Abnormal birth weights for gestational age in relation to maternal characteristics in Sweden: a five year cross-sectional study.

BACKGROUND: Abnormal birth weight - small for gestational age (SGA) and large for gestational age (LGA) - are important indicators for newborn health. Due to changes in lifestyle in recent decades, it is essential to keep up-to-date with the latest information on maternal factors linked to abnormal birth weight. The aim of this study is to investigate SGA and LGA in relation to maternal individual, lifestyle and socioeconomic characteristics. . METHODS: This is a register-based cross-sectional study. Self-reported data from Sweden's Salut Programme maternal questionnaires (2010-2014) were linked with records in the Swedish Medical Birth Register (MBR). The analytical sample comprised 5089 singleton live births. A Swedish standard method using ultrasound-based sex-specific reference curves defines the abnormality of birth weight in MBR. Univariable and multivariable logistic regressions were used to examine crude and adjusted associations between abnormal birth weights and maternal individual, lifestyle and socioeconomic characteristics. A sensitivity analysis, using alternative definitions of SGA and LGA under the percentile method, was undertaken. RESULTS: In multivariable logistic regression, maternal age and parity were associated with LGA (aOR = 1.05, CI = 1.00, 1.09) and (aOR = 1.31, CI = 1.09, 1.58). Maternal overweight and obesity were strongly associated with LGA (aOR = 2.28, CI = 1.47, 3.54) and (aOR = 4.55, CI = 2.85, 7.26), respectively. As parity increased, the odds of delivering SGA babies decreased (aOR = 0.59, CI = 0.42, 0.81) and preterm deliveries were associated with SGA (aOR = 9.46, CI = 5.67, 15.79). The well-known maternal determinants of abnormal birthweight, such as unhealthy lifestyles and poor socioeconomic factors, were not statistically significant in this Swedish setting. CONCLUSIONS: The main findings suggest that multiparity, maternal pre-pregnancy overweight and obesity are strong determinants for LGA babies. Public health interventions should address modifiable risk factors, especially maternal overweight and obesity. These findings suggest that overweight and obesity is an emerging public health threat for newborn health. This might also result in the intergenerational transfer of overweight and obesity. These are important messages for public health policy and decision making.

Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial.

CONTEXT: Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAA receptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models. OBJECTIVE: The objective was to test whether inhibition of allopregnanolone by treatment with the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD). The pharmacokinetic parameters of UC1010 when given as a subcutaneous injection were measured in healthy women prior to the study in women with PMDD. DESIGN: This was an explorative randomized, double-blind, placebo-controlled study. SETTING: Swedish multicentre study with 10 centers. PARTICIPANTS: Participants were 26 healthy women in a pharmacokinetic phase I study part, and 126 women with PMDD in a phase II study part. Diagnosis followed the criteria for PMDD in DSM-5 using Daily Record of Severity of Problems (DRSP) and Endicott's algorithm. INTERVENTION: Subjects were randomized to treatment with UC1010 (10 or 16mg) subcutaneously every second day during the luteal phase or placebo during one menstrual cycle. OUTCOME MEASURES: The primary outcome measure was the sum of all 21 items in DRSP (Total DRSP score). Secondary outcomes were Negative mood score i.e. the ratings of the 4 key symptoms in PMDD (anger/irritability, depression, anxiety and lability) and impairment (impact on daily life). RESULTS: 26 healthy women completed the pharmacokinetic phase I study and the dosing in the following trial was adjusted according to the results. 106 of the 126 women completed the phase II study. Within this group, a significant treatment effect with UC1010 compared to placebo was obtained for the Total DRSP score (p=0.041) and borderline significance (p=0.051) for the sum of Negative mood score. Nineteen participants however showed symptoms during the follicular phase that might be signs of an underlying other conditions, and 27 participants had not received the medication as intended during the symptomatic phase. Hence, to secure that the significant result described above was not due to chance, a post hoc sub-group analysis was performed, including only women with pure PMDD who completed the trial as intended (n=60). In this group UC1010 reduced Total DRSP scores by 75% compared with 47% following placebo; the effect size 0.7 (p=0.006), and for sum of Negative mood score (p=0.003) and impairment (p=0.010) with the effect size 0.6. No severe adverse events were reported during the treatment and safety parameters (vital signs and blood chemistry) remained normal during the study. CONCLUSIONS: This explorative study indicates promising results for UC1010 as a potential treatment for PMDD. The effect size was comparable to that of SSRIs and drospirenone containing oral contraceptives. UC1010 was well tolerated and deemed safe.

Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls-a pilot study.

RATIONALE: In premenstrual dysphoric disorder (PMDD), a condition that afflicts 3-8 % of women in fertile ages, the cyclic recurrence of debilitating mood symptoms is restricted to the luteal phase of the menstrual cycle. The progesterone metabolite allopregnanolone is produced by the corpus luteum, and circulating levels are reflected in the brain. Allopregnanolone is a modulator of the GABAA receptor, enhancing the effect of γ-aminobutyric acid (GABA). Previous studies have demonstrated different sensitivity to other GABAA receptor agonists, i.e., benzodiazepines, alcohol, and pregnanolone, in PMDD patients compared to controls. OBJECTIVES: This study aimed to investigate the sensitivity to intravenous allopregnanolone over the menstrual cycle in PMDD patients. METHODS: Allopregnanolone, 0.05 mg/kg, was administered intravenously once in the mid-follicular and once in the luteal phase of the menstrual cycle to 10 PMDD patients and 10 control subjects. The saccadic eye velocity (SEV) was recorded by electrooculography as a measurement of functional GABAA receptor activity, at baseline and repeatedly after the injection. A mixed model was used to analyze data. RESULTS: There was a highly significant group × phase interaction in the SEV response to allopregnanolone (F(1,327.489) = 12.747, p < 0.001). In the PMDD group, the SEV response was decreased in the follicular phase compared to the luteal phase (F(1,168) = 7.776, p = 0.006), whereas in the control group, the difference was opposite during the menstrual cycle (F(1,158.45) = 5.70, p = 0.018). CONCLUSIONS: The effect of exogenous allopregnanolone is associated with menstrual cycle phase in PMDD patients and in controls. The results suggest an altered sensitivity to allopregnanolone in PMDD patients.

Allopregnanolone, a GABAA receptor agonist, decreases gonadotropin levels in women. A preliminary study.

Animal studies suggest regulatory effects on the hypothalamic-pituitary-gonad axis by allopregnanolone, an endogenous gamma-aminobutyric acid A (GABA(A)) receptor agonist. Elevated levels of allopregnanolone in women with hypothalamic amenorrhea have been seen. Isoallopregnanolone is an isomer to allopregnanolone, but without GABA(A) receptor effects. The purpose of this study was to investigate effects of allopregnanolone and isoallopregnanolone on gonadotropin levels in healthy women of fertile age. Ten women were given allopregnanolone and five women isoallopregnanolone intravenously in follicular phase. Repeated blood samples were drawn during the test day. Main outcomes were changes in serum levels of follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, and progesterone. Serum-FSH decreased between 5 and 105 min after the allopregnanolone injection (F(16,144)=2.18, p=0.008). Serum-LH was reduced between 5 and 35 min following the allopregnanolone injection (F(16,144)=2.63, p=0.001). Serum-oestradiol and -progesterone were not significantly changed after allopregnanolone injections. No effect on gonadotropin levels were seen after administration of isoallopregnanolone. Allopregnanolone reduces FSH and LH levels in women and the effect might be mediated via a specific GABA(A) receptor activation since isoallopregnanolone lacked this effect. Although the number of women was small, the results suggest a regulatory mechanism on the hypothalamic-pituitary-gonadal axis by allopregnanolon.

Pharmacokinetic and behavioral effects of allopregnanolone in healthy women.

RATIONALE: The behavioral effects of allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) in women are not known. OBJECTIVE: Allopregnanolone, a neuroactive steroid secreted by the mammalian ovary, exerts its anesthetic, anxiolytic, and sedative/hypnotic effects through potentiation of GABAA receptors. The purpose of this study was to evaluate the behavioral effects of allopregnanolone in healthy women. METHODS: Ten healthy women were given three increasing intravenous doses of allopregnanolone in the follicular phase of the menstrual cycle. Saccadic eye movement parameters and visual analogue scales of sedation were used to evaluate the behavioral response of allopregnanolone. Repeated blood samples for analyses of allopregnanolone were drawn throughout the study day. RESULTS: Exogenously administered allopregnanolone decreases saccadic eye movement parameters and increases subjective ratings of sedation that correlate with increased serum concentrations of this neuroactive steroid. CONCLUSION: The behavioral effects of allopregnanolone are similar to that of its 5beta-stereoisomer, pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one). Apart from fatigue and mild nausea, allopregnanolone given in a cumulative dose of 0.09 mg/kg did not have any adverse effects.