Hany Abdel-Aleem

WHO multicentre randomised trial of misoprostol in the management of the third stage of labour

BACKGROUND Postpartum haemorrhage is a leading cause of maternal morbidity and mortality. Active management of the third stage of labour, including use of a uterotonic agent, has been shown to reduce blood loss. Misoprostol (a prostaglandin E1 analogue) has been suggested for this purpose because it has strong uterotonic effects, can be given orally, is inexpensive, and does not need refrigeration for storage. We did a multicentre, double-blind, randomised controlled trial to determine whether oral misoprostol is as effective as oxytocin during the third stage of labour. METHODS In hospitals in Argentina, China, Egypt, Ireland, Nigeria, South Africa, Switzerland, Thailand, and Vietnam, we randomly assigned women about to deliver vaginally to receive 600 microg misoprostol orally or 10 IU oxytocin intravenously or intramuscularly, according to routine practice, plus corresponding identical placebos. The medications were administered immediately after delivery as part of the active management of the third stage of labour. The primary outcomes were measured postpartum blood loss of 1000 mL or more, and the use of additional uterotonics without an unacceptable level of side-effects. We chose an upper limit of a 35% increase in the risk of blood loss of 1000 mL or more as the margin of clinical equivalence, which was assessed by the confidence interval of the relative risk. Analysis was by intention to treat. FINDINGS 9264 women were assigned misoprostol and 9266 oxytocin. 37 women in the misoprostol group and 34 in the oxytocin group had emergency caesarean sections and were excluded. 366 (4%) of women on misoprostol had a measured blood loss of 1000 mL or more, compared with 263 (3%) of those on oxytocin (relative risk 1.39 [95% CI 1.19-1.63], p<0.0001). 1398 (15%) women in the misoprostol group and 1002 (11%) in the oxytocin group required additional uterotonics (1.40 [1.29-1.51], p<0.0001). Misoprostol use was also associated with a significantly higher incidence of shivering (3.48 [3.15-3.84]) and raised body temperature (7.17 [5.67-9.07]) in the first hour after delivery. INTERPRETATION 10 IU oxytocin (intravenous or intramuscular) is preferable to 600 microg oral misoprostol in the active management of the third stage of labour in hospital settings where active management is the norm.

Causes of stillbirths and early neonatal deaths: data from 7993 pregnancies in six developing countries

OBJECTIVE To report stillbirth and early neonatal mortality and to quantify the relative importance of different primary obstetric causes of perinatal mortality in 171 perinatal deaths from 7993 pregnancies that ended after 28 weeks in nulliparous women. METHODS A review of all stillbirths and early newborn deaths reported in the WHO calcium supplementation trial for the prevention of pre-eclampsia conducted at seven WHO collaborating centres in Argentina, Egypt, India, Peru, South Africa and Viet Nam. We used the Baird-Pattinson system to assign primary obstetric causes of death and classified causes of early neonatal death using the International classification of diseases and related health problems, Tenth revision (ICD-10). FINDINGS Stillbirth rate was 12.5 per 1000 births and early neonatal mortality rate was 9.0 per 1000 live births. Spontaneous preterm delivery and hypertensive disorders were the most common obstetric events leading to perinatal deaths (28.7% and 23.6%, respectively). Prematurity was the main cause of early neonatal deaths (62%). CONCLUSIONS Advancements in the care of premature infants and prevention of spontaneous preterm labour and hypertensive disorders of pregnancy could lead to a substantial decrease in perinatal mortality in hospital settings in developing countries.

Effect of Surgical Menopause on Cognitive Functions

To investigate the effect of estrogen deficiency on cognitive function in surgically menopausal women, a prospective study was conducted at the University Hospital in Assiut, Egypt, during the period of July 1997 to August 1999. The study included 35 women subjected to total abdominal hysterectomy and bilateral salpingo-oophorectomy for nonmalignant causes. They were subjected to cognitive assessment by Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) subtests, and measurement of auditory Event-Related Potentials (ERPs) and serial serum estradiol levels determination. Eighteen age- and education-, body-weight- and parity-matched control women were recruited for comparison. A significant decline in MMSE, WMS subtests (digit span, visual memory, logical memory and mental control) and prolongation of P300 of ERP latency was observed in the patient group at 3 and 6 months postoperatively. These changes were not observed in the control group. A significant correlation was found between serum estradiol level and mental control subtest score and P300 latency in patients preoperatively. Patients who had a drop of estrogen level >50% had more cognitive function decline. Rapid decline in estrogen level following surgical menopause was associated with a deleterious effect on cognitive function. Such observations may contribute to more understanding of the age-related cognitive decline in females.

Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial

BACKGROUND Active management of the third stage of labour reduces the risk of post-partum haemorrhage. We aimed to assess whether controlled cord traction can be omitted from active management of this stage without increasing the risk of severe haemorrhage. METHODS We did a multicentre, non-inferiority, randomised controlled trial in 16 hospitals and two primary health-care centres in Argentina, Egypt, India, Kenya, the Philippines, South Africa, Thailand, and Uganda. Women expecting to deliver singleton babies vaginally (ie, not planned caesarean section) were randomly assigned (in a 1:1 ratio) with a centrally generated allocation sequence, stratified by country, to placental delivery with gravity and maternal effort (simplified package) or controlled cord traction applied immediately after uterine contraction and cord clamping (full package). After randomisation, allocation could not be concealed from investigators, participants, or assessors. Oxytocin 10 IU was administered immediately after birth with cord clamping after 1-3 min. Uterine massage was done after placental delivery according to local policy. The primary (non-inferiority) outcome was blood loss of 1000 mL or more (severe haemorrhage). The non-inferiority margin for the risk ratio was 1·3. Analysis was by modified intention-to-treat, excluding women who had emergency caesarean sections. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN 12608000434392. FINDINGS Between June 1, 2009, and Oct 30, 2010, 12,227 women were randomly assigned to the simplified package group and 12,163 to the full package group. After exclusion of women who had emergency caesarean sections, 11,861 were in the simplified package group and 11,820 were in the full package group. The primary outcome of blood loss of 1000 mL or more had a risk ratio of 1·09 (95% CI 0·91-1·31) and the upper 95% CI limit crossed the pre-stated non-inferiority margin. One case of uterine inversion occurred in the full package group. Other adverse events were haemorrhage-related. INTERPRETATION Although the hypothesis of non-inferiority was not met, omission of controlled cord traction has very little effect on the risk of severe haemorrhage. Scaling up of haemorrhage prevention programmes for non-hospital settings can safely focus on use of oxytocin. FUNDING United States Agency for International Development and UN Development Programme/UN Population Fund/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research.

Making stillbirths count, making numbers talk - Issues in data collection for stillbirths

BackgroundStillbirths need to count. They constitute the majority of the worlds perinatal deaths and yet, they are largely invisible. Simply counting stillbirths is only the first step in analysis and prevention. From a public health perspective, there is a need for information on timing and circumstances of death, associated conditions and underlying causes, and availability and quality of care. This information will guide efforts to prevent stillbirths and improve quality of care.DiscussionIn this report, we assess how different definitions and limits in registration affect data capture, and we discuss the specific challenges of stillbirth registration, with emphasis on implementation. We identify what data need to be captured, we suggest a dataset to cover core needs in registration and analysis of the different categories of stillbirths with causes and quality indicators, and we illustrate the experience in stillbirth registration from different cultural settings. Finally, we point out gaps that need attention in the International Classification of Diseases and review the qualities of alternative systems that have been tested in low- and middle-income settings.SummaryObtaining high-quality data will require consistent definitions for stillbirths, systematic population-based registration, better tools for surveys and verbal autopsies, capacity building and training in procedures to identify causes of death, locally adapted quality indicators, improved classification systems, and effective registration and reporting systems.

Misoprostol as an adjunct to standard uterotonics for treatment of post-partum haemorrhage: a multicentre, double-blind randomised trial

BACKGROUND Post-partum haemorrhage is a leading cause of global maternal morbidity and mortality. Misoprostol, a prostaglandin analogue with uterotonic activity, is an attractive option for treatment because it is stable, active orally, and inexpensive. We aimed to assess the effectiveness of misoprostol as an adjunct to standard uterotonics compared with standard uterotonics alone for treatment of post-partum haemorrhage. METHODS Women delivering vaginally who had clinically diagnosed post-partum haemorrhage due to uterine atony were enrolled from participating hospitals in Argentina, Egypt, South Africa, Thailand, and Vietnam between July, 2005, and August, 2008. Computer-generated randomisation was used to assign women to receive 600 microg misoprostol or matching placebo sublingually; both groups were also given routine injectable uterotonics. Allocation was concealed by distribution of sealed and sequentially numbered treatment packs in the order that women were enrolled. Providers and women were masked to treatment assignment. The primary outcome was blood loss of 500 mL or more within 60 min after randomisation. Analysis was by intention to treat. This study is registered, number ISRCTN34455240. FINDINGS 1422 women were assigned to receive misoprostol (n=705) or placebo (n=717). The proportion of women with blood loss of 500 mL or more within 60 min was similar between the misoprostol group (100 [14%]) and the placebo group (100 [14%]; relative risk 1.02, 95% CI 0.79-1.32). In the first 60 min, an increased proportion of women on misoprostol versus placebo, had shivering (455/704 [65%] vs 230/717 [32%]; 2.01, 1.79-2.27) and body temperature of 38 degrees C or higher (303/704 [43%] vs 107/717 [15%]; 2.88, 2.37-2.50). INTERPRETATION Findings from this study do not support clinical use of 600 microg sublingual misoprostol in addition to standard injectable uterotonics for treatment of post-partum haemorrhage. FUNDING Bill & Melinda Gates Foundation, and UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.

The pharmacokinetics of the prostaglandin E1 analogue misoprostol in plasma and colostrum after postpartum oral administration.

OBJECTIVE To study pharmacokinetics of prostaglandin E1 analogue, misoprostol in plasma and colostrum after postpartum oral administration. STUDY DESIGN Twenty women received 600 microg doses of misoprostol orally after delivery. Plasma levels of the principal metabolite, misoprostol acid, were measured at 2, 10, 20, 30, 40, 50, 60, 90, 120, 180, 240 and 300 min (48 samples). Colostrum was expressed from the breasts to measure misoprostol acid at 60, 120, 180, 240, and 300 min (24 samples). Assay was done using isotope dilution gas chromatography (GC)/negative ion chemical ionisation mass spectrometry (MS). RESULTS The plasma concentration of misoprostol acid rose quickly. Two minutes after oral administration its mean level was 91.5 pg/ml, peaked at 20 min (344 pg/ml), then fell steeply by 120 min (27.8 pg/ml) and remained low for the duration of the study. Misoprostol acid in colostrum reached maximum concentration of 20.9 pg/m within 1h after oral administration. It then declined gradually to 17.8 pg/ml at 2h, 2.8 pg/ml at 4h and to <1 pg/ml at 5h. Areas under misoprostol concentration versus time curves up to 5h were 290.1 pgh/ml in the plasma and 51.4 pgh/ml in colostrum, respectively. CONCLUSION Misoprostol acid is secreted in colostrum within 1h of oral administration of 600 microg of misoprostol; the pharmacokinetics of misoprostol after oral administration during postpartum is similar to that of other pregnancy periods.

Management of severe postpartum hemorrhage with misoprostol

This descriptive prospective study explored the use of rectal misoprostol in the treatment of severe cases of atonic postpartum hemorrhage not responding to oxytocin or methergine. A total of 18 cases of atonic postpartum hemorrhage at the Department of Obstetrics and Gynecology Assiut University Hospital Assiut Egypt were studied between May and December 1999. It is noted that only 5 women were delivered by cesarean section while 13 were delivered vaginally. Among the 18 cases of severe atonic postpartum hemorrhage not responding to oxytocin methylergometrine and enzaprost 16 cases responded promptly to misoprostol (88.2%). The response to misoprostol appeared within 30 seconds to 3 minutes (mean = 1.4 minutes). This finding indicates that rectal misoprostol is an effective line of treatment in cases of atonic hemorrhage refractory to other drugs. Further study on the pharmacokinetics of rectal misoprostol and a properly designed randomized trial are recommended.

Effectiveness of tranexamic acid on blood loss in patients undergoing elective cesarean section: randomized clinical trial

Abstract Objective: Cesarean section is associated with more blood loss than vaginal delivery. This could increase the risk of morbidity and mortality especially among anemic women. The objective of the trial is to assess the possible effect of tranexamic acid on blood loss during and after elective cesarean section. Methods: We conducted a randomized controlled trial at Womens Health Hospital, Assiut University, Assiut, Egypt. All pregnant women with singleton fetus planned to have elective cesarean section at ≥37 wks gestation were randomized to receive 1 g tranexamic acid slowly intravenously over 10 min before elective cesarean section group or not. Blood loss was measured during and for two hours after operation. Any side effects, complications, medications, changes in vital signs and duration of hospital stay were recorded. This study is registered, number ACTRN12612000313831. Results: Seven hundred and forty women were randomized (373 in study group and 367 in control group). Mean total blood loss was 241.6 (SE 6.77) ml in the tranexamic acid group versus 510 (SE 7.72) ml in the control group. The mean drop in hematocrit and hemoglobin levels were statistically significantly lower in the tranexamic acid group than in the control group. There were no statistically or clinically significant differences in other outcomes. Conclusions: Pre-operative use of tranexamic acid is associated with reduced blood loss during and after elective cesarean section. This could be of benefit for anemic women or those who refuse blood transfusion.

Uterine massage to reduce postpartum hemorrhage after vaginal delivery.

To determine the effectiveness of sustained uterine massage started before delivery of the placenta in reducing postpartum hemorrhage.