. Outcome measures included pregnancy-induced hypertension (PIH), pre-eclampsia (PE), small for gestational age neonates (SGA), spontaneous preterm birth (sPTB), gestational diabetes mellitus (GDM), chromosomal aberrations, and congenital structural anomalies. Results Test failure due to low FF occurred in 295 women (1.12% of tests performed). Information regarding pregnancy outcomes was available for 96.3% of these women. The incidence of PIH, PE, SGA, sPTB, and GDM was 11.2%, 4.1%, 7.3%, 5.1%, and 14.8%, respectively. The prevalence of chromosomal aberrations and congenital structural anomalies was 1.4% and 4.1%, respectively. Incidences of PIH, PE >= 34 weeks of gestation, GDM, and prevalence of aneuploidy and congenital structural anomalies were higher in women with low FF compared to the general Dutch obstetric population. Conclusion Low FF is associated with adverse pregnancy outcomes. The value of FF in the prediction of these outcomes needs to be further established.

Objective Low fetal fraction (LFF) in prenatal cell-free DNA (cfDNA) testing is an important cause of test failure and no-call results. LFF might reflect early abnormal placentation and therefore be associated with adverse pregnancy outcome. Here, we review the available literature on the relationship between LFF in cfDNA testing and adverse pregnancy outcome. Method A systematic literature search was conducted in MEDLINE and EMBASE up to November 1, 2020. Results Five studies met the criteria for inclusion; all were retrospective observational cohort studies. The cohort sizes ranged from 370 to 6375 pregnancies, with all tests performed in the first trimester or early second trimester. A 4% cutoff for LFF was used in two studies, two studies used the 5th and 25th percentiles, respectively, and one study used a variety of cutoff values for LFF. LFF in prenatal cfDNA testing was observed to be associated with hypertensive disease of pregnancy, small for gestational age neonates, and preterm birth. Conflicting results were found regarding the association between LFF and gestational diabetes mellitus. Conclusions LFF in cfDNA testing is associated with adverse pregnancy outcome,specifically pregnancy-related hypertensive disorders, preterm birth, and impaired fetal growth related to placental dysfunction. Since the available evidence is limited, a large prospective cohort study on the relationship between fetal fraction and pregnancy outcomes is needed.

NAFLD is closely related with the metabolic syndrome (MetS) and increased risk of cardiovascular disease. Liver fat associates with post‐prandial hypertriglyceridemia, potentially contributing to triglyceride‐enrichment of high‐density lipoproteins (HDL‐TG), and subsequent HDL dysfunction. We assessed liver fat by MR spectroscopy, and its association with HDL physiochemical properties, and endothelial function, measured as flow‐mediated dilation (FMD), before and following three consecutive meals, in 36 men with type 2 diabetes mellitus (T2DM), with the MetS, and controls. Plasma triglycerides increased significantly following the meals ( P < .001). Fasting HDL‐TG was highest in T2DM, relative to MetS and controls ( P = .002), and increased post‐prandially in all groups ( P < .001). HDL function was negatively associated with HDL‐TG following three meals ( r = −.32, P <.05). Liver fat associated with HDL‐TG after three meals ( r = .65, P < .001). HDL‐TG was independently associated with FMD following three consecutive meals ( r = −.477, P = .003). We conclude liver fat is associated with post‐prandial HDL‐TG enrichment which was closely related with endothelial and HDL dysfunction.

OBJECTIVE:To determine the human dose-response relationship between a stepwise increase in arterial oxygen tension and its associated changes in DO2 and sublingual microcirculatory perfusion.METHODS:Fifteen healthy volunteers breathed increasing oxygen fractions for 10 minutes to reach arterial oxygen tensions of baseline (breathing air), 20, 40, 60 kPa, and max kPa (breathing oxygen). Systemic hemodynamics were measured continuously by the volume-clamp method. At the end of each period, the sublingual microcirculation was assessed by SDF.RESULTS:Systemic DO2 was unchanged throughout the study (Pslope  = .8). PVD decreased in a sigmoidal fashion (max -15% while breathing oxygen, SD18, Pslope  = .001). CI decreased linearly (max -10%, SD10, Pslope  < .001) due to a reduction in HR (max -10%, SD7, Pslope  = .009). There were no changes in stroke volume or MAP. Most changes became apparent above an arterial oxygen tension of 20 kPa.CONCLUSIONS:In healthy volunteers, supraphysiological arterial oxygen tensions have no effect on systemic DO2 . Sublingual microcirculatory PVD decreased in a dose-dependent fashion. All hemodynamic changes appear negligible up to an arterial oxygen tension of 20 kPa.

The risk ofmaternal alloimmunization due to RhD incompatibility has decreased with use of antenatal and postnatal anti-D immunoglobulin prophylaxis. The discovery of cell-free fetal (cff) DNA in maternal plasma during pregnancy and the feasibility of fetal RhD testing using this source of DNA make it possible to determine fetal RhD type and to restrict the use of antenatal anti-D immunoglobulin to only those RhD-negative women carrying an RhD-positive fetus. Variable and low amount of fetal DNA present in maternal plasma and the genetic variation of RHD alleles in the fetus or mother complicate such noninvasive testing. This study was done to evaluate the efficacy of noninvasive fetal RHD testing in week 27 of pregnancy to restrict use of antenatal and postnatal anti-D immunoglobulin use to RhD-negative women carrying an RhD-positive fetus.Duplex real-time polymerase chain reaction analysis was carried out for RHD exon 5 and RHD exon 7 in triplicate on cellfreeDNA isolated frommaternal plasma. Cord blood serologywas used as the reference standard as it is the best test available for determination of neonatal RhD status. The sensitivity for detection of fetal RHD was 99.94% (95% confidence interval [CI], 99.89%-99.97%), and specificity was 97.74% (95% CI, 97.43%-98.02%). Cord blood serology showed 9 falsenegative fetal RHD test results (0.03%; 95% CI, 0.02%-0.07%) and 225 false-positive fetal RHD test results (0.87%; 95% CI, 0.76%-1.00%). The overall negative predictive value was 99.91%(95% CI, 99.82%-99.95%), and the positive predictive value was 98.60% (95% CI, 98.40%-98.77%). The results demonstrate that fetal RHD assay performed at week 27 of pregnancy as part of an antenatal screening program is reliable and effective and can be used to restrict the use of both antenatal and postnatal anti-D immunoglobulin in RhD-negative pregnant women.

Background Oxidative stress is increasingly important in health research. Therefore, it is necessary to understand which factors determine basal oxidative stress. This study examines the associations of various determinants with markers of oxidative DNA and lipid damage: 8-hydroxy-2’-deoxyguanosine (8-OHdG) and F2-isoprostanes. Methods Data are from the Netherlands Study of Depression and Anxiety; 1117 subjects (18–65 years) without a current psychiatric diagnosis. Multivariable regression analyses were conducted with plasma levels of 8-OHdG and F2-isoprostanes (measured by LC/MS-MS) including sociodemographic, lifestyle, and sampling variables. Associations with metabolic syndrome (MetS) and chronic disease were examined. Results 8-OHdG and F2-isoprostanes were weakly correlated (r = 0.06, p = 0.045). Both were positively associated with age and cotinine (cigarette exposure); 8-OHdG was lower in females. F2-isoprostanes were higher in females, alcohol users, and in samples collected in spring and lower in supplement users and those with more education. Both markers were lower in fasting subjects. F2-isoprostanes, not 8-OHdG, were positively associated with MetS. Conclusion The weak correlation between 8-OHdG and F2-isoprostanes suggests they reflect specific aspects of oxidative stress. Both markers are associated with a range of sociodemographic, lifestyle, and sampling determinants which should be considered in future research. F2-isoprostanes are associated with MetS.

BackgroundOxidative stress has been implicated in the pathophysiology of major depressive disorder (MDD) and anxiety disorders and may be influenced by antidepressant use. This study investigated the association of oxidative stress, measured by plasma levels of F2-isoprostanes and 8-hydroxy-2′-deoxyguanosine (8-OHdG) reflecting oxidative lipid and DNA damage respectively, with MDD, anxiety disorders and antidepressant use in a large cohort.MethodData was derived from the Netherlands Study of Depression and Anxiety including patients with current (N = 1619) or remitted (N = 610) MDD and/or anxiety disorder(s) (of which N = 704 antidepressant users) and 612 controls. Diagnoses were established with the Composite International Diagnostic Interview. Plasma 8-OHdG and F2-isoprostanes were measured using LC-MS/MS. ANCOVA was performed adjusted for sampling, sociodemographic, health and lifestyle variables.ResultsF2-isoprostanes did not differ between controls and patients, or by antidepressant use. Patients with current disorders had lower 8-OHdG (mean 42.1 pmol/l, 95% CI 40.4–43.8) compared to controls (45.0 pmol/l, 95% CI 42.9–47.2; p < 0.001) after adjustment for sampling, sociodemographics and lifestyle, but these differences disappeared after further adjustment for antidepressant use (p = 0.562). Antidepressant users had lower 8-OHdG levels (38.2 pmol/l, 95% CI 36.5–39.9) compared to controls (44.9 pmol/l, 95% CI 43.2–46.6; Cohen's d = 0.21, p < 0.001). Results for 8-OHdG were comparable across disorders (MDD and/or anxiety disorders), and all antidepressant types (SSRIs, TCAs, other antidepressants).ConclusionContrary to previous findings this large-scale study found no increased oxidative stress in MDD and anxiety disorders. Antidepressant use was associated with lower oxidative DNA damage, suggesting antidepressants may have antioxidant effects.

BACKGROUND:Uric acid has neuroprotective effects, owing to its antioxidant properties. Lowered antioxidant capacity, causing increased oxidative stress, may be involved in affective disorders and might be altered by antidepressants. This study investigated the association of plasma uric acid, the greatest contributor to blood antioxidant capacity, with major depressive disorder (MDD) and anxiety disorders. METHODS:Data were from the Netherlands Study of Depression and Anxiety including patients with current (N = 1648), remitted (N = 609) MDD and/or anxiety disorders (of which N = 710 antidepressant users) and 618 controls. Diagnoses were established with the Composite International Diagnostic Interview. Symptom severity was assessed with the Inventory of Depressive Symptoms-Self Report, Beck Anxiety Inventory and Fear Questionnaire. Uric acid was measured in plasma. Analyses were adjusted for sociodemographic, health and lifestyle variables. RESULTS:Plasma uric acid adjusted mean levels were lower in current MDD and/or anxiety disorder(s) (289μmol/l) compared to remitted disorders (298μmol/l, p < .001) and controls (299μmol/l, p < .001; Cohen's d .10). This finding was independent of antidepressant use. Depressive (β-.05, p = .0012), anxiety (β-.04, p = .009) and phobic (β-.03, p = .036) symptom severity, and symptom duration (β-.04, p = .009) were negatively associated with uric acid. LIMITATIONS:Limitations include the lack of data on dietary intake which could be a potential confounding factor. From these cross-sectional findings, the association between uric acid and psychopathology cannot be inferred to be causal. CONCLUSION:This large scale study finds plasma uric acid levels are lower in current, but not remitted, MDD and/or anxiety disorders, according to a dose-response gradient. This suggests the involvement of decreased antioxidant status in affective disorders, and points to their potential as an avenue for treatment.

Background: Increased activity of the three major physiological stress systems (immune-inflammatory system, hypothalamic-pituitary-adrenal-axis [HPA-axis], and autonomic nervous system [ANS]) is part of the pathophysiology of various somatic and psychiatric"diseases. Oxidative damage is a key mechanism in both ageing and disease. Elucidating the relationship between these stress systems and oxidative damage would contribute to the understanding of the role of physiological stress in disease. This study therefore investigates associations between various measures of physiological stress and oxidative DNA (8-hydroxy-2'-deoxyguanosine, 8-OHdG) and lipid (F2-isoprostanes) damage.Methods: Plasma 8-OHdG and F2-isoprostanes were measured using LC-MS/MS in 2858 subjects (aged 18-65). Plasma inflammation markers, salivary cortisol and ANS markers (three for each stress system) were determined. Linear regression analyses were adjusted for sociodemographics, sampling factors and medication.Results: 8-OHdG was positively associated with all inflammation markers (beta=0.047-0.050, p < 0.01), evening cortisol (( = 0.073, p<0.001), and unexpectedly with low respiratory sinus arrhythmia (RSA) reflecting low ANS stress (beta=0.073, p <0.001). F2-isoprostanes were associated with higher C-reactive protein (13 = 0.072, p < 0.001), high ANS stress reflected in heart rate (beta = 0.064, p < 0.001) and RSA (beta = 0.076, p =0.001), but not with cortisol. Analyses investigating the cumulative impact of the stress systems demonstrated that the number of systems with >1 marker in the high risk quartile showed a positive linear trend with both 8-OHdG (p= 0.030) and F2-isoprostanes (p =0.009).Conclusion: This large-scale study showed that markers of inflammation, the HPA-axis and ANS are associated with oxidative DNA damage. Oxidative lipid damage is associated with inflammation and the ANS. Increased physiological stress across systems is associated with increasing oxidative damage in a dose-response fashion. 2017 Elsevier Ltd. All rights reserved.

IntroductionOxidative stress has been implicated in the pathophysiology of depression and anxiety disorders and may be influenced by antidepressant use.ObjectivesThis study investigated the association of oxidative stress, measured by plasma levels of F2-isoprostanes and 8-hydroxy-2′-deoxyguanosine (8-OHdG), reflecting oxidative lipid and DNA damage respectively, with major depressive disorder (MDD), generalized anxiety disorder, social phobia, panic disorder, agoraphobia and antidepressant use in a large cohort.MethodsData was derived from the Netherlands Study of Depression and Anxiety including patients with current (n = 1641) or remitted (n = 610) MDD and/or anxiety disorder(s) (of which n = 709 antidepressant users) and 633 controls. Diagnoses were established with the Composite Interview Diagnostic Instrument. Plasma 8-OHdG and F2-isoprostanes were measured using UHPLC-MS/MS. ANCOVA was performed adjusting for sampling, sociodemographic, health and lifestyle variables.ResultsF2-isoprostanes did not differ between controls and patients, or by antidepressant use. Patients (current or remitted) using antidepressants had lower 8-OHdG (adjusted mean 38.3 pmol/L) compared to patients (current or remitted) without antidepressants (44.7 pmol/L) and controls (44.9 pmol/L, P < 0.001; Cohen's d 0.26). Findings for 8-OHdG were similar over all disorders and all antidepressant types (SSRIs, TCAs, SNRIs; P < 0.001).ConclusionContrary to previous findings this large-scale study did not find increased oxidative stress measured by F2-isoprostanes or 8-OHdG in MDD or anxiety disorders. 8-OHdG levels were lower in antidepressant users, which suggests antidepressants may have antioxidant properties.Disclosure of interestThe authors have not supplied their declaration of competing interest.