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.

Changes in Intrapersonal Factors of Participants in the Pregnancy Remote Monitoring Study Who Are at Risk for Pregnancy-Induced Hypertension: Descriptive Quantitative Study.

BACKGROUND: The peripartum period, defined as the period from the beginning of the gestation until 1 year after the delivery, has long been shown to be potentially associated with increased levels of stress and anxiety with regard to one's transition to the status of parent and the accompanying parental tasks. Yet, no research to date has investigated changes in intrapersonal factors during the peripartum period in women at risk for pregnancy-induced hypertension (PIH). OBJECTIVE: The aim of this study is to explore and describe changes in intrapersonal factors in participants at risk for PIH. METHODS: We used an explorative design in which 3 questionnaires were sent by email to 110 participants the day following enrollment in the Pregnancy Remote Monitoring program for pregnant women at risk for PIH. Women were invited to complete the questionnaires at the beginning of their participation in the Pregnancy Remote Monitoring project (mostly at 14 weeks of gestation) and after approaching 32 weeks of gestational age (GA). The Generalized Anxiety Disorder-7 Scale (GAD-7) and the Patient Health Questionnaire-9 were used to assess anxiety and depression, and adaptation of the Pain Catastrophizing Scale was used to measure trait pain catastrophizing. RESULTS: Scores were significantly higher at 32 weeks of GA than at the moment of enrollment (GAD-7 score=7, range 4-11 vs 5, range 3-8; P=.01; and Patient Health Questionnaire-9 score=6, range 4-10 vs 4, range 2-7; P<.001). The subscale scores of the Pain Catastrophizing Scale were all lower at 32 weeks of GA compared with 14 weeks of GA (rumination: 4, range 1-6 vs 5, range 2-9.5; P=.11; magnification: 3, range 1-5.5 vs 4, range 3-7; P=.04; and helplessness: 5, range 2-9 vs 6, range 3.5-12; P=.06). The proportion of women with a risk for depression (GAD-7 score >10) was 13.3% (10/75) at enrollment and had increased to 35.6% (26/75) at 32 weeks of GA. CONCLUSIONS: This study shows that pregnant women at risk for PIH have higher levels of stress and anxiety at 32 weeks of GA than at the moment of enrollment. Further research is recommended to investigate potential strategies to help pregnant women at risk for PIH manage feelings of stress and anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT03246737; https://clinicaltrials.gov/study/NCT03246737.

Cell-free DNA methylome analysis for early preeclampsia prediction.

Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis in the prevention of PE, pregnancies at risk of PE must be identified early-in the first trimester. To identify at-risk pregnancies we profiled methylomes of plasma-derived, cell-free DNA from 498 pregnant women, of whom about one-third developed early-onset PE. We detected DNA methylation differences between control and PE pregnancies that enabled risk stratification at PE diagnosis but also presymptomatically, at around 12 weeks of gestation (range 9-14 weeks). The first-trimester risk prediction model was validated in an external cohort collected from two centers (area under the curve (AUC) = 0.75) and integrated with routinely available maternal risk factors (AUC = 0.85). The combined risk score correctly predicted 72% of patients with early-onset PE at 80% specificity. These preliminary results suggest that cell-free DNA methylation profiling is a promising tool for presymptomatic PE risk assessment, and has the potential to improve treatment and follow-up in the obstetric clinic.

Origins of abnormal placentation: why maternal veins must not be forgotten.

The importance of uterine microvascular adaptations during placentation in pregnancy has been well established for decades. Inadequate dilatation of spiral arteries is associated with gestational complications, such as preeclampsia and/or intrauterine growth restriction. More recently, it has become clear that trophoblast cells invade and adapt decidual veins and lymphatic vessels 1 month before spiral arteries become patent and before intervillous space perfusion starts. Normal intervillous space hemodynamics is characterized by high volume flow at low velocity and pressure in the interseptal compartments surrounding the chorionic villi, hereby facilitating efficient maternal-fetal exchange. In case of shallow decidual vein dilatation, intervillous arterial supply exceeds venous drainage. This will cause congestion in the interseptal compartments with subsequently reduced perfusion and increased pressure. An efficient mechanism to counteract venous congestion and safeguard the viability of the conceptus is by reducing arterial inflow via shallow dilatation of the spiral arteries. This review made the case for intervillous space congestion as an unexplored trigger for inadequate spiral artery dilatation during the placentation process, eventually leading to abnormal systemic circulatory dysfunctions. An abnormal maternal venous function can result from an abnormal maternal immune response to paternal antigens with an imbalanced release of vasoactive mediators or can exist before conception. To get the full picture of abnormal placentation, maternal veins must not be forgotten.

Is it feasible to measure intra-abdominal pressure using a balloon-tipped rectal catheter? Results of a validation study.

The gold standard to measure intra-abdominal pressure (IAP) is intra-vesical measurement via the urinary bladder. However, this technique is restricted in ambulatory settings because of the risk of iatrogenic urinary tract infections. Rectal IAP measurements (IAPrect) may overcome these limitations, but requires validation. This validation study compares the IAPrect technique against gold standard intra-vesical IAP measurements (IAPves). IAPrect using an air-filled balloon catheter and IAPves using Foley Manometer Low Volume were measured simultaneously in sedated and ventilated patients. Measurements were performed twice in different positions (supine and HOB 45° elevated head of bed) and with an external abdominal pressure belt. Sixteen patients were included. Seven were not eligible for analysis due to unreliable IAPrect values. IAPrect was significantly higher than IAPves for all body positions (p < 0.01) and the correlation between IAPves and IAPrect was poor and not significant in each position (p ≥ 0.25, R2 < 0.6, Lin's CCC < 0.8, bias - 8.1 mmHg and precision of 5.6 mmHg with large limits of agreement between - 19 to 2.9 mmHg, high percentage error 67.3%, and low concordance 86.2%). Repeatability of IAPrect was not reliable (R = 0.539, p = 0.315). For both techniques, measurements with the external abdominal pressure belt were significantly higher compared to those without (p < 0.03). IAPrect has important shortcomings making IAP estimation using a rectal catheter unfeasible because the numbers cannot be trusted nor validated.

First-Trimester Normotension Is a Weak Indicator of Normal Maternal Cardiovascular Function.

BACKGROUND: As by definition, mean arterial pressure equals the product of cardiac output (CO) and total vascular resistance (TPR), we hypothesized that, irrespective of thresholds to define hypertension, a CO-TPR imbalance might exist in first-trimester normotensive pregnancies with altered risks for adverse gestational outcomes. METHODS: A standard protocol was used for automated blood pressure measurement combined with impedance cardiography assessment of CO and TPR (NICCOMO). First-trimester normotensive pregnant women were categorized into 3 groups relative to the reference 75th percentile (P75) of CO and TPR: (1) normal CO and TPR, (2) high CO, and (3) high TPR. These subgroups were compared at blood pressure thresholds 140/90, 130/85, and 130/80 mmHg. The gestational outcome was categorized after birth according to International Society for Studies of Hypertension in Pregnancy criteria. RESULTS: Compared with pregnancies with normal CO and TPR (≤P75), women with high TPR at blood pressure <140/90 mmHg are at risk for developing gestational hypertension (odds ratio, 3.795 [1.321-10.904]; P<0.010), late-onset preeclampsia (odds ratio, 3.137 [1.060-9.287]; P<0.050), and neonates small for gestational age (odds ratio, 1.780 [1.056-2.998]; P<0.050). CONCLUSIONS: Cardiovascular imbalance can present in normotensive women in the first trimester and is associated with increased risks for adverse gestational outcomes. This study illustrates the relevance of CO and TPR assessments as an adjunct to blood pressure measurement and invites for further exploring their value in screening algorithms for gestational hypertensive disorders and/or small for gestational age.

Early-onset preeclampsia is characterised by an increased vascular tone in internal jugular veins.

Purpose: This study aimed to investigate Doppler characteristics of maternal internal jugular veins in uncomplicated pregnancies vs. those affected by hypertensive disorders. Materials and methods: Venous pulse transit time and venous impedance index were measured at three different locations (right proximal, right distal, left proximal) of internal jugular veins according to a standardised combined Doppler-Electrocardiogram protocol in five different groups of pregnant women: uncomplicated pregnancy, early-onset preeclampsia, late-onset preeclampsia, gestational hypertension, and normotensive pregnancies with a small for gestational age foetus. Values of both parameters of the latter four groups were plotted against the reference range of uncomplicated pregnancies at corresponding gestation. Linear mixed models with random intercept were used to investigate gestational changes in venous pulse transit time and venous impedance index at the three internal jugular vein locations within and between the different groups. Results: A total of 127 women were included: 41 had uncomplicated pregnancies, 13 had early-onset preeclampsia, 25 had late-onset preeclampsia, 22 had gestational hypertension, and 26 had normotensive pregnancies with a small for gestational age foetus. Venous pulse transit time values were lower than uncomplicated pregnancy (p ≤ 0.001) at all three locations in the third trimester of early-onset preeclampsia. Conclusion: Contrary to late-onset preeclampsia and gestational hypertension, early-onset preeclampsia is characterised by a lower venous pulse transit time at internal jugular veins compared to uncomplicated pregnancy, suggesting increased venous vascular tone.

Nailfold Video Capillaroscopy in Pregnant Women With and Without Cardiovascular Risk Factors.

Objective: To evaluate microvasculature in pregnant women with and without cardiovascular risk factors. Design: Cross-sectional, observational study. Population: Women were recruited at the outpatient clinic for high risk prenatal care. Out of a total of 345 women assessed at first and/or second and/or third trimester, 169 women without and 176 with cardiovascular risk factors were included. Methods: Nailfold video capillaroscopy (NVC) measurements were performed at magnification of 200x at all fingers except thumbs. Images were stored for offline measurement of capillary density (CDe) and capillary diameters (CDi). Maternal anthropometrics, obstetric, and medical history were used for categorization in low and high cardiovascular risk. Comparison between groups and trimesters, with respect to pregnancy outcome, was performed using linear mixed model analysis. Results: Women with a high risk cardiovascular profile show higher CDe, regardless of pregnancy outcome. CDi drops during pregnancy, with lowest CDi in third trimester in patients with preeclampsia. Capillary bed (CB), as a composite of CDe and CDi, is stable during pregnancy in women with low risk cardiovascular profile. In women with high risk cardiovascular profile, CB drops from the first to the second trimester, regardless of pregnancy outcome. Only in women with pre-eclampsia, the CB is lower in the third trimester as compared to the first trimester.There is an inverse association between CDe and mean arterial pressure (MAP) in women with high cardiovascular risk and pre-eclampsia. Conclusion: Microcirculation is altered during the course of pregnancy and microcirculatory behavior is different in patients with low and high cardiovascular risk profile, as well as in patients with preeclampsia.

Maternal Low Volume Circulation Relates to Normotensive and Preeclamptic Fetal Growth Restriction.

This narrative review summarizes current evidence on the association between maternal low volume circulation and poor fetal growth. Though much work has been devoted to the study of cardiac output and peripheral vascular resistance, a low intravascular volume may explain why high vascular resistance causes hypertension in women with preeclampsia (PE) that is associated with fetal growth restriction (FGR) and, at the same time, presents with normotension in FGR itself. Normotensive women with small for gestational age babies show normal gestational blood volume expansion superimposed upon a constitutionally low intravascular volume. Early onset preeclampsia (EPE; occurring before 32 weeks) is commonly associated with FGR, and poor plasma volume expandability may already be present before conception, thus preceding gestational volume expansion. Experimentally induced low plasma volume in rodents predisposes to poor fetal growth and interventions that enhance plasma volume expansion in FGR have shown beneficial effects on intrauterine fetal condition, prolongation of gestation and birth weight. This review makes the case for elevating the maternal intravascular volume with physical exercise with or without Nitric Oxide Donors in FGR and EPE, and evaluating its role as a potential target for prevention and/or management of these conditions.

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol.

INTRODUCTION: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. METHODS AND ANALYSIS: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. ETHICS AND DISSEMINATION: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. TRIAL REGISTRATION NUMBER: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200.

Characteristics of the Maternal Jugular Venous Pulse Waveform by Combined Doppler-Electrocardiogram Assessment.

Standardized combined Doppler-electrocardiogram assessment was performed longitudinally at three different locations of internal jugular veins between 12 wk of gestation and 6 wk postnatally in 24 uncomplicated pregnancies. All images were classified as typical or non-typical based on the presence of the physiologic deflections A, X, H and C. Linear mixed models with random intercepts of typical images were used to investigate gestational changes in venous pulse transit time and venous impedance index. Unequivocal identification of venous pulse transit time and venous impedance index was possible in 2617 of 3798 (69%) and 2234 of 3798 (59%) images, respectively. The best identification rate (80%, 1018/1266) was at the right distal internal jugular vein. Venous pulse transit time increased with gestational age at all locations; venous impedance index decreased at the right sided internal jugular vein. Maternal jugular venous pulse waveform by combined Doppler-electrocardiogram allows unequivocal identification of A-deflection and calculation of venous pulse transit time and venous impedance index in around two-thirds of assessments, with the highest success rate at the right distal internal jugular vein. Gestational evolutions of venous pulse transit time and venous impedance index are similar to those reported at the level of renal interlobar and hepatic veins.

Hemodynamic pathways of gestational hypertension and preeclampsia.

Gestational hypertension and preeclampsia are the 2 main types of hypertensive disorders in pregnancy. Noninvasive maternal cardiovascular function assessment, which helps obtain information from all the components of circulation, has shown that venous hemodynamic dysfunction is a feature of preeclampsia but not of gestational hypertension. Venous congestion is a known cause of organ dysfunction, but its potential role in the pathophysiology of preeclampsia is currently poorly investigated. Body water volume expansion occurs in both gestational hypertension and preeclampsia, and this is associated with the common feature of new-onset hypertension after 20 weeks of gestation. Blood pressure, by definition, is the product of intravascular volume load and vascular resistance (Ohm's law). Fundamentally, hypertension may present as a spectrum of cardiovascular states varying between 2 extremes: one with a predominance of raised cardiac output and the other with a predominance of increased total peripheral resistance. In clinical practice, however, this bipolar nature of hypertension is rarely considered, despite the important implications for screening, prevention, management, and monitoring of disease. This review summarizes the evidence of type-specific hemodynamic profiles in the latent and clinical stages of hypertensive disorders in pregnancy. Gestational volume expansion superimposed on an early gestational closed circulatory circuit in a pressure- or volume-overloaded condition predisposes a patient to the gradual deterioration of overall circulatory function, finally presenting as gestational hypertension or preeclampsia-the latter when venous dysfunction is involved. The eventual phenotype of hypertensive disorder is already predictable from early gestation onward, on the condition of including information from all the major components of circulation into the maternal cardiovascular assessment: the heart, central and peripheral arteries, conductive and capacitance veins, and body water content. The relevance of this approach, outlined in this review, openly invites for more in-depth research into the fundamental hemodynamics of gestational hypertensive disorders, not only from the perspective of the physiologist or the scientist, but also in assistance of clinicians toward understanding and managing effectively these severe complications of pregnancy.

Preeclampsia has two phenotypes which require different treatment strategies.

The opinion on the mechanisms underlying the pathogenesis of preeclampsia still divides scientists and clinicians. This common complication of pregnancy has long been viewed as a disorder linked primarily to placental dysfunction, which is caused by abnormal trophoblast invasion, however, evidence from the previous two decades has triggered and supported a major shift in viewing preeclampsia as a condition that is caused by inherent maternal cardiovascular dysfunction, perhaps entirely independent of the placenta. In fact, abnormalities in the arterial and cardiac functions are evident from the early subclinical stages of preeclampsia and even before conception. Moving away from simply observing the peripheral blood pressure changes, studies on the central hemodynamics reveal two different mechanisms of cardiovascular dysfunction thought to be reflective of the early-onset and late-onset phenotypes of preeclampsia. More recent evidence identified that the underlying cardiovascular dysfunction in these phenotypes can be categorized according to the presence of coexisting fetal growth restriction instead of according to the gestational period at onset, the former being far more common at early gestational ages. The purpose of this review is to summarize the hemodynamic research observations for the two phenotypes of preeclampsia. We delineate the physiological hemodynamic changes that occur in normal pregnancy and those that are observed with the pathologic processes associated with preeclampsia. From this, we propose how the two phenotypes of preeclampsia could be managed to mitigate or redress the hemodynamic dysfunction, and we consider the implications for future research based on the current evidence. Maternal hemodynamic modifications throughout pregnancy can be recorded with simple-to-use, noninvasive devices in obstetrical settings, which require only basic training. This review includes a brief overview of the methodologies and techniques used to study hemodynamics and arterial function, specifically the noninvasive techniques that have been utilized in preeclampsia research.

Cardiovascular determinants of impaired placental function in women with cardiac dysfunction.

Female heart disease has for a long time been an underrecognized problem in the field of cardiology. With an ever-growing number of these patients getting pregnant, cardiac dysfunction during pregnancy is an increasingly large medical problem. Previous work has shown that maternal heart disease may have an adverse effect on pregnancy outcome in both mother and child. The placenta forms the connection and it is postulated that cardiac dysfunction negatively affects the placenta, and consequently, neonatal outcome. Given the paucity of data in this field, more research on the influence of cardiac (mal)function on placental (mal)function is needed. The present review describes placental function in women with various types of cardiac dysfunction, thereby aiming to provide more insight into possible underlying mechanisms of placental malfunction. Organ dysfunction in patients with heart failure is for an important part based on reduced perfusion and venous congestion. This has been shown in other organs such as kidneys, liver and brain. In pregnant women with cardiac dysfunction, placental dysfunction may follow similar patterns. Moreover, other factors, such as pre-existing hypertension and chronic hypoxia may lead to further impairment of placental function, through abnormal vascular remodeling of the uterine spiral arteries. The pathophysiology of placental dysfunction in pregnant women with cardiac dysfunction may thus be multifactorial. It is therefore important to monitor closely cardiac and placental function in such high-risk pregnancies. Gaining a better understanding of the underlying pathophysiological mechanisms may have important clinical implications in terms of pregnancy counseling, monitoring and outcome.

Corrigendum: Nailfold video capillaroscopy in pregnant women with and without cardiovascular risk factors.

[This corrects the article DOI: 10.3389/fmed.2022.904373.].

Cord blood acrylamide levels and birth size, and interactions with genetic variants in acrylamide-metabolising genes.

BACKGROUND: Up to now, 3 epidemiological studies have shown clear inverse associations between prenatal acrylamide exposure and birth size. In addition to studying the association between acrylamide and birth size, we investigated the interaction between acrylamide and polymorphisms in acrylamide-metabolising genes, with the aim of probing the causality of the inverse relationship between acrylamide and fetal growth. METHODS: We investigated the association between prenatal acrylamide exposure (acrylamide and glycidamide hemoglobin adduct levels (AA-Hb and GA-Hb) in cord blood) and birth weight, length and head circumference in 443 newborns of the ENVIRONAGE (ENVIRonmental influence ON AGEing in early life) birth cohort. In addition, we studied interaction with single nucleotide polymorphisms (SNPs) in CYP2E1, EPHX1 and GSTP1, using multiple linear regression analysis. RESULTS: Among all neonates, the body weight, length and head circumference of neonates in the highest quartile was - 101 g (95% CI: - 208, 7; p for trend = 0.12), - 0.13 cm (95% CI: - 0.62, 0.36; p for trend = 0.69) and - 0.41 cm (- 0.80, - 0.01; p for trend = 0.06) lower, respectively, compared to neonates in the lowest quartile of AA-Hb in cord blood, For GA-Hb, the corresponding effect estimates were - 222 g (95% CI: - 337, - 108; p for trend = 0.001), - 0.85 (95% CI: - 1.38, - 0.33; p for trend = 0.02) and - 0.55 (95% CI: - 0.98, - 0.11; p for trend = 0.01), respectively. The associations for GA-Hb were similar or stronger in newborns of non-smoking mothers. There was no statistically significant interaction between acrylamide exposure and the studied genetic variations but there was a trend of stronger inverse associations with birth weight and head circumference among newborns with homozygous wildtypes alleles for the CYP2E1 SNPS and with variant alleles for a GSTP1 SNP (rs1138272). CONCLUSIONS: Prenatal dietary acrylamide exposure, specifically in the form of its metabolite glycidamide, was inversely associated with birth weight, length and head circumference. The interaction pattern with SNPs in CYP2E1, although not statistically significant, is an indication for the causality of this association. Other studies are needed to corroborate this finding.

Lower iodine storage in the placenta is associated with gestational diabetes mellitus.

BACKGROUND: The micronutrient iodine is essential for a healthy intrauterine environment and is required for optimal fetal growth and neurodevelopment. Evidence linking urinary iodine concentrations, which mainly reflects short-term iodine intake, to gestational diabetes mellitus (GDM) is inconclusive. Although the placental concentrations would better reflect the long-term gestational iodine status, no studies to date have investigated the association between the placental iodine load and the risk at GDM. Moreover, evidence is lacking whether placental iodine could play a role in biomarkers of insulin resistance and ß-cell activity. METHODS: We assessed the incidence of GDM between weeks 24 and 28 of gestation for 471 mother-neonate pairs from the ENVIRONAGE birth cohort. In placentas, we determined the iodine concentrations. In maternal and cord blood, we measured the insulin concentrations, the Homeostasis Model Assessment (HOMA) for insulin resistance (IR) index, and ß-cell activity. Logistic regression was used to estimate the odds ratios (OR) of GDM, and the population attributable factor (PAF) was calculated. Generalized linear models estimated the changes in insulin, HOMA-IR, and ß-cell activity for a 5 µg/kg increase in placental iodine. RESULTS: Higher placental iodine concentrations decreased the risk at GDM (OR = 0.82; 95%CI 0.72 to 0.93; p = 0.003). According to the PAF, 54.2% (95%CI 11.4 to 82.3%; p = 0.0006) of the GDM cases could be prevented if the mothers of the lowest tertile of placental iodine would have placental iodine levels as those belonging to the highest tertile. In cord blood, the plasma insulin concentration was inversely associated with the placental iodine load (ß = - 4.8%; 95%CI - 8.9 to - 0.6%; p = 0.026). CONCLUSIONS: Higher concentrations of placental iodine are linked with a lower incidence of GDM. Moreover, a lower placental iodine load is associated with an altered plasma insulin concentration, HOMA-IR index, and ß-cell activity. These findings postulate that a mild-to-moderate iodine deficiency could be linked with subclinical and early-onset alterations in the normal insulin homeostasis in healthy pregnant women. Nevertheless, the functional link between gestational iodine status and GDM warrants further research.