The effectiveness of the levonorgestrel-releasing intrauterine system in menorrhagia: a systematic review

Objective: To determine whether the levonorgestrel-releasing intrauterine device (LNG-IUS), licensed at present for contraceptive use, may reduce menstrual blood loss with few side effects. If effective, surgery could be avoided with consequent resource savings. Methods: A systematic review addressing the effectiveness and cost effectiveness of the LNG-IUS for menorrhagia was undertaken. Results: Five controlled trials and five case series were found which measured menstrual blood loss. Nine studies recorded statistically significant average menstrual blood loss reductions with LNG-IUS (range 74%–97%). Another showed reduction in menstrual disturbance score. The LNG-IUS was more effective than tranexamic acid, but slightly less effective than endometrial resection at reducing menstrual blood loss. In one study, 64% of women cancelled surgery at six months, compared with 14% of control group women. In another, 82% were taken off surgical waiting lists at one year. No cost effectiveness studies were found. Discussion: Small studies of moderate quality indicate the LNG-IUS is an effective treatment for menorrhagia. Costs may be less than for tranexamic acid in primary and secondary care. Although its use may reduce surgical waiting lists, cost effectiveness assessment requires longer follow up. Conclusion: Effectiveness and cost effectiveness relative to other treatments and the effect on surgical waiting lists can only be established in larger trials measuring patient-centred outcomes in women with menorrhagia.

Lactation in Australian women : the effect of oral contraceptives on the vitamin and trace element content of breast milk

The aim of this project was to investigate the effects of oral contraceptives on the nutrient composition of breast milk. The design of the study also allowed the effects of stage of lactation and maternal diet on milk composition to be observed. A prospective study was designed to measure maternal dietary intake and vitamin and trace element concentration in milk and plasma. Vitamin A, ascorbic acid and iron, copper, zinc, manganese, selenium, cobalt, chromium, rubidium and caesium were measured. Two groups of women participated, oral contraceptive users and controls. Fasting milk and blood samples and 24-hour food records were collected from the women once a week for 20 weeks commencing 3-8 weeks post-partum, and 1-2 weeks before they began to take oral contraceptives. Fifteen women participated in the study; 5 took progestogen-only oral contraceptives, 1 took an oestrogen-progestogen oral contraceptive and 9 acted as controls. Progestogen-only oral contraceptives did not affect the milk or plasma concentration of the vitamins and trace elements measured. As only 1 subject took an oestrogen-progestogen preparation no conclusion could be drawn as to its effect. The mean milk and plasma concentration of all nutrients studied did not change significantly with the progression of lactation, with the exception of iron and zinc. The mean milk iron concentration was significantly higher at 16 weeks post-partum than at 8 and 23 weeks post-partum. The mean milk zinc concentration was significantly lower at 23 weeks post-partum than at 8 and 16 weeks post-partum. The infants1 mean estimated daily intakes of ascorbic acid and vitamin A from breast milk were above the U.S. and British Recommended Dietary Allowance for those vitamins. However, their mean estimated intakes of iron, zinc, copper, manganese and selenium were well below the U.S. recommendations. Effects of the maternal dietary intake on milk and plasma composition were variable. Implications of these findings have been discussed.

Debating the evidence : oral contraceptives containing drospirenone and risk of blood clots

Skepticism is an essential quality in science. We doubt, re-examine and demand the highest quality of evidence. However, sometimes this puts us in an awkward situation. How much evidence do we need before we act? This dilemma is a constant problem in drug safety. Treatment decisions are always a balance of risks and benefits and there may be a paucity of evidence about rare or very rare adverse events.

Cardiovascular disease risk in the offspring of diabetic women: the impact of the intrauterine environment

The incidence of gestational diabetes is increasing worldwide, exposing large numbers of infants to hyperglycaemia whilst in utero. This exposure may have a long-term negative impact on the cardiovascular health of the offspring. Novel methods to assess cardiovascular status in the neonatal period are now available—including measuring arterial intima-media thickness and retinal photography. These measures will allow researchers to assess the relative impact of intrauterine exposures, distinguishing these from genetic or postnatal environmental factors. Understanding the long-term impact of the intrauterine environment should allow the development of more effective health policy and interventions to decrease the future burden of cardiovascular disease. Initiating disease prevention aimed at the developing fetus during the antenatal period may optimise community health outcomes.

Exercise as an intervention to improve metabolic outcomes after intrauterine growth restriction

Individuals born after intrauterine growth restriction (IUGR) are at an increased risk of developing diabetes in their adult life. IUGR impairs β-cell function and reduces β-cell mass, thereby diminishing insulin secretion. IUGR also induces insulin resistance, with impaired insulin signaling in muscle in adult humans who were small for gestational age (SGA) and in rodent models of IUGR. There is epidemiological evidence in humans that exercise in adults can reduce the risk of metabolic disease following IUGR. However, it is not clear whether adult IUGR individuals benefit to the same extent from exercise as do normal-birth-weight individuals, as our rat studies suggest less of a benefit in those born IUGR. Importantly, however, there is some evidence from studies in rats that exercise in early life might be able to reverse or reprogram the long-term metabolic effects of IUGR. Studies are needed to address gaps in current knowledge, including determining the mechanisms involved in the reprogramming effects of early exercise in rats, whether exercise early in life or in adulthood has similar beneficial metabolic effects in larger animal models in which insulin resistance develops after IUGR. Human studies are also needed to determine whether exercise training improves insulin secretion and insulin sensitivity to the same extent in IUGR adults as in control populations. Such investigations will have implications for customizing the recommended level and timing of exercise to improve metabolic health after IUGR.

Midwifery: a profession in transition

This paper presents the findings of a pilot study carried out in one regional center in Queensland, Australia. The study aimed to develop a snapshot image of teenage mothers. Of the thirty mothers who participated; just over half (16/30; 53%) reported using contraceptives, less than a third (8/30; 27%) used condoms to protect themselves from STDs and the majority (23/30; 77%) said their pregnancy was unplanned. Despite this, 16 (53%) attended prenatal classes, 16 (53%) breast-fed their infants and 27 (90%) were satisfied with motherhood. On average the fathers were almost four years older than the mother were (range 17 to 29 years), most fathers (23/30; 77%) were not teenagers themselves and only 11 (37%) were resident fathers following the birth of the baby. Exploratory analysis suggests that the fathers were significantly older than the teenage mothers were (t=−6.73, df 29, p=0.0001). Although these preliminary results are similar to those reported in the American literature further research is needed to confirm if the findings presented are representative of teenage mothers in Australia. While we await the results of future studies, practitioners are encouraged to continue to educate young women about appropriate and safer sexual practices.

Drug-herb interactions: eliminating toxicity with hard drug design.

By searching the literatures, it was found that a total of 32 drugs interacting with herbal medicines in humans. These drugs mainly include anticoagulants (warfarin, aspirin and phenprocoumon), sedatives and antidepressants (midazolam, alprazolam and amitriptyline), oral contraceptives, anti-HIV agents (indinavir, ritonavir and saquinavir), cardiovascular drug (digoxin), immunosuppressants (cyclosporine and tacrolimus) and anticancer drugs (imatinib and irinotecan). Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (PgP) and many of which have narrow therapeutic indices. However, several drugs including acetaminophen, carbamazepine, mycophenolic acid, and pravastatin did not interact with herbs. Both pharmacokinetic (e.g. induction of hepatic CYPs and intestinal PgP) and/or pharmacodynamic mechanisms (e.g. synergistic or antagonistic interaction on the same drug target) may be involved in drug-herb interactions, leading of altered drug clearance, response and toxicity. Toxicity arising from drug-herb interactions may be minor, moderate, or even fatal, depending on a number of factors associated with the patients, herbs and drugs. Predicting drug-herb interactions, timely identification of drugs that interact with herbs, and therapeutic drug monitoring may minimize toxic drug-herb interactions. It is likely to predict pharmacokinetic herb-drug interactions by following the pharmacokinetic principles and using proper models that are used for predicting drug-drug interactions. Identification of drugs that interact with herbs can be incorporated into the early stages of drug development. A fourth approach for circumventing toxicity arising from drug-herb interactions is proper design of drugs with minimal potential for herbal interaction. So-called ”hard drugs” that are not metabolized by CYPs and not transported by PgP are believed not to interact with herbs due to their unique pharmacokinetic properties. More studies are needed and new approached are required to minimize toxicity arising from drug-herb interactions.

Herb-drug interactions: a literature review

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.
Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.
Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).
In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Maternal creatine : does it reach the fetus and improve survival after an acute hypoxic episode in the spiny mouse (Acomys cahirinus)?

Objective
We hypothesized that elevating creatine in the maternal diet would reach fetal and placental tissues and improve fetal survival after acute hypoxia at birth.
Study Design
Pregnant spiny mice were fed a control or 5% creatine-supplemented diet from day 20 of gestation (term, approximately 39 days). On days 37-38, intrauterine hypoxia was induced by placement of the isolated uterus in a saline solution bath for 7.5-8 minutes, after which fetuses were expelled from the uterus and resuscitation was attempted by manual palpation of the chest. Total creatine content (creatine + phosphocreatine) of placental, fetal, and maternal organs was measured.
Results
The maternal creatine diet significantly increased total creatine content in the placenta, fetal brain, heart, liver, and kidney and increased the capacity of offspring to survive birth hypoxia. Maternal creatine improved postnatal growth after birth hypoxia.
Conclusion
This study provides evidence that creatine has potential as a prophylactic therapy for pregnancies that are classified as high risk for fetal hypoxia.