Predicting Spontaneous Preterm Birth Using the Immunome.

Throughout pregnancy, the maternal peripheral circulation contains valuable information reflecting pregnancy progression, detectable as tightly regulated immune dynamics. Local immune processes at the maternal-fetal interface and other reproductive and non-reproductive tissues are likely to be the pacemakers for this peripheral immune "clock." This cellular immune status of pregnancy can be leveraged for the early risk assessment and prediction of spontaneous preterm birth (sPTB). Systems immunology approaches to sPTB subtypes and cross-tissue (local and peripheral) interactions, as well as integration of multiple biological data modalities promise to improve our understanding of preterm birth pathobiology and identify potential clinically actionable biomarkers.

Study protocol for two randomised controlled trials evaluating the effects of Cerclage in the reduction of extreme preterm birth and perinatal mortality in twin pregnancies with a short cervix or dilatation: the TWIN Cerclage studies.

INTRODUCTION: Twin pregnancies have a high risk of extreme preterm birth (PTB) at less than 28 weeks of gestation, which is associated with increased risk of neonatal morbidity and mortality. Currently there is a lack of effective treatments for women with a twin pregnancy and a short cervix or cervical dilatation. A possible effective surgical method to reduce extreme PTB in twin pregnancies with an asymptomatic short cervix or dilatation at midpregnancy is the placement of a vaginal cerclage. METHODS AND ANALYSIS: We designed two multicentre randomised trials involving eight hospitals in the Netherlands (sites in other countries may be added at a later date). Women older than 16 years with a twin pregnancy at <24 weeks of gestation and an asymptomatic short cervix of ≤25 mm or cervical dilatation will be randomly allocated (1:1) to both trials on vaginal cerclage and standard treatment according to the current Dutch Society of Obstetrics and Gynaecology guideline (no cerclage). Permuted blocks sized 2 and 4 will be used to minimise the risk of disbalance. The primary outcome measure is PTB of <28 weeks. Analyses will be by intention to treat. The first trial is to demonstrate a risk reduction from 25% to 10% in the short cervix group, for which 194 patients need to be recruited. The second trial is to demonstrate a risk reduction from 80% to 35% in the dilatation group and will recruit 44 women. A cost-effectiveness analysis will be performed from a societal perspective. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committees in the Netherlands on 3/30/2023. Participants will be required to sign an informed consent form. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT05968794.

Clomiphene citrate administered in peri-conception phase causes fetal loss and developmental impairment in mice.

Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated in mice the consequences for fetal development and pregnancy outcome of peri-conception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 h after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in three independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30 h average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed post-weaning growth and development comparable to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can inhibit implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the peri-conception phase unless its use is well-supervised.

Vaginal delivery in women with perianal Crohn's disease: why not?

BACKGROUND: Pregnant women with active perianal Crohn's disease indicate a cesarean delivery according to the current European Crohn's and Colitis Organisation guidelines. This advice is based on the assumption that vaginal delivery leads to exacerbation of perianal disease and worsening of fecal continence. However, there is no strong evidence to support this. OBJECTIVE: This study aims to examine the effects of the delivery method on perianal disease progression and fecal incontinence in women with perianal Crohn's disease. STUDY DESIGN: In this retrospective cohort study, 102 women were selected from the 1000 inflammatory bowel disease cohort of a tertiary hospital in the Netherlands. All women are aged >18 years, have perianal Crohn's disease, and have given birth. In addition, all women completed a questionnaire. Fecal continence was scored using the Vaizey score. Using SPSS, descriptive analysis and linear regression analysis were performed, and P values <.05 were considered statistically significant. RESULTS: The cesarean delivery rate within our cohort was 19.5%. Within the group of women who delivered at least one child vaginally (n=84), 25.5% reported alteration of fecal continence, compared with 13.1% in women who only had cesarean delivery (n=18). After a mean follow-up of 15 years, the median Vaizey score within the cesarean delivery group was 5, compared with 7 in the vaginal delivery group. Within the vaginal delivery group, 18.8% reported perianal disease progression, compared with 22.2% in the cesarean delivery group. No significant relation between mode of delivery and fecal continence or perianal disease progression was found (B, 0,97 [-1,19 to 3,14], P=.38). CONCLUSION: Fecal incontinence and perianal disease progression after vaginal delivery in Crohn's disease women with active perianal fistula is not significantly increased in this retrospective cohort. This study opens the discussion for more tailored obstetric advice in women with perianal Crohn's disease.

Pharmacokinetics of Tacrolimus in Pregnant Solid-Organ Transplant Recipients: A Retrospective Study.

Data on the pharmacokinetics of tacrolimus during pregnancy are limited. Therefore, the aim of this retrospective study was to characterize the whole-blood pharmacokinetics of tacrolimus throughout pregnancy. In this single-center retrospective cohort study, whole-blood tacrolimus trough concentrations corrected for the dose (concentration-to-dose [C/D] ratios) were compared before, monthly during, and after pregnancy in kidney, liver, and lung transplant recipients who became pregnant and gave birth between 2000 and 2022. Descriptive statistics and linear mixed models were used to characterize changes in tacrolimus C/D ratios before, during, and after pregnancy. The total study population included 46 pregnancies (31 pregnant women). Nineteen, 21, and 6 pregnancies were following kidney, liver, and lung transplantation, respectively. Immediate-release or extended-release formulations were used in 54.5% and 45.5% of the women, respectively. Tacrolimus C/D ratios significantly (P < .001) decreased (-48%) compared to the prepregnancy state at 7 months of pregnancy. These ratios recovered within 3 months postpartum (P = .002). C/D ratios tended to be lower during treatment with an extended-release formulation than with an immediate-release formulation (P = .071). Transplantation type did not significantly affect C/D ratios during pregnancy (P = .873). In conclusion, we found that tacrolimus whole-blood pharmacokinetics change throughout pregnancy, with the lowest C/D ratios (48% decrease) in the 7th month of pregnancy. In general, the decrease in C/D ratios seems to stabilize from month 4 onward compared to prepregnancy.

Fetal Thyrotoxicosis due to Maternal TSH Receptor Stimulating Antibodies Causes Infant Central Hypothyroidism.

INTRODUCTION: Women with a current diagnosis or past history of Graves' disease (GD) are at risk of developing fetal thyrotoxicosis (FT) during pregnancy when they are inadequately treated, or because of placental passage of TSH receptor antibodies (TRAb). It is known that FT induced by high maternal thyroid hormone concentrations may result in infant (central) hypothyroidism. CASE PRESENTATION: In a euthyroid woman with a history of GD treated with radioactive iodide (I131), persistently high levels of maternal TRAb resulted in recurrent FT during two separate pregnancies, followed by neonatal hyperthyroidism and infant central hypothyroidism. DISCUSSION: This case demonstrates the novel insight that FT due to high fetal thyroid hormone concentrations stimulated by high maternal TRAb levels might also result in (central) hypothyroidism, requiring long-term evaluation of the hypothalamus-pituitary-thyroid axis in these children.

Cold Mechanical Isolation of Placental Macrophages as a Method to Limit Procedure-Induced Activation of Macrophages.

Isolation of placental macrophages using enzymatic digestion at warm temperatures is widely used for in vitro studies. However, studies in brain and kidney tissue show that this method activates immune cells, immediate early genes, and heat shock proteins. Isolating placental macrophages while preserving their tissue-specific characteristics as much as possible is pivotal to reliably studying their functions. We therefore developed a mechanical dissociation protocol at low temperatures and compared this to enzymatic digestion at high temperatures. Decidual and villous macrophages were isolated from term human placentas. A cell suspension was generated by mechanical dissociation using a gentleMACS. For warm enzymatic digestion, Accutase was added, followed by incubation at 37°C. Macrophages were isolated after Ficoll density gradient centrifugation. Cell types were analyzed with flow cytometry (CD45, CD14, CD80, CD86, CD163, and CD206) and their activation status with real-time PCR (FOS, JUN, HSP27, HSP70, IL1ß, TNFα, IL10, and TGFß) after cell sorting. A higher proportion of leukocytes and macrophages was obtained from the villi with cold mechanical dissociation (p < 0.05). Compared to warm enzymatic digestion, cold mechanical dissociation resulted in a higher expression of CD163 in villous and decidual macrophages (p < 0.05). Warm enzymatic digestion showed higher levels of TNFα, IL1ß, and IL10 in decidual and villous macrophages, and HSP70 in villous macrophages. Our data show that mechanical dissociation of placental tissue at low temperatures is associated with less activation of placental macrophages. This suggests that cold mechanical dissociation is a preferred method, resulting in macrophages that more closely resemble their in-tissue state.

Preconception clinical factors related to adverse pregnancy outcomes in patients with systemic lupus erythematosus or primary Sjögren's syndrome: a retrospective cohort study.

OBJECTIVE: To identify preconception clinical factors associated with adverse pregnancy outcomes (APO) in patients with systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (pSS). METHODS: A single-centre, retrospective cohort study was conducted, which included pregnant women treated at the University Medical Center Groningen between January 2010 and August 2021 who fulfilled classification criteria for SLE or pSS. Demographic data, relevant comorbidities, disease duration, disease activity before and during pregnancy, APO, laboratory parameters and treatment regimens were recorded. Associations between the presence of APO and preconception characteristics were evaluated. RESULTS: Our study population included 48 (70%) SLE and 21 (30%) pSS pregnancies concerning 70 fetuses (one twin). Preterm birth (n=9, 19%) was the most frequent APO in SLE pregnancies, while in pSS pregnancies this was miscarriages (n=3, 14%). There were no associations between the presence of APO in SLE pregnancies and clinical parameters, laboratory parameters or medication use prior to conception. In the pSS group, significant associations were found between the presence of APO and body mass index (p=0.010), parity (p=0.046), C4 (p=0.021) and low C4 levels (p=0.002). CONCLUSIONS: No preconception risk factors related to APO were found in SLE pregnancies, whereas preconception complement levels were associated with APO development in patients with pSS.

Role of infections in miscarriage.

Infections with certain pathogens can lead to perinatal complications. Several infections have been also associated with an increased likelihood of miscarriage. This manuscript discusses these infections, their modes of transmission, the evidence linking them to an increased risk of miscarriage, and whether prevention or treatment strategies are available.

Placenta-on-a-Chip as an In Vitro Approach to Evaluate the Physiological and Structural Characteristics of the Human Placental Barrier upon Drug Exposure: A Systematic Review.

Quantification of fetal drug exposure remains challenging since sampling from the placenta or fetus during pregnancy is too invasive. Currently existing in vivo (e.g., cord blood sampling) and ex vivo (e.g., placenta perfusion) models have inherent limitations. A placenta-on-a-chip model is a promising alternative. A systematic search was performed in PubMed on 2 February 2023, and Embase on 14 March 2023. Studies were included where placenta-on-a-chip was used to investigate placental physiology, placenta in different obstetric conditions, and/or fetal exposure to maternally administered drugs. Seventeen articles were included that used comparable approaches but different microfluidic devices and/or different cultured maternal and fetal cell lines. Of these studies, four quantified glucose transfer, four studies evaluated drug transport, three studies investigated nanoparticles, one study analyzed bacterial infection and five studies investigated preeclampsia. It was demonstrated that placenta-on-a-chip has the capacity to recapitulate the key characteristics of the human placental barrier. We aimed to identify knowledge gaps and provide the first steps towards an overview of current protocols for developing a placenta-on-a-chip, that facilitates comparison of results from different studies. Although models differ, they offer a promising approach for in vitro human placental and fetal drug studies under healthy and pathological conditions.

Prevalence of chronic kidney disease in women of reproductive age and observed birth rates.

INTRODUCTION: Women of reproductive age with chronic kidney disease (CKD) are recognised to have decreased fertility and a higher risk of adverse pregnancy outcomes. How often CKD afflicts women of reproductive age is not well known. This study aimed to evaluate the burden of CKD and associated birth rates in an entire region. METHODS: This was a retrospective cohort study including women of childbearing age in Stockholm during 2006-2015. We estimated the prevalence of "probable CKD" by the presence of an ICD-10 diagnosis of CKD, a single estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or history of maintenance dialysis. By linkage with the Swedish Medical Birth Register we identified births during the subsequent three years from study inclusion and evaluated birth rates. RESULTS: We identified 817,730 women in our region, of whom 55% had at least one creatinine measurement. A total of 3938 women were identified as having probable CKD, providing an age-averaged CKD prevalence of 0.50%. Women with probable CKD showed a lower birth rate 3 years after the index date (35.7 children per 1000 person years) than the remaining women free from CKD (46.5 children per 1000 person years). CONCLUSION: As many as 0.50% of individuals in this cohort had probable CKD, defined on the basis of at least one eGFR<60 ml/min1.73 m2 test result, dialysis treatment (i.e. CKD stages 3-5) or an ICD-10 diagnosis of CKD. This prevalence is lower than previous estimates. Women with probable CKD, according to a study mainly capturing CKD 3-5, had a lower birth rate than those without CKD, illustrating the challenges of this population to successfully conceive.

Differences in Immune phenotype in decidual tissue from multigravid women compared to primigravid women.

PROBLEM: Women with a previous uncomplicated pregnancy have lower risks of immune-associated pregnancy disorders in a subsequent pregnancy. This could indicate a different maternal immune response in multigravid women compared to primigravid women. In a previous study, we showed persistent higher memory T cell proportions with higher CD69 expression after uncomplicated pregnancies. To our knowledge no studies have reported on immune cells in general, and immune memory cells and macrophages specifically in multigravid and primigravid women. METHOD OF STUDY: T cells and macrophages were isolated from term decidua parietalis and decidua basalis tissue from healthy primigravid women (n = 12) and multigravid women (n = 12). Using flow cytometry, different T cell populations including memory T cells and macrophages were analyzed. To analyze whether a different immune phenotype is already present in early pregnancy, decidual tissue from uncomplicated ongoing pregnancies between 9 and 12 weeks of gestation from multigravida and primigravid women was investigated using qRT-PCR. RESULTS: Nearly all T cell subsets analyzed in the decidua parietalis had significantly higher CD69+ proportions in multigravid women compared to primigravid women. A higher proportion of decidual (CD50- ) M2-like macrophages was found in the decidua parietalis in multigravid women compared to primigravid women. In first trimester decidual tissue higher FOXP3 mRNA expression was found in multigravid women compared to primigravid women. CONCLUSIONS: This study shows that decidual tissue from multigravid women has a more activated and immunoregulatory phenotype compared to decidual tissue from primigravid women in early pregnancy and at term which could suggest a more balanced immune adaptation towards pregnancy after earlier uncomplicated pregnancies.

Systemic Oxidative Stress in Severe Early-Onset Fetal Growth Restriction Associates with Concomitant Pre-Eclampsia, Not with Severity of Fetal Growth Restriction.

BACKGROUND: Placental insufficiency is an important mechanism underlying early-onset fetal growth restriction (eoFGR). Reduced placental function causes impaired metabolic and gaseous exchange. This unfavorable placental environment is among other processes characterized by increased oxidative stress. Systemic free thiols (FT) are known for their reactive oxygen species scavenging capacity, and higher plasma levels of FT are associated with a better outcome in a multitude of ischemic and inflammatory diseases. We aimed to investigate the relationships between systemic FT levels and maternal and perinatal clinical characteristics and outcomes. STUDY DESIGN: In a post hoc analysis of the Dutch Strider study, a cohort of women with eoFGR, we investigated the association between the maternal redox status (FT) levels at study inclusion, placental biomarkers, and maternal and neonatal outcomes in 108 patients. RESULTS: FT were significantly lower in pregnancies complicated with eoFGR with concurrent maternal hypertensive disorders (pregnancy-induced hypertension; ρ = -0.281 p = 0.004, pre-eclampsia; ρ = -0.505 p = 0.000). In addition, lower FT levels were significantly associated with higher systolic (ρ = -0.348 p = 0.001) and diastolic blood pressure (ρ = -0.266 p = 0.014), but not with the severity of eoFGR. FT levels were inversely associated with sFlt (ρ = -0.366, p < 0.001). A strong relation between systemic FT levels and PlGF levels was observed in women with pre-eclampsia at delivery (ρ = 0.452, p = 0.002), which was not found in women without hypertensive disorders (ρ = 0.008, p = 0.958). CONCLUSIONS: In women with pregnancies complicated with eoFGR, FT levels reflect the severity of maternal disease related to the underlying placental insufficiency rather than the severity of the placental dysfunction as reflected in eoFGR or perinatal outcomes.

Distribution of decidual mast cells in fetal growth restriction and stillbirth at (near) term.

INTRODUCTION: Placental pathology and pregnancy complications are associated with unfavorable regulation of the maternal immune system. Although much research has been performed towards the role of immune cells like macrophages and T cells in this context, little is known about the presence and function of mast cells (MC). MC can be sub classified in tryptase-positive (MCT) and tryptase- and chymase-positive (MCTC). This study investigates the presence of MC in the decidua of pregnancies complicated by fetal growth restriction (FGR) and stillbirth (SB). METHODS: Placental tissue from FGR (n = 250), SB (n = 64) and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to the Amsterdam Placental Workshop Group criteria. Tissue sections were stained for tryptase and chymase. Decidual MC were counted manually, and the results were expressed as number of cells/mm2 decidual tissue. RESULTS: A significant lower median number of MCTC was found in the decidua of FGR (0.40 per mm2; p < 0.001) and SB (0.51 per mm2; p < 0.05) compared to healthy controls (1.04 per mm2). No difference in MCT number (1.19 per mm2, 1.88 per mm2 and 1.37 per mm2 respectively) was seen between the groups. There was no difference in number of MCT and MCTC between placental pathological lesions. DISCUSSION: Our findings suggest a shift in decidual MC balance towards MCT in pregnancy complications. No difference in numbers of MC subtypes was found to be related to histopathologic lesions.

Follow-Up of Offspring Born to Parents With a Solid Organ Transplantation: A Systematic Review.

Pregnancy after solid organ transplantation (SOT) has potential risks for the offspring. Most existing research focused on short-term pregnancy outcomes. The aim of this systematic review was to evaluate available data concerning longer term outcomes (>1 year) of these children. A systematic literature search, following PRISMA guidelines, of PubMed and Embase was performed from the earliest date of inception through to 6th April 2022. Publications on all types of (combined) SOT were eligible for inclusion. In total, 53 articles were included. The majority assessed offspring after kidney (78% of offspring) or liver transplantation (17% of offspring). 33 studies included offspring aged >4 years and five offspring aged >18 years. One study was included on fathers with SOT. The majority of the 1,664 included children after maternal SOT had normal intellectual, psychomotor, and behavioral development. Although prematurity and low birth weight were commonly present, regular growth after 1 year of age was described. No studies reported opportunistic or chronic infections or abnormal response to vaccinations. In general, pregnancy after SOT appears to have reassuring longer term outcomes for the offspring. However, existing information is predominantly limited to studies with young children. Longer prospective studies with follow-up into adulthood of these children are warranted.

The Effect of Pregnancy and Inflammatory Bowel Disease on the Pharmacokinetics of Drugs Related to Inflammatory Bowel Disease-A Systematic Literature Review.

Due to ethical and practical reasons, a knowledge gap exists on the pharmacokinetics (PK) of inflammatory bowel disease (IBD)-related drugs in pregnant women with IBD. Before evidence-based dosing can be proposed, insight into the PK has to be gained to optimize drug therapy for both mother and fetus. This systematic review aimed to describe the effect of pregnancy and IBD on the PK of drugs used for IBD. One aminosalicylate study, two thiopurine studies and twelve studies with biologicals were included. Most drugs within these groups presented data over multiple moments before, during and after pregnancy, except for mesalazine, ustekinumab and golimumab. The studies for mesalazine, ustekinumab and golimumab did not provide enough data to demonstrate an effect of pregnancy on concentration and PK parameters. Therefore, no evidence-based dosing advice was given. The 6-thioguanine nucleotide levels decreased during pregnancy to 61% compared to pre-pregnancy levels. The potentially toxic metabolite 6-methylmercaptopurine (6-MMP) increased to maximal 209% of the pre-pregnancy levels. Although the PK of the thiopurines changed throughout pregnancy, no evidence-based dosing advice was provided. One study suggested that caution should be exercised when the thiopurine dose is adjusted, due to shunting 6-MMP levels. For the biologicals, infliximab levels increased, adalimumab stayed relatively stable and vedolizumab levels tended to decrease during pregnancy. Although the PK of the biologicals changed throughout pregnancy, no evidence-based dosing advice for biologicals was provided. Other drugs retrieved from the literature search were mesalazine, ustekinumab and golimumab. We conclude that limited studies have been performed on PK parameters during pregnancy for drugs used in IBD. Therefore, more extensive research to determine the values of PK parameters is warranted. After gathering the PK data, evidence-based dosing regimens can be developed.

The influence of the dietary exposome on oxidative stress in pregnancy complications.

Pregnancy complications including fetal growth restriction, preeclampsia, and preterm birth, as well as gestational diabetes, affect one in every four to five pregnancies. Accumulating evidence indicates that increased production of reactive oxygen species accompanies these complications. Given that reactive oxygen species are cell stress-inducing agents, they may have a causal role in disease pathophysiology, although the exact mechanisms by which they contribute to pregnancy complications are not completely understood. Since many environmental and lifestyle factors and exposures are known to modulate reactive oxygen species production, the exposome of pregnant women could contribute to increased generation of reactive oxygen species. The objective of this review is to provide a comprehensive overview of the endogenous and exogenous exposome factors that regulate reactive species in healthy and complicated pregnancies. We also provide a description of dietary interventions aimed at the reduction of reactive species in order to attenuate adverse pregnancy outcome. Dietary interventions in general hold minimal risk in pregnancy and could therefore be considered a promising therapeutic approach.

Pregnancy Outcomes: Effects of Metformin (POEM) study: a protocol for a long-term, multicentre, open-label, randomised controlled trial in gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common disorder of pregnancy with health risks for mother and child during pregnancy, delivery and further lifetime, possibly leading to type 2 diabetes mellitus (T2DM). Current treatment is focused on reducing hyperglycaemia, by dietary and lifestyle intervention and, if glycaemic targets are not reached, insulin. Metformin is an oral blood glucose lowering drug and considered safe during pregnancy. It improves insulin sensitivity and has shown advantages, specifically regarding pregnancy-related outcomes and patient satisfaction, compared with insulin therapy. However, the role of metformin in addition to usual care is inconclusive and long-term outcome of metformin exposure in utero are lacking. The primary aim of this study is to investigate the early addition of metformin on pregnancy and long-term outcomes in GDM. METHODS AND ANALYSIS: The Pregnancy Outcomes: Effects of Metformin study is a multicentre, open-label, randomised, controlled trial. Participants include women with GDM, between 16 and 32 weeks of gestation, who are randomised to either usual care or metformin added to usual care, with insulin rescue in both groups. Metformin is given up to 1 year after delivery. The study consists of three phases (A-C): A-until 6 weeks after delivery; B-until 1 year after delivery; C-observational study until 20 years after delivery. During phase A, the primary outcome is a composite score consisting of: (1) pregnancy-related hypertension, (2) large for gestational age neonate, (3) preterm delivery, (4) instrumental delivery, (5) caesarean delivery, (6) birth trauma, (7) neonatal hypoglycaemia, (8) neonatal intensive care admission. During phase B and C the primary outcome is the incidence of T2DM and (weight) development in mother and child. ETHICS AND DISSEMINATION: The study was approved by the Central Committee on Research Involving Human Subjects in the Netherlands. Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02947503.

Oxidative stress biomarkers in fetal growth restriction with and without preeclampsia.

INTRODUCTION: Oxidative stress as observed in fetal growth restriction (FGR) and preeclampsia (PE) can be identified by decreased levels of systemic free thiols (FT) and increased levels of plasma ischemia-modified albumin (IMA), which may serve as biomarkers in maternal blood for pregnancy complications. We evaluate the performance of oxidative stress-associated potential biomarkers for FGR and PE, and their relationship with clinical characteristics. METHODS: A prospective clinical pilot study was performed in healthy controls and women with pregnancies complicated by severe FGR with or without PE. Blood samples were taken directly after inclusion and analyzed for FT; IMA; soluble FMS-like tyrosine kinase-1 (sFlt-1); placenta growth factor (PlGF); and biomarkers like leptin and soluble receptors for advanced glycation end products (sRAGE). Placentas were examined microscopically. Descriptive statistics and receiver operating characteristics statistics were performed. RESULTS: Mothers with both severe FGR and PE had significantly reduced FT levels (p < 0.001) and PlGF levels (p < 0.001), and increased levels of plasma IMA (p < 0.05), sFlt (p < 0.001), leptin (p < 0.05) and sRAGE (p < 0.01) compared to women with FGR only. Systemic FT levels were significantly inversely associated with blood pressure (p < 0.01) and plasma IMA (p < 0.001), leptin (p = 0.01) and sRAGE (p < 0.001). Systemic FT and leptin showed significant discriminative ability to differentiate mothers with both FGR and PE from mothers with uncomplicated pregnancies or pregnancies complicated by FGR only. DISCUSSION: There is a significant discriminative capacity of FT, IMA, leptin and sRAGE that harbor potential as biomarkers of pregnancies complicated by combined FGR and PE.