Effect of Spinal Cord Burst Stimulation vs Placebo Stimulation on Disability in Patients With Chronic Radicular Pain After Lumbar Spine Surgery: A Randomized Clinical Trial.

Importance: The use of spinal cord stimulation for chronic pain after lumbar spine surgery is increasing, yet rigorous evidence of its efficacy is lacking. Objective: To investigate the efficacy of spinal cord burst stimulation, which involves the placement of an implantable pulse generator connected to electrodes with leads that travel into the epidural space posterior to the spinal cord dorsal columns, in patients with chronic radiculopathy after surgery for degenerative lumbar spine disorders. Design, Setting, and Participants: This placebo-controlled, crossover, randomized clinical trial in 50 patients was conducted at St Olavs University Hospital in Norway, with study enrollment from September 5, 2018, through April 28, 2021. The date of final follow-up was May 20, 2022. Interventions: Patients underwent two 3-month periods with spinal cord burst stimulation and two 3-month periods with placebo stimulation in a randomized order. Burst stimulation consisted of closely spaced, high-frequency electrical stimuli delivered to the spinal cord. The stimulus consisted of a 40-Hz burst mode of constant-current stimuli with 4 spikes per burst and an amplitude corresponding to 50% to 70% of the paresthesia perception threshold. Main Outcomes and Measures: The primary outcome was difference in change from baseline in the self-reported Oswestry Disability Index (ODI; range, 0 points [no disability] to 100 points [maximum disability]; the minimal clinically important difference was 10 points) score between periods with burst stimulation and placebo stimulation. The secondary outcomes were leg and back pain, quality of life, physical activity levels, and adverse events. Results: Among 50 patients who were randomized (mean age, 52.2 [SD, 9.9] years; 27 [54%] were women), 47 (94%) had at least 1 follow-up ODI score and 42 (84%) completed all stimulation randomization periods and ODI measurements. The mean ODI score at baseline was 44.7 points and the mean changes in ODI score were -10.6 points for the burst stimulation periods and -9.3 points for the placebo stimulation periods, resulting in a mean between-group difference of -1.3 points (95% CI, -3.9 to 1.3 points; P = .32). None of the prespecified secondary outcomes showed a significant difference. Nine patients (18%) experienced adverse events, including 4 (8%) who required surgical revision of the implanted system. Conclusions and Relevance: Among patients with chronic radicular pain after lumbar spine surgery, spinal cord burst stimulation, compared with placebo stimulation, after placement of a spinal cord stimulator resulted in no significant difference in the change from baseline in self-reported back pain-related disability. Trial Registration: ClinicalTrials.gov Identifier: NCT03546738.

Surgery for herniated lumbar disc in private vs public hospitals: A pragmatic comparative effectiveness study.

BACKGROUND: There is limited evidence on the comparative performance of private and public healthcare. Our aim was to compare outcomes following surgery for lumbar disc herniation (LDH) in private versus public hospitals. METHODS: Data were obtained from the Norwegian registry for spine surgery. Primary outcome was change in Oswestry disability index (ODI) 1 year after surgery. Secondary endpoints were quality of life (EuroQol EQ-5D), back and leg pain, complications, and duration of surgery and hospital stays. RESULTS: Among 5221 patients, 1728 in the private group and 3493 in the public group, 3624 (69.4%) completed 1-year follow-up. In the private group, mean improvement in ODI was 28.8 points vs 32.3 points in the public group (mean difference - 3.5, 95% CI - 5.0 to - 1.9; P for equivalence < 0.001). Equivalence was confirmed in a propensity-matched cohort and following mixed linear model analyses. There were differences in mean change between the groups for EQ-5D (mean difference - 0.05, 95% CI - 0.08 to - 0.02; P = 0.002) and back pain (mean difference - 0.2, 95% CI - 0.2, - 0.4 to - 0.004; P = 0.046), but after propensity matching, the groups did not differ. No difference was found between the two groups for leg pain. Complication rates was lower in the private group (4.5% vs 7.2%; P < 0.001), but after propensity matching, there was no difference. Patients operated in private clinics had shorter duration of surgery (48.4 vs 61.8 min) and hospital stay (0.7 vs 2.2 days). CONCLUSION: At 1 year, the effectiveness of surgery for LDH was equivalent in private and public hospitals.

Incidence and case fatality of aneurysmal subarachnoid hemorrhage admitted to hospital between 2008 and 2014 in Norway.

BACKGROUND: To provide age- and sex-specific incidence and case fatality rates for non-traumatic aneurysmal subarachnoid hemorrhage (aSAH) in Norway. We also studied time trends in incidence and case fatality, as well as predictors of death following aSAH. METHODS: A nationwide study using discharge data for patients admitted with aSAH between 2008 and 2014. RESULTS: A total of 1732 patients with aSAH were included. The mean age was 60 years (SD 14) and 63% were females. Crude annual incidence was 5.7 per 100,000 person-years (95% CI 5.4-6.0) and was higher in females (6.3 per 100,000, 95% CI 5.9-6.7) compared with males (4.9 per 100,000, 95% CI 4.5-5.3). The annual decline in aSAH incidence was 3.2% per year (p = 0.007). The cumulative proportions of fatalities at days 30, 90, and 1 year were 22%, 25%, and 37%, respectively. The 30-day mortality rate did not change during the study period. Age (HR 0.7-2.2) and aneurysms in the posterior circulation (HR 1.7, 95% CI 1.3-2.3, p = 0.001) were associated with higher 30-day case fatality following aSAH, while aneurysm repair (HR 0.2, 95% CI 0.2-0.3, p < 0.001) was associated with lower risk. CONCLUSIONS: The incidence of aSAH declined in Norway between 2008 and 2014. Case fatality following aSAH continues to be high, and the 30-day mortality during the study period was unchanged. Increasing age and aneurysms in the posterior circulation were associated with increased risk of death within 30 days following aSAH.

Six-Month Follow-up of a Trial of Spinal Cord Burst Stimulation vs Placebo Stimulation and Disability in Patients With Chronic Radicular Pain After Lumbar Spine Surgery.

This follow-up study examines back pain­related disability at 6 months following a randomized trial of spinal cord burst stimulation for chronic radicular pain after lumbar spine surgery.

Uterine artery Doppler measurements during first and second trimesters of normal pregnancy.

INTRODUCTION: The aim of this study was to construct a reference curve based on longitudinal Doppler blood flow measurements of the uterine artery during the first and second trimesters of normal pregnancy. MATERIAL AND METHODS: Healthy pregnant women (n = 124) between 18 and 38 years of age were included. The uterine artery pulsatility index (UtAPI) was measured with transvaginal ultrasound in the first trimester (gestational weeks 8-10 and 11-13) and with transabdominal ultrasound in the second trimester (gestational weeks 18 and 24). Individual longitudinal curves were constructed and a reference curve was created. RESULTS: A centile curve with the normal distribution of the UtAPI during the first and second trimesters was constructed. We found that 90% of the women alternated between quartiles during the four examinations between gestational weeks 8 and 24, but 75% remained within the higher or lower range. CONCLUSIONS: A UtAPI reference curve was constructed for the first and second trimesters of pregnancy. Although the mean UtAPI values may vary from one examination to the next, most mean UtAPI values remain within the higher or lower range, i.e. above or below the 50th centile.

Gestational diabetes mellitus among Nordic Caucasian women: prevalence and risk factors according to WHO and simplified IADPSG criteria.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with both maternal and offspring adverse effects. The World Health Organization (WHO) has recently adopted novel GDM criteria. The aim of this study was to evaluate the former WHO and a simplified version of the new International Association for Diabetes in Pregnancy Study Group (IADPSG) criteria as to prevalence of and risk factors for GDM in a Nordic Caucasian population. METHODS: A 75 g oral glucose tolerance test was performed in 687 women at 18-22 and 32-36 pregnancy weeks. GDM was defined according to the WHO criteria as fasting plasma glucose ≥ 7.0 mmol/L and/or 2-hour plasma glucose ≥ 7.8 mmol/L and by a simplified version of the IADPSG criteria as either fasting glucose ≥ 5.1 mmol/L and/or 2-h plasma glucose ≥ 8.5 mmol/L. One-hour glucose values were not available and were thus not included in the diagnosis of GDM by IADPSG. Prevalence of GDM during pregnancy and risk factors for GDM at 18-22 weeks were studied in retrospect according to each of the two criteria. RESULTS: The total prevalence of GDM during pregnancy was 6.1% (42/687) for the WHO criteria and 7.4% (51/687) for the simplified IADPSG criteria. High maternal age and short stature were independently associated with WHO GDM. Maternal age, fasting insulin and no regular exercise at 18-22 pregnancy weeks associated with simplified IADPSG GDM. CONCLUSIONS: Simplified IADPSG criteria moderately increase GDM prevalence compared with the WHO criteria. Risk factors for GDM differ with the diagnostic criteria used.

Anti-Mullerian hormone in the diagnosis of polycystic ovary syndrome: can morphologic description be replaced?

STUDY QUESTION: Can anti-Müllerian hormone (AMH) level replace the morphologic description in the diagnosis of polycystic ovary syndrome (PCOS) and what is the relationship between AMH and different diagnostic criteria of PCOS? SUMMARY ANSWER: AMH may be a good substitute for polycystic ovarian morphology (PCOM) in diagnosing PCOS. WHAT IS KNOWN ALREADY: AMH has been suggested as an alternative to antral follicle count (AFC) in diagnosing PCOS. Cut-off values for AMH studied so far show an acceptable specificity but a rather poor sensitivity, leaving up to one-third of PCOS women undiagnosed. STUDY DESIGN, SIZE, DURATION: We used data from a cross-sectional, case-control study on women with prior preterm birth and their controls, i.e. women with prior full-term birth. Among 262 women, 56 met the Rotterdam criteria (PCOS-R) and 44 the Androgen Excess-PCOS Society (PCOS-AES) criteria of PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fasting blood samples were collected, a transvaginal ultrasound investigation and a clinical examination were performed. PCOS-R and PCOS-AES were re-diagnosed by replacing PCOM with AMH. Main outcome measures were the prevalence of PCOS, PCOM, hirsutism, oligoamenorrhoea and serum levels of AMH and androgens. MAIN RESULTS AND THE ROLE OF CHANCE: When replacing PCOM with AMH, the specificity and sensitivity for identifying PCOS were 97.1 and 94.6% according to the PCOS-R criteria and 97.2 and 95.5% according to the PCOS-AES criteria, respectively, at an AMH cut-off value of 20 pmol/l. LIMITATIONS, REASONS FOR CAUTION: The results need to be confirmed when international standards and methods for AMH measurements are established. WIDER IMPLICATIONS OF THE FINDINGS: AMH may be a good substitute for PCOM in diagnosing PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was financed by the Cooperative of Central Norway Regional Health Authority and Norwegian University of Science and Technology. The authors have no interests to disclose. TRIAL REGISTRATION NUMBER: This study is registered at www.clinicaltrials.gov as NCT01355536.

Androgen levels are associated with blood pressure in pregnant women after term.

OBJECTIVE: To assess possible associations between androgen, estrogen and insulin levels and blood pressure in pregnant women after term, compared with the effect of other well-known factors. DESIGN: Cross-sectional retrospective study. SETTING: University Hospital, Trondheim region. POPULATION: Four hundred and eighty-nine post-term women with uncomplicated pregnancies. METHODS: Blood pressure measurements and fasting serum samples drawn one week beyond the estimated day of delivery (defined as 41(+2) weeks). MAIN OUTCOME MEASURES: Blood pressure, maternal age, body mass index, parity, smoking habits and serum levels of dehydroepiandrosterone sulfate, androstendione, free testosterone index, estradiol, estriol, progesterone, 17-hydroxy-progesterone and insulin. RESULTS: In univariate linear regression analyses, body mass index, androstendione, free testosterone index and insulin were positively associated and parity was negatively associated with both systolic and diastolic blood pressure. In multivariate linear regression analyses, systolic blood pressure was positively associated with body mass index and free testosterone index, but negatively associated with parity and 17-hydroxy-progesterone levels, while diastolic blood pressure was positively associated with age and free testosterone index, but negatively associated with parity and 17-hydroxy-progesterone levels. CONCLUSION: Testosterone may increase blood pressure in pregnant women, while 17-hydroxy-progesterone may have the opposite effect.

On the potential of metformin to prevent preterm delivery in women with polycystic ovary syndrome - an epi-analysis.

Our aim was to re-evaluate whether metformin may reduce late miscarriage/preterm delivery, pre-eclampsia and gestational diabetes in women with polycystic ovary syndrome (PCOS). We performed an epi-analysis of two randomized controlled trials. The participants were 313 women aged 18-42 years with PCOS who had singleton pregnancies. They were randomized to metformin or placebo treatment from first trimester until delivery. We analysed the prevalence of late miscarriage/preterm delivery, pre-eclampsia and gestational diabetes according to both the intention-to-treat principle and per protocol analysis. The metformin-treated patients had less late miscarriage/preterm delivery; five (3%) vs. 18 (11%) in the placebo group (p < 0.01). There was no difference in the prevalence of gestational diabetes and pre-eclampsia between the metformin and the placebo group. In this epi-analysis, metformin treatment during pregnancy seems to reduce early delivery in women with PCOS. We believe that further randomized studies should be performed before firm conclusions can be drawn.

Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero.

OBJECTIVES: To investigate the possible long-term effects of metformin exposure on growth and development of the offspring born to mothers with polycystic ovary syndrome (PCOS). The drug passes through the placenta and can potentially influence the fetus. PATIENTS AND METHODS: This is a follow-up study of a randomized, controlled trial on PCOS women, randomized to metformin or placebo in pregnancy. Out of 37 children aged 7-9 years, 25 agreed to participate. Primary outcome measures were growth, body composition and metabolic parameters. RESULTS: There were no differences in height, weight or body composition between those exposed to metformin and those exposed to placebo. We found a higher fasting glucose level in the metformin group (4.93 mmol/L vs. 4.60 mmol/L, p = 0.04). In the metformin group there was a trend towards higher systolic blood pressure (106 mmHg vs. 101 mmHg, p = 0.05) and a lower LDL cholesterol level (2.42 mmol/L vs. 2.99 mmol/L, p = 0.07). CONCLUSION: Metformin exposure during fetal life does not seem to influence growth and body composition at the age of 8 years. A higher fasting glucose level and a possible higher systolic blood pressure and lower LDL cholesterol level in the metformin group may be coincidental and should be further explored.

Six-month preoperative octreotide treatment in unselected, de novo patients with acromegaly: effect on biochemistry, tumour volume, and postoperative cure.

OBJECTIVE: Treatment with somatostatin analogues is the primary medical treatment of acromegaly. Controversies still exist whether acute octreotide effect predicts long-term biochemical effects, tumour regression or surgical cure. This prospective study investigates effect of 6-month treatment with octreotide long-acting repeatable (LAR) on insulin-like growth factor-1 (IGF-1) and growth hormone (GH) levels, pituitary function, tumour regression and postoperative cure in de novo acromegalic patients. DESIGN AND METHODS: After a baseline evaluation including fasting hormone levels, MRI scan and an acute 50 µg octreotide test, 32 patients were treated with octreotide LAR 20 mg every 28th day for 6 months before surgery. Treatment effects on IGF-1 and GH levels, serum hormone levels and tumour volume were monitored. Surgical cure was evaluated 3 months postoperatively. RESULTS: Mean tumour volume reduction was 35%, in one-third of the patients more than 50%, while approximately one-third achieved biochemical remission evaluated by normalized IGF-1 levels. The GH reduction following an acute octreotide test was 81 ± 19% and associated with long-term GH reduction (r = 0·78, P < 0·0005). However, neither acute (r = 0·29, P = 0·12) nor the long-term octreotide effect (r = 0·11, P = 0·58) on GH levels was associated with tumour volume reduction and did not predict subsequent surgical cure. CONCLUSION: Six months of long-acting octreotide using a fixed dose, 1/3 of the patients came in biochemical remission, while 2/3 had significant tumour reduction. Moreover, an acute effect of octreotide seemed to be a prerequisite for long-term effect.

PCOS--what matters in early pregnancy?--data from a cross-sectional, multicenter study.

OBJECTIVE: To describe patient characteristics according to different diagnostic criteria in early pregnancy, in women with polycystic ovary syndrome (PCOS). DESIGN: Descriptive, cross-sectional study of 257 women with PCOS in the first trimester of pregnancy. SETTING: Data from a multicenter trial at the time of inclusion. POPULATION: 257 PCOS women with singleton pregnancies. METHODS: Investigator-administrated questionnaires were filled out. Clinical examination was performed by the investigators. Fasting blood samples were collected. MAIN OUTCOME MEASURES: Biometric data, androgens, glucose and insulin levels. RESULTS: Women who met the National Institutes of Health (NIH) criteria for PCOS had higher body mass index (BMI), testosterone, dehydroepiandrostenedione, free testosterone index (FTI) and insulin levels compared with those who only met the Rotterdam consensus criteria. Adjusted for age and BMI, only testosterone and FTI were higher in those who met the NIH criteria. BMI was a strong, independent predictor of both systolic and diastolic blood pressure in early PCOS pregnancy, while both FTI and fasting insulin were independent predictors of systolic blood pressure. Twenty-two (9%) of the participants had gestational diabetes mellitus in the first trimester of pregnancy. CONCLUSIONS: In the first trimester, PCOS women diagnosed according to NIH criteria were more metabolically and endocrinologically abnormal compared with those who only met the Rotterdam consensus criteria. BMI and FTI were independent predictive factors for blood pressure. There was a high prevalence of gestational diabetes mellitus in early PCOS pregnancies.

Metformin in Pregnancy Study (MiPS): protocol for a systematic review with individual patient data meta-analysis.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps. METHODS AND ANALYSIS: MEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD. ETHICS AND DISSEMINATION: All IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.

Sex ratio and pregnancy complications according to mode of conception in women with polycystic ovary syndrome.

OBJECTIVE: To investigate pregnancy complications and offspring sex ratio according to mode of conception in women with polycystic ovary syndrome (PCOS). DESIGN: Retrospective, descriptive study. SETTING: Tertiary, university hospital. POPULATION: A total of 176 women with PCOS diagnosed according to the Rotterdam criteria. METHODS: Women with PCOS who have participated in one or more clinical studies were invited to answer a questionnaire on the mode of conception, pregnancy complications, gestational length and offspring gender. A total of 139 women responded. Data were quality checked against hospital files. MAIN OUTCOME MEASURES: Fertility, mode of conception, offspring gender and pregnancy complications. RESULTS: More than half (54%) of the singleton pregnancies were conceived spontaneously. More complications were seen in pregnancies achieved while using metformin than without (p = 0.02). Compared to spontaneous conception, more boys than girls were born in singleton pregnancies after in vitro fertilization/intracytoplasmatic sperm injection treatment (p = 0.004). CONCLUSIONS: In women with PCOS the mode of conception may influence both the rate of pregnancy complications and the offspring sex ratio.

[Use of metformin in polycystic ovary syndrome]. / Bruk av metformin ved polycystisk ovarie-syndrom.

The preferred treatment for polycystic ovary syndrome, which affects women of fertile age, is diet and lifestyle interventions - especially in association with overweight. However, an increasing number of studies have shown that metformin has a beneficial effect on many of the syndrome's manifestations. Norwegian physicians should therefore consider metformin treatment of patients with polycystic ovary syndrome.

Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5-10 year follow-up of the PregMet randomised controlled trial.

BACKGROUND: Metformin is increasingly used to treat gestational diabetes and type 2 diabetes in pregnancy, and in attempts to improve pregnancy outcomes in polycystic ovary syndrome and obesity. It passes across the placenta with possible long-term consequences for the offspring. We previously explored the effect of metformin, given to women with polycystic ovary syndrome during pregnancy, on children's growth up to 4 years of age. In this 5-10 year follow-up, we examined the cardiometabolic risk factors in these children. METHODS: This is a follow-up of children from the PregMet study, a double-blind, randomised controlled trial comparing metformin with placebo in polycystic ovary syndrome pregnancies. In the PregMet study, between Feb 4, 2005, and Jan 27, 2009, 257 pregnant women aged 18-45 years with polycystic ovary syndrome according to the Rotterdam criteria were included with 274 singleton pregnancies at 5-12 weeks of gestation at 11 study centres in Norway. 17 women participated twice. Pregnant women were randomised to metformin (2000 mg/day) or placebo from inclusion in the first trimester to birth. Randomisation was stratified according to metformin use at conception. In this follow-up, the primary endpoint was body-mass index (BMI) in the offspring at 5-10 years of age assessed by the standard deviation score (Z score). The primary endpoint was analysed with independent sample t tests. ClinicalTrials.gov number NCT00159536. FINDINGS: Of the 255 invited children from the PregMet study, 141 (55%) consented to participate and were included between April 29, 2014, and July 12, 2016. Maternal baseline characteristics in the first trimester were similar between groups. Children in the metformin group had a higher BMI Z score than those in the placebo group (difference in means=0·41, 95% CI 0·03-0·78, p=0·03). INTERPRETATION: The increased BMI in metformin-exposed children might indicate a potential risk of inferior cardiometabolic health. Implications for adult health cannot be excluded. FUNDING: The Research Council of Norway, Novo Nordisk Foundation, St Olavs University Hospital, and the Norwegian University of Science and Technology.

Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy complications. Epi-analysis of two previous randomised controlled trials that compared metformin with placebo during pregnancy in women with PCOS showed a significant reduction in late miscarriages and preterm births in the metformin group. The aim of this third randomised trial (PregMet2) was to test the hypothesis that metformin prevents late miscarriage and preterm birth in women with PCOS. METHODS: PregMet2 was a randomised, placebo-controlled, double-blind, multicentre trial done at 14 hospitals in Norway, Sweden, and Iceland. Singleton pregnant women with PCOS aged 18-45 years were eligible for inclusion. After receiving information about the study at their first antenatal visit or from the internet, women signed up individually to participate in the study. Participants were randomly assigned (1:1) to receive metformin or placebo by computer-generated random numbers. Randomisation was in blocks of ten for each country and centre; the first block had a random size between one and ten to assure masking. Participants were assigned to receive oral metformin 500 mg twice daily or placebo during the first week of treatment, which increased to 1000 mg twice daily or placebo from week 2 until delivery. Placebo tablets and metformin tablets were identical and participants and study personnel were masked to treatment allocation. The primary outcome was the composite incidence of late miscarriage (between week 13 and week 22 and 6 days) and preterm birth (between week 23 and week 36 and 6 days), analysed in the intention-to-treat population. Secondary endpoints included the incidence of gestational diabetes, preeclampsia, pregnancy-induced hypertension, and admission of the neonate to the neonatal intensive care unit. We also did a post-hoc individual participant data analysis of pregnancy outcomes, pooling data from the two previous trials with the present study. The study was registered with ClinicalTrials.gov, number NCT01587378, and EudraCT, number 2011-002203-15. FINDINGS: The study took place between Oct 19, 2012, and Sept 1, 2017. We randomly assigned 487 women to metformin (n=244) or placebo (n=243). In the intention-to-treat analysis, our composite primary outcome of late miscarriage and preterm birth occurred in 12 (5%) of 238 women in the metformin group and 23 (10%) of 240 women in the placebo group (odds ratio [OR] 0·50, 95% CI 0·22-1·08; p=0·08). We found no significant differences for our secondary endpoints, including incidence of gestational diabetes (60 [25%] of 238 women in the metformin group vs 57 [24%] of 240 women in the placebo group; OR 1·09, 95% CI 0·69-1·66; p=0·75). We noted no substantial between-group differences in serious adverse events in either mothers or offspring, and no serious adverse events were considered drug-related by principal investigators. In the post-hoc pooled analysis of individual participant data from the present trial and two previous trials, 18 (5%) of 397 women had late miscarriage or preterm delivery in the metformin group compared with 40 (10%) of 399 women in the placebo group (OR 0·43, 95% CI 0·23-0·79; p=0·004). INTERPRETATION: In pregnant women with PCOS, metformin treatment from the late first trimester until delivery might reduce the risk of late miscarriage and preterm birth, but does not prevent gestational diabetes. FUNDING: Research Council of Norway, Novo Nordisk Foundation, St Olav's University Hospital, and Norwegian University of Science and Technology.

Preoperative octreotide treatment in newly diagnosed acromegalic patients with macroadenomas increases cure short-term postoperative rates: a prospective, randomized trial.

CONTEXT: Surgery is the primary treatment of acromegaly. However, it often fails to cure the patient. New strategies that improve surgical outcome are needed. OBJECTIVE: Our objective was to investigate whether 6-month preoperative treatment with octreotide improves the surgical outcome in newly diagnosed acromegalic patients. PATIENTS: During a 5-yr period (1999-2004), all newly diagnosed acromegalic patients between 18 and 80 yr of age in Norway were screened and invited to participate in the study. A total of 62 patients was included in the Preoperative Octreotide Treatment of Acromegaly study. RESEARCH DESIGN AND METHODS: After a baseline evaluation, patients were randomized directly to transsphenoidal surgery (n = 30) or pretreatment with octreotide (n = 32) 20 mg im every 28th day for 6 months before transsphenoidal surgery. Cure was evaluated 3 months postoperatively primarily by IGF-I levels. RESULTS: According to the IGF-I criteria, 14 of 31 (45%) pretreated patients vs. seven of 30 (23%) patients with direct surgery were cured by surgery (P = 0.11). In patients with microadenomas (< or = 10 mm), one of five (20%) pretreated vs. three of five (60%) with direct surgery were cured (P = 0.52). In patients with macroadenomas, 13 of 26 (50%) pretreated vs. four of 25 (16%) with direct surgery were cured (P = 0.017). CONCLUSIONS: Six-month preoperative octreotide treatment might improve surgical cure rate in newly diagnosed acromegalic patients with macroadenomas. These results have to be confirmed in future studies.

Breastfeeding in polycystic ovary syndrome.

BACKGROUND: To investigate the breastfeeding rate in new mothers with polycystic ovary syndrome (PCOS). METHODS: Case-control study. Thirty-six women with PCOS and 99 controls matched for age, gestational length and parity, answered a questionnaire. Breastfeeding at one-, three- and six-months postpartum was registered and the two groups were compared. In the women with PCOS, androgen levels through pregnancy were analysed and related to breastfeeding rate. RESULTS: At one-month postpartum, 27 (75%) of the women with PCOS were breastfeeding exclusively, whereas five (14%) did not breastfeed at all. Among controls, 88 (89%) were breastfeeding exclusively and two (2%) did not breastfeed (p=0.001). At three- and six-months postpartum, breastfeeding was equal in the two groups. Problems with sore nipples and seeking professional lactation support were also equal. Dehydroepiandrosterone-sulphate levels at gestational week 32 and 36 showed a weak negative association with breastfeeding in PCOS women. Breastfeeding rate was not associated with maternal gestational levels of androstenedione, testosterone, sex-hormone binding globulin, or free testosterone index in PCOS. CONCLUSIONS: Women with PCOS appear to have a reduced breastfeeding rate in the early postpartum period. Possibly, gestational dehydroepiandrosterone-sulphate might negatively influence breastfeeding rate in women with the syndrome.

Uterine Artery Doppler in Pregnancy: Women with PCOS Compared to Healthy Controls.

The objective of this study was to investigate possible differences in uterine artery pulsatility index (UtAPI) between pregnant women with PCOS and healthy controls and to explore possible effects of metformin on UtAPI. Material and Methods. The study was conducted in a tertiary center. Forty-eight pregnant women diagnosed with PCOS before pregnancy and 124 healthy pregnant women were included. Women with PCOS were randomly assigned to metformin 2000 mg daily or a placebo. UtAPI was measured five times during 1st and 2nd trimesters of pregnancy in women with PCOS and four times in healthy controls. Results. There was no difference in UtAPI between PCOS women and healthy controls at any point in time (p = 0.34-0.77). In women with PCOS, randomly assigned to metformin 2000 mg or placebo, UtAPI was unaffected by metformin two hours after intake of the first dose of study medication (p = 0.34). All PCOS women, regardless of randomization, had higher UtAPI two hours after intake of study medication and a meal compared to before a meal (p = 0.02). Conclusions. In the first and second trimesters of pregnancy, there was no difference in UtAPI between women with PCOS and healthy controls. Metformin had no immediate effect on the UtAPI. Interestingly, blood flow decreased after a meal, suggesting that time since last meal should be taken into consideration when interpreting the results of UtAPI measurements in pregnancy. This trial is registered with ClinicalTrials.gov (NCT00466622) Metformin in Pregnant PCOS women (PregMet) (NCT00159536).