Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of recurrent pregnancy loss. Evidence on whether levothyroxine treatment improves pregnancy outcomes in women who are TPO-Ab positive women with recurrent pregnancy loss is scarce. The aim of this study was to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. METHODS: The T4LIFE trial was an international, double-blind, placebo-controlled, phase 3 study done in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium, and one tertiary hospital in Denmark. Women (18-42 years) who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range were eligible for inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibodies, or ß2-glycoprotein-I IgG or IgM antibodies), other autoimmune diseases, thyroid disease, previous enrolment in this trial, or contraindications for levothyroxine use. Before conception, women were randomly assigned (1:1) to receive either levothyroxine or placebo orally once daily. The daily dose of levothyroxine was based on preconception TSH concentration and ranged from 0·5-1·0 µg/kg bodyweight. Levothyroxine or placebo was continued until the end of pregnancy. The primary outcome was live birth, defined as the birth of a living child beyond 24 weeks of gestation measured in the intention-to-treat population. The trial was registered within the Netherlands Trial Register, NTR3364 and with EudraCT, 2011-001820-39. RESULTS: Between Jan 1, 2013, and Sept 19, 2019, 187 women were included in the study: 94 (50%) were assigned to the levothyroxine group and 93 (50%) were assigned to the placebo group. The trial was prematurely stopped when 187 (78%) of the 240 predefined patients had been included because of slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (risk ratio 1·03 [95% CI 0·77 to 1·38]; absolute risk difference 1·6% [95% CI -12·7 to 15·9]). Seven (7%) women in the levothyroxine group and seven (8%) in the placebo group reported adverse events, none of them were directly related to the study procedure. INTERPRETATION: Compared with placebo, levothyroxine treatment did not result in higher live birth rates in euthyroid women with recurrent pregnancy loss who were positive for TPO-Ab. On the basis of our findings, we do not advise routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. FUNDING: Dutch Organization for Health Research and Development, Fonds NutsOhra, Dutch Patient Organization of Thyroid Disorders, the Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Dutch Patient Organization of Thyroid Disorders.

Comparison of clean intermittent and transurethral indwelling catheterization for the treatment of overt urinary retention after vaginal delivery: a multicentre randomized controlled clinical trial.

INTRODUCTION AND HYPOTHESIS: Overt postpartum urinary retention (PUR) is the inability to void after delivery and affects up to 7% of patients. Clean intermittent catheterization (CIC) and transurethral indwelling catheterization (TIC) are both standard treatments, but have not previously been compared. Clinical guidelines on postpartum bladder management are lacking. METHODS: A total of 85 patients were randomised for TIC (n=45) and CIC (n=40). In total 68 patients (34 patients with TIC and 34 patients with CIC) completed the UDI-6 questionnaire 3 months after delivery.. Patients allocated to TIC received an indwelling catheter for 24 h and if necessary, another catheter for 48 h. Patients with CIC were intermittently catheterized or taught to self-catheterize until adequate voiding with a postvoid residual volume (PVRV) of <150 mL was achieved. The primary outcome was the presence of bothersome micturition symptoms as measured using the Dutch-validated Urogenital Distress Inventory (UDI-6). RESULTS: Only seven patients (10%) reported bothersome micturition problems 3 months after delivery. No significant differences in the occurrence of micturition symptoms were found. Median PVRV was 800 mL in the CIC group and 650 mL in the TIC group. PVRV was ≥1,000 mL in 24% of the patients. The median duration of catheterization was significantly shorter in the CIC group than in the TIC group (12 h vs. 24 h, p < 0,01). In patients with CIC, 35% required only one catheterization before complete bladder emptying occurred. The duration of treatment was not related to the initial PVRV. Both treatments were equally well accepted by the patients. CONCLUSIONS: In patients with overt PUR, CIC is the preferred treatment as a considerable percentage of patients appear to be over-treated when the standard duration of TIC is 24 h. The occurrence of micturition symptoms is not associated with the catheterization method used. CIC is well tolerated in patients with overt PUR.

Randomized Trial of a Lifestyle Program in Obese Infertile Women.

BACKGROUND: Small lifestyle-intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcomes, but large randomized, controlled trials are lacking. METHODS: We randomly assigned infertile women with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 29 or higher to a 6-month lifestyle intervention preceding treatment for infertility or to prompt treatment for infertility. The primary outcome was the vaginal birth of a healthy singleton at term within 24 months after randomization. RESULTS: We assigned women who did not conceive naturally to one of two treatment strategies: 290 women were assigned to a 6-month lifestyle-intervention program preceding 18 months of infertility treatment (intervention group) and 287 were assigned to prompt infertility treatment for 24 months (control group). A total of 3 women withdrew consent, so 289 women in the intervention group and 285 women in the control group were included in the analysis. The discontinuation rate in the intervention group was 21.8%. In intention-to-treat analyses, the mean weight loss was 4.4 kg in the intervention group and 1.1 kg in the control group (P<0.001). The primary outcome occurred in 27.1% of the women in the intervention group and 35.2% of those in the control group (rate ratio in the intervention group, 0.77; 95% confidence interval, 0.60 to 0.99). CONCLUSIONS: In obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization. (Funded by the Netherlands Organization for Health Research and Development; Netherlands Trial Register number, NTR1530.).

Dopamine and noradrenaline efflux in the medial prefrontal cortex during serial reversals and extinction of instrumental goal-directed behavior.

The prefrontal cortex (PFC) of the rat supports cognitive flexibility, the ability to spontaneously adapt goal-directed behavior in response to radically changing situational demands. We have shown previously that transient inactivation of the rat medial PFC (mPFC) impairs initial reversal learning in a spatial 2-lever discrimination task. Given the importance of dopamine (DA) for PFC function, we studied DA (and noradrenaline [NA]) efflux in the mPFC during reversal learning. We observed a higher and more extended increase in DA efflux in rats performing the first reversal compared with controls performing the previously acquired discrimination. The results of an additional experiment suggest that such a difference between the reversal- and control-induced DA increases was absent during a third reversal. During the extinction session, DA efflux did not increase from basal levels. Increases in NA efflux were less than in DA and did not differ between control and any condition. We conclude that prefrontal DA activity is increased during execution of instrumental discrimination tasks and that this increase is amplified during the acquisition of a first, but not of later reversals. These data corroborate our previous findings and indicate that DA is critically involved in this form of cognitive flexibility.

Noradrenaline and dopamine efflux in the prefrontal cortex in relation to appetitive classical conditioning.

We trained rats to learn that an auditory stimulus predicted delivery of reward pellets in the Skinner box. After 2 d of training, we measured changes in efflux of noradrenaline (NA) and dopamine (DA) in the medial prefrontal cortex using microdialysis on the third day. Animals were subjected to a normal rewarded session and an extinction session, in which the auditory stimulus was presented alone. In the rewarded session, both NA and DA efflux were increased, but in extinction, only NA was activated. The data suggest that NA has a role in the reaction to reward-predicting stimuli, which complements that of DA.

Pretraining or previous non-spatial experience improves spatial learning in the Morris water maze of nucleus basalis lesioned rats.

Previous experiments have shown that infusions of ibotenic acid in the nucleus basalis magnocellularis (NBM) induce a strong impairment in spatial navigation for a hidden platform in the Morris water maze. This effect was initially attributed to a cholinergic deficit, but later studies showed that performance level did not correlate with the degree of cholinergic denervation. Therefore, this impairment is due to a combined cholinergic and non-cholinergic deficit. However, it is not clear in which particular processes the NBM is involved. In this study we have evaluated the origin of behavioural impairment in spatial navigation in the water maze after an ibotenic acid-induced lesion of NBM. In the first experiment, Wistar rats were trained preoperatively in an allocentric navigation task. Postoperatively, they were tested in the same task. All lesioned animals showed a performance level similar to controls. Lesions did not impede the acquisition of new positions in the water maze, nor did affect the ability of animals to remember new platform positions after an intertrial interval of 20s, even if animals had received only allocentric experience with the platform position, or allocentric and path integration information concurrently. Lesions also failed to affect the ability to locate a hidden platform in a new environment. However, hippocampal infusions of scopolamine (5 microg) produced a severe impairment in NBM-damaged animals, without impairing performance of controls. In the second experiment Wistar rats with the same lesion were first trained in a visual-guided task in the water maze, and subsequently evaluated in the spatial task. In both tasks lesioned animals were not different from controls. These results suggest that the NBM played an important role during acquisition phases but not in the execution of spatial navigation. Moreover, the excessive emotional response displayed by lesioned animals is postulated as a relevant cause for the impairment observed in spatial navigation after NBM damage.

The NMDA-receptor antagonist MK-801 selectively disrupts reversal learning in rats.

We tested the hypothesis that inhibition of NMDA-receptors in rats would lead to a selective impairment of reversal learning in a serial reversal task in the Skinner box. Low doses of MK-801 (0.025 and 0.05 mg/kg) did not affect acquisition of the two-lever discrimination, but impaired performance during the first reversal more than during the third reversal. Similar effects were observed during the series of extinction sessions. The high dose (0.1 mg/kg) completely inhibited reversal and extinction learning, as the rats perseverated in pressing the previously rewarded lever(s). We conclude that NMDA receptor blockade leads to a selective impairment in cognitive flexibility, and shows some similarity to transient inactivation of the medial prefrontal cortex in this respect.

Cholinergic receptor blockade in prefrontal cortex and lesions of the nucleus basalis: implications for allocentric and egocentric spatial memory in rats.

In this study we have examined the involvement of the prefrontal cortex (PFC) along with the Nucleus basalis magnocellularis (NBM) in two types of spatial navigation tasks. We evaluated the effects of excitotoxic (ibotenate-induced) lesions of the NBM in an allocentric and an egocentric task in the Morris water maze, using sham operations for a comparison. In both cases we also assessed the effects of local cholinergic receptor blockade in the PFC by infusing the muscarinic receptor antagonist scopolamine (4 or 20 microg). Anatomically, the results obtained showed that this lesion produced a profound loss of acetylcholinesterase (AChE) positive cells in the NBM, and a loss of AChE positive fibres in most of the neocortex, but hardly in the medial PFC. Behaviourally, such lesions led to a severe impairment in the allocentric task. Intraprefrontal infusions of scopolamine led to a short-lasting impairment in task performance when the high dose was used. In the second experiment, using the same surgical manipulations, we examined the performance in the egocentric task. Like in the allocentric task animals with NBM lesions were also impaired, but with continued training they acquired a level of performance similar to the sham-operated ones. This time, infusions of scopolamine in the medial PFC led to a severe disruption of performance in both groups of animals. We conclude that acetylcholine in the medial PFC is important for egocentric but not allocentric spatial memory, whereas the NBM is involved in the learning of both tasks, be it to a different degree.