Low-dose Copper Research Articles

Low-dose Cu exposure enhanced α-synuclein accumulation associates with mitochondrial impairments in mice model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder that mainly affects the elder population, and its etiology is enigmatic. Both environmental risks and genetics may influence the development of PD. Excess copper causes neurotoxicity and accelerates the progression of neurodegenerative diseases. However, the underlying mechanisms of copper-induced neurotoxicity remain controversial. In this study, A53T transgenic α-synuclein (A53T) mice and their matching wild-type (WT) mice were treated with a low dose of copper (0.13 ppm copper chlorinated drinking water, equivalent to the copper exposure of human daily copper intake dose) for 4 months, and copper poisoning was performed on human A53T mutant SHSY5Y cells overexpressed with α-synuclein (dose of 1/4 IC50), to test the effects of copper exposure on the body. The results of the open field test showed that the moto function of Cu-treated mice was impaired. Proteomics revealed changes in neurodevelopment, transport function, and mitochondrial membrane-related function in Cu-treated WT mice, which were associated with reduced expression of mitochondrial complex (NDUFA10, ATP5A), dopamine neurons (TH), and dopamine transporter (DAT). Mitochondrial function, nervous system development, synaptic function, and immune response were altered in Cu-treated A53T mice. These changes were associated with increased mitochondrial splitting protein (Drp1), decreased mitochondrial fusion protein (OPA1, Mfn1), abnormalities in mitochondrial autophagy protein (LC3BII/I, P62), decreased dopamine neuron (TH) expression, increased α-synuclein expression, inflammatory factors (IL-6, IL-1β, and TNF-α) release and microglia (Iba1) activation. In addition, we found that Cu2+ (30 μM) induced excessive ROS production and reduced mitochondrial ATP production in human A53T mutant α-synuclein overexpressing SHSY5Y cells by in vitro experiments. In conclusion, low-dose copper treatment altered critical proteins involved in mitochondrial, neurodevelopmental, and inflammatory responses and affected mitochondria's ROS and ATP production levels.

Study Participants' and Clinicians' Experiences With Placement of a Novel Low-Dose Copper Intrauterine Device With a Nitinol Frame in Nulliparous Versus Parous Participants [ID: 1374840

INTRODUCTION: Clinicians may perceive intrauterine device (IUD) placement to be more challenging for nulliparous versus parous users. This study assesses nulliparous versus parous study participants' and clinicians' experiences with placement of a novel, low-dose copper (175 mm2) IUD with a flexible nitinol frame. METHODS: This single-arm, IRB-approved, phase 3 clinical trial recruited pregnancy-capable people aged 17–45 at 42 U.S. centers. We compared nulliparous and parous participants' experiences for first IUD placement attempt including successful placement, participant-reported pain (on an 11-point numeric pain rating scale), investigator-reported ease of IUD placement (on a 5-point Likert scale), need for mechanical cervical dilation, and uterine perforation. RESULTS: Of 1,620 participants enrolled, 973 (60.1%) reported nulliparity and 647 (39.9%) parity. Successful IUD placement occurred at first attempt for 929 (96.0%) nulliparous versus 625 (96.6%) parous participants. Including second attempts, successful placement occurred for 1,601 (98.8%) participants. Nulliparous participants reported a mean pain score of 5.6 (±2.19) versus 4.0 (±2.55) for parous participants (P<.001), and investigators more frequently reported hard or very hard IUD placement in 81 (8.4%) nulliparous versus 22 (3.4%) parous participants (P<.001). Among nulliparous participants, 203 (21.2%) reported pain-related adverse events associated with placement versus 65 (10.1%) in parous participants (P<.001). Mechanical dilation was required for 202 (20.8%) nulliparous versus 79 (12.2%) parous participants (P<.001). Uterine perforation occurred in 1 nulliparous (0.10%) and 1 parous participant (0.15%). CONCLUSION: Despite experiencing more challenging IUD placements than parous participants, nulliparous trial participants experienced similar IUD placement success with this novel, low-dose copper IUD.

Society of Family Planning Committee statement on IUD nomenclature

Society of Family Planning Committee statement on IUD nomenclature

COMPARATIVE COPPER PHARMACOKINETIC PROPERTIES OF A NOVEL LOW-DOSE NITINOL FRAME COPPER INTRAUTERINE DEVICE (IUD) AND THE COPPER T380A IUD: A RANDOMIZED CONTROLLED TRIAL

We compared the pharmacokinetics and bioavailability of serum copper in women receiving either a novel low-dose nitinol frame copper IUD or the copper T380A IUD through the first 57 days of use. Two sites participated in this parallel -single-blind study that randomized reproductive age women 1:1 to an investigational low-dose copper IUD (with 175 mm2 of exposed copper) or the approved copper T380A (Paragard, 380 mm2) IUD. Participants provided two baseline total serum copper samples at least 24 hours apart within 28 days prior to IUD placement followed by seven samples following randomization on days 1, 3, 8, 15, 22, 29, and 57. We used a noncompartmental mixed-effects linear analysis of variance (ANOVA) model with treatment as a fixed effect and subject as a random effect to calculate uncorrected PK parameters Cmax, Cmean, and AUC0-56 days. We compared relative bioavailability between the two groups by geometric mean ratios and 90% confidence intervals. We hypothesized that the relative bioavailability of total serum copper for the low-dose device would not exceed established normal (490 to 1840 ng/ml) or levels seen in users of the copper T380A. Of the 41 participants enrolled, 39 had successful IUD placements (20 in the low-dose group and 19 in the T380A group) with 36 of those subjects completing the treatment comparison phase of the study (19 low-dose and 17 T380A). Participants reported a mean age of 28.4 years. The baseline mean serum copper concentrations for the low-dose group were 1220 ng/ml standard deviation (SD) ± 285 ng/ml vs. 1250 ng/ml ± 276 ng/ml for the T380A group. Observed copper concentrations in both groups remained in the normal range; with the relative mean Cmax, Cmean, and AUC 0-56 days of 1210 ng/ml, 1070 ng/ml, and 59,700 for the low-dose IUD group vs. 1300, 1150, and 63,600 for the T380A group. Post IUD placement values for both the low-dose group and the copper T380A group were slightly lower than baseline values over the seven timepoints from 0-56 days. Respective baseline-corrected mean values for the low-dose group were 7.8 to 29.8 ng/ml and for the T380A group were 14.9 to 34.3 ng/ml lower than baseline. Relative bioavailability by geometric mean copper exposure for all parameters ranged from 0.93-0.94 (90% CI for all values 0.85-1.02) with all mean values for the low-dose IUD lower than the T380A. Serum copper concentrations for the two IUDs remained within the normal range and trended toward lower values for participants assigned to the low-dose copper IUD relative to the T380A. Neither IUD generated clinically meaningful changes in total serum copper concentrations during the first 56 days after IUD placement.

A Novel IUD Platform Design Uses a Flexible Nitinol Frame to Deliver Either Copper or Levonorgestrel: Phase 2 Data [03I

INTRODUCTION: Current IUD applicators vary among copper and levonorgestrel devices. We present data on a new intrauterine contraceptive platform that uses a flexible nitinol frame provided in a preloaded applicator with precut strings and a tapered leading edge to deliver either low-dose copper (175 mm2) or a levonorgestrel (52 mg) IUD. METHODS: Two Phase 2 studies provide information, one for copper and the other for the levonorgestrel IUD. Subjects met standard inclusion & exclusion criteria for each IUD, per the CDC. IUD placement occurred any day in the menstrual cycle. The primary outcome for both studies was efficacy, measured by Pearl Index (PI). Secondary outcomes include placement success, ease, and pain as well as overall tolerability and safety. RESULTS: The copper and levonorgestrel IUD studies enrolled 286 and 279 women, respectively; 60.8% and 64.2% were nulliparous. Investigators described IUD placements as “easy” or “very easy” in 91.5% and 88.9%, while participants rated pain as “moderate” or “very painful” in 19.0% and 21.5%, respectively. Placement required cervical dilation in 41 (14.5%) and 42 (15.1%); 99% of placements were successful in both studies. One pregnancy occurred in the Copper IUD study (PI=0.73, 95% CI 0.09-2.65) and none in the levonorgestrel study (PI=0.0, 97.5% confidence upper bound=1.88). We identified no uterine perforations. First year expulsions occurred in 1 (0.4%) and 7 (2.5%) participants. CONCLUSION: This novel IUD platform design successfully delivers both a low dose copper and levonorgestrel IUD with promising efficacy and safety data.

Efficacy, Safety, and Tolerability of a New Low-Dose Copper and Nitinol Intrauterine Device

To assess in parous and nulliparous women, the efficacy, safety, and tolerability of a new, low-dose copper (175 mm) intrauterine contraceptive with a flexible nitinol frame provided in a preloaded applicator. Institutional review boards at 12 U.S. sites approved this commercially funded project. Patients met standard inclusion and exclusion criteria for a copper-based intrauterine device (IUD), generally consistent with the Centers for Disease Control and Prevention's U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. Intrauterine device placement occurred at any day in the eligible patient's menstrual cycle after assuring she was not pregnant. The primary outcome measure assessed efficacy (measured by the Pearl Index) in this 1-year study with a 2-year extension. Secondary outcomes included placement success, ease of placement, safety as measured by adverse events, and tolerability assessed by discontinuation rate and bleeding and spotting patterns. A total of 286 women provided 5,640 cycles evaluable for pregnancy. Patients averaged 27.1 years of age. Nulliparous women represented 60.8% of the patients. Over 36 months of observation, we identified two pregnancies (Pearl Index 0.46 [95% CI 0.06-1.67]) and 10 serious adverse events; none were study-related. Successful placement occurred in 283 participants (99.0%). Median (range) continuation times were 2.7 years (0-3.4). We identified five expulsions (1.8%), zero uterine perforations, and one report of pelvic inflammatory disease. Adverse events prompted 30 women (10.6%) to discontinue early in the first year of use with 23 (8.1%) discontinuing for issues of bleeding, pain, or both. Altogether, 107 (37.8%) completed 36 months of device use. Mean bleeding days per cycle decreased from 7.6 in cycle 1 to 5.2 in cycle 13. The novel, low-dose copper and nitinol IUD demonstrated high efficacy and safety in this phase 2 U.S. Food and Drug Administration trial and warrants further expanded study in a phase 3 clinical trial. ClinicalTrials.gov, NCT02446821. Sebela Pharmaceuticals, Inc.

Low-dose oral copper treatment changes the hippocampal phosphoproteomic profile and perturbs mitochondrial function in a mouse model of Alzheimer's disease

Excessive copper can cause neurotoxicity and contribute to the development of some neurological diseases; however, copper neurotoxicity and the potential mechanisms remain poorly understood. We used proteomics and phosphoproteomics to quantify protein changes in the hippocampus of wild-type and 3xTg-AD mice, both of which were treated at 6 months of age with 2 months of drinking water with or without added copper chloride (0.13 ppm concentration). A total of 3960 unique phosphopeptides (5290 phosphorylation sites) from 1406 phosphoproteins was identified. Differentially expressed phosphoproteins involved neuronal and synaptic function, transcriptional regulation, energy metabolism and mitochondrial function. In addition, low-dose copper treatment of wild-type mice decreased hippocampal mitochondrial copy number, mitochondrial biogenesis and disrupted mitochondrial dynamics; these changes were associated with increased hydrogen peroxide production (H2O2), reduced cytochrome oxidase activity and decreased ATP content. In 3xTg-AD mice, identical low-dose oral copper treatment increased axonal degeneration, which was associated with altered phosphorylation of Camk2α at T286 and phosphorylation of mitogen-activated protein kinase (ERK1/2), which involved long-term potentiation (LTP) signaling. Mitochondrial dysfunction was mainly related to changes in phosphorylation levels of glycogen synthase kinase-3 beta (GSK3β) and serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform (Ppp3ca), which involved mitochondrial biogenesis signaling. In sum, low-dose oral copper treatment changes the phosphorylation of key hippocampal proteins involved in mitochondrial, synaptic and axonal integrity. These data showing that excess of copper speeds some early events of AD changes observed suggest that excess circulating copper has the potential to perturb brain function of wild-type mice and exacerbate neurodegenerative changes in a mouse model of AD.

Phase 2 efficacy, safety and tolerability results of the veracept low-dose copper intrauterine contraceptive: 24-month data

Phase 2 efficacy, safety and tolerability results of the veracept low-dose copper intrauterine contraceptive: 24-month data

Hippocampal Subcellular Organelle Proteomic Alteration of Copper-Treated Mice.

Copper neurotoxicity has been implicated in multiple neurological diseases. However, there is a lack of deep understanding on copper neurotoxicity, especially for low-dose copper exposure. In this study, we investigated the effects of chronic, low-dose copper treatment (0.13 ppm copper chloride in drinking water) on hippocampal mitochondrial and nuclear proteome in mice by 2-dimensional fluorescence difference gel electrophoresis coupled with MALDI-TOF-MS/MS. Behavioral tests revealed that low-dose copper caused spatial memory impairment, DNA oxidative damage as well as loss of synaptic proteins. Proteomic analysis revealed modulation of 31 hippocampal mitochondrial proteins (15 increased and 16 decreased), and 46 hippocampal nuclear proteins (18 increased and 28 decreased) in copper-treated versus untreated mice. Bioinformatic analysis indicated that these differentially expressed proteins are mainly involved energy metabolism (NDUV1, COX5B, IDH3A, and PGAM1), synapses (complexin-2, synapsin-2), DNA damage (PDIA3), apoptosis (GRP75), and oxidative stress (SODC, PRDX3). Among these differentially expressed proteins, synapsin-2, a synaptic-related protein, was found to be significantly decreased as confirmed by Western-blot analysis. In addition, we found that superoxide dismutase [Cu-Zn] (SODC), a copper ion target protein, was identified to be decreased in copper-treated mice versus untreated mice. We also found that stathmin (STMN1), a microtubule-destabilizing neuroprotein, was significantly decreased in hippocampal nuclei of copper-treated mice versus untreated mice. Taken together, we conclude that low-dose copper exposure causes spatial memory impairment and perturbs multiple biological/pathogenic processes by dysregulating the mitochondrial and nuclear proteome, particularly the proteins related to respiratory chain, synaptic vesicle fusion, axonal/neurtic integrity, and oxidative stress. The change of STMN1 and SODC may represent early novel biomarkers of copper neurotoxicity.

Combined and individual strategy of exercise generated preconditioning and low dose copper nanoparticles serve as superlative approach to ameliorate ISO-induced myocardial infarction in rats.

Myocardial infarction (MI) is a solitary fatal condition with towering prevalence of mortality worldwide. Our previous study reports that low-dose copper nanoparticles (CuNP) can halt the progression of diabetes-induced cardiotoxicity as copper has anti-inflammatory, anti-proliferative and anti-oxidant potential. In addition, exercise training has also been considered a hallmark for cardiac health. Cardioprotective potential of CuNP (1mg/kg/day, po, 4 weeks) and exercise (swimming, 90min, 5days/4 weeks) either alone or in combination was estimated by measuring the surge in serum nitrite/nitrate concentration and reduction in creatine kinase MB (CKMB), lactate dehydrogenase (LDH), cardiac troponin I (cTnI), lipid profile, oxidative stress, structural abnormalities against isproterenol (ISO)-induced MI. ISO significantly increased CKMB, LDH, cTnI, lipid alteration, oxidative stress, structural abnormalities and decrease nitrite/nitrate concentration in serum. Quantitative estimation of total and phosphorylated Akt(SER-473)/GSK-3b(SER-9) indicated the significant reduction in pAkt and pGSK-3b in ISO treated animal. Individual and combined treatment of CuNP and exercise significantly reduce ISO -induced CKMB, cTnI, LDH, and improve nitrite/nitrate concentration and lipid profile. Attenuation of myocardial oxidative stress and serum TBARS revealed the associated preconditioning effect of exercise and CuNP against oxidative stress. Exercise and CuNP also showed the protective potential against structural abnormalities. However, the cardioprotective effect of individual and combined strategy of exercise and CuNP was vanished by wortmannin and also avoid the downregulation of pGSK-3b. Low-dose CuNP and exercise training significantly prevents ISO-induced MI through preconditioning and GSK-3b inhibition. Ability to upsurge the NO level, lipid profile and reduced oxidative stress improve the potency of combined strategy.

Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: implication for Alzheimer's disease.

Excessive copper intake can lead to neurotoxicity, but there is a lack of comprehensive understanding on the potential impact of copper exposure especially at a low-dose on brain. We used 3xTg-AD mice to explore the potential neurotoxicity of chronic, low-dose copper treatment (0.13ppm copper chloride in drinking water) on behavior and the brain hippocampal mitochondrial and nuclear proteome. Low-dose copper increased the spatial memory impairment of these animals, increased accumulation of intracellular amyloid 1-42 (Aβ1-42), decreased ATP content, increased the positive staining of 8-hydroxyguanosine (8-OHdG), a marker of DNA oxidative damage, and caused apoptosis and a decrease in synaptic proteins. Mitochondrial proteomic analysis by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) revealed modulation of 24 hippocampal mitochondrial proteins (14 increased and 10 decreased) in copper-treated vs. untreated 3xTg-AD mice. Nuclear proteomic analysis revealed 43 modulated hippocampal nuclear proteins (25 increased and 18 decreased) in copper-treated 3xTg-AD vs. untreated mice. Classification of modulated mitochondrial and nuclear proteins included functional categories such as energy metabolism, synaptic-related proteins, DNA damage and apoptosis-related proteins, and oxidative stress-related proteins. Among these differentially expressed mitochondrial and nuclear proteins, nine proteins were abnormally expressed in both hippocampus mitochondria and nuclei, including electron transport chain-related proteins NADH dehydrogenase 1 alpha subcomplex subunit 10 (NDUAA), cytochrome b-c1 complex subunit Rieske (UCRI), cytochrome c oxidase subunit 5B (COX5B), and ATP synthase subunit d (ATP5H), glycolytic-related pyruvate kinase PKM (KPYM) and pyruvate dehydrogenase E1 component subunit alpha (ODPA). Furthermore, we found coenzyme Q10 (CoQ10), an endogenous mitochondrial protective factor/antioxidant, modulated the expression of 12 differentially expressed hippocampal proteins (4 increased and 8 decreased), which could be classified in functional categories such as glycolysis and synaptic-related proteins, oxidative stress-related proteins, implying that CoQ10 improved synaptic function, suppress oxidative stress, and regulate glycolysis. For the proteomics study, we validated the expression of several proteins related to synapses, DNA and apoptosis. The data confirmed that synapsin-2, a synaptic-related protein, was significantly decreased in both mitochondria and nuclei of copper-exposed 3xTg-AD mice. In mitochondria, dynamin-1 (DYN1), an apoptosis-related proteins, was significantly decreased. In the cellular nuclei, paraspeckle protein 1 (PSPC1) and purin-rich element-binding protein alpha (Purα), two DNA damage-related proteins, were significantly decreased and increased, respectively. We conclude that low-dose copper exposure exacerbates the spatial memory impairment of 3xTg-AD mice and perturbs multiple biological/pathogenic processes by dysregulating the mitochondrial and nuclear proteome. Exposure to copper might therefore contribute to the evolution of AD.

Mitochondrial proteomic alterations caused by long-term low-dose copper exposure in mouse cortex

Mitochondrial dysfunction is involved in neurotoxicity caused by exposure of various chemicals such as copper. However, the effects of long-term low-dose copper exposure on mitochondrial proteome remain unclear. In this study, we found the treatment of copper (0.13ppm copper sulfate in drinking water) for 12 months caused abnormal expression of a total of 13 mitochondrial proteins (7 up-regulated and 6 down-regulated) as revealed by two-dimensional electrophoresis coupled with mass spectrometry in mouse cortex. Protein functional analysis revealed that these differentially expressed proteins mainly included apoptosis-associated proteins, axon guidance-associated proteins, axonogenesis-associated proteins and mitochondrial respiratory chain complex. Among these differentially expressed mitochondrial proteins, GRP75 (75kDa glucose-regulated protein) and GRP78 (78kDa glucose-regulated protein) were found to be significantly down-regulated as confirmed by Western-blot analysis. The down-regulation of GRP75 was shown to promote apoptosis. The down-regulation of GRP78/BiP could up-regulate endoplasmic reticulum (ER) stress mediators and thus cause apoptosis. Our study suggested that these differentially expressed mitochondrial proteins such as GRP75 and GRP78 could be involved in neurotoxicity caused by long-term low-dose copper exposure and serve as potential molecular targets for the treatment of copper neurotoxicity.

Intrauterine Contraception.

Currently, there are only two basic types of intrauterine devices (IUDs): copper and hormonal. However, other types of IUDs are under development, some of which are in clinical trials around the world. Continued development has focused on increasing efficacy, longer duration of use, and noncontraceptive benefits. This review discusses currently available intrauterine contraceptives, such as the Cu380A IUD and levonorgestrel-releasing intrauterine systems; novel intrauterine contraceptives that are available in select parts of the world including the intrauterine ball, low-dose copper products, frameless devices, and intrauterine delivery systems impregnated with noncontraceptive medication; and novel products currently in development.

Synthesis and preliminary therapeutic evaluation of copper nanoparticles against diabetes mellitus and -induced micro- (renal) and macro-vascular (vascular endothelial and cardiovascular) abnormalities in rats

Current study synthesized and investigated the effect of low-dose copper nanoparticles (CuNPs) against diabetes mellitus and -induced experimental micro- (nephropathy) and macro-vascular (cardio and endothelium) complications.

Low-dose copper infusion into the coronary circulation induces acute heart failure in diabetic rats: New mechanism of heart disease

Diabetes impairs copper (Cu) regulation, causing elevated serum Cu and urinary Cu excretion in patients with established cardiovascular disease; it also causes cardiomyopathy and chronic cardiac impairment linked to defective Cu homeostasis in rats. However, the mechanisms that link impaired Cu regulation to cardiac dysfunction in diabetes are incompletely understood. Chronic treatment with triethylenetetramine (TETA), a Cu2+-selective chelator, improves cardiac function in diabetic patients, and in rats with heart disease; the latter displayed ∼3-fold elevations in free Cu2+ in the coronary effluent when TETA was infused into their coronary arteries. To further study the nature of defective cardiac Cu regulation in diabetes, we employed an isolated-perfused, working-heart model in which we infused micromolar doses of Cu2+ into the coronary arteries and measured acute effects on cardiac function in diabetic and non-diabetic-control rats. Infusion of CuCl2 solutions caused acute dose-dependent cardiac dysfunction in normal hearts. Several measures of baseline cardiac function were impaired in diabetic hearts, and these defects were exacerbated by low-micromolar Cu2+ infusion. The response to infused Cu2+ was augmented in diabetic hearts, which became defective at lower infusion levels and underwent complete pump failure (cardiac output=0ml/min) more often (P<0.0001) at concentrations that only moderately impaired function of control hearts. To our knowledge, this is the first report describing the acute effects on cardiac function of pathophysiological elevations in coronary Cu2+. The effects of Cu2+ infusion occur within minutes in both control and diabetic hearts, which suggests that they are not due to remodelling. Heightened sensitivity to the acute effects of small elevations in Cu2+ could contribute substantively to impaired cardiac function in patients with diabetes and is thus identified as a new mechanism of heart disease.

A Randomized Single-Blinded Trial of VeraCept, a Novel Nitinol Low-Dose Copper Intrauterine Contraceptive Compared With a Copper T380S Intrauterine Contraceptive [16

INTRODUCTION: We aimed to compare VeraCept, a novel low-profile nitinol intrauterine contraceptive with 175 mm2 of copper surface area, with a commercially available copper T380S. METHODS: We performed a randomized subject-blinded comparison of VeraCept and a copper T380S in a two-to-one fashion. The primary outcome was total continuation. We also examined pain on insertion, ease of placement, expulsion, satisfaction, tolerability, and pregnancy. Satisfaction ratings were on a 5-point Likert scale. We report data from insertion through 9-month follow-up. RESULTS: We enrolled women in a single clinic with 199 allocated to VeraCept and 101 to the T380S. Insertion was successful in 198 women for VeraCept and 100 for the T380S (P>.2). Mean age was 25 years, and median parity was two (range 1–4) with 39% having only had cesarean deliveries. No women developed clinical infection or reported serious adverse events. In the VeraCept and T380S groups, mean pain at insertion was 1.4 and 2.4, respectively (P<.01). At the 9-month visit for VeraCept and T380S, respectively, continuation was 86% and 70% (P=.004) with partial and complete expulsions in 5.0% and 12.0% (P<.05) and removal for pain or bleeding in 3.5% and 13.0% (P<.05). No pregnancies were diagnosed after insertion with 1,562 and 643 women-months for VeraCept and T380S, respectively. One “luteal phase” pregnancy was identified at the first follow-up with conception estimated at 1–1.5 weeks before VeraCept insertion. CONCLUSION: VeraCept resulted in less pain at insertion, fewer expulsions, and higher total continuation than the T380S with equal contraceptive efficacy to date.