Exosomal microRNA profiling in early and late onset preeclamptic pregnant women reflects pathophysiology.

Background: Preeclampsia is the leading cause of maternal and fetal mortality due to the inability to diagnose and treat the disorder early in pregnancy. This is attributed to the complex pathophysiology and unknown etiology of the disorder, which is modulated by several known and unknown factors. Exosomes have recently been implicated as possible mediators of the pathogenesis of preeclampsia, with, however, no evidence linking these nanovesicles to the pathophysiology of preeclampsia and its subtypes. Methods: To better understand the pathophysiological role of exosomes in preeclampsia, we have analyzed the exosomal microRNA in early and late onset preeclamptic women in comparison to their gestationally matched normotensive controls using Digital Direct Detection (NanoString Technologies). Results: For the first time, distinct exosomal microRNA signatures in early and late onset preeclampsia have been identified. Moreover, these signatures indicate that exosomes are involved in key pathological features associated with preeclampsia and differentiate between the subtypes. Conclusion: This study forms the basis for the diagnostic and functional validation of the identified signatures as biomarkers of preeclampsia and its subtypes.

The costs and cost effectiveness of providing first-trimester, medical and surgical safe abortion services in KwaZulu-Natal Province, South Africa.

BACKGROUND: Despite a liberal abortion law, access to safe abortion services in South Africa is challenging for many women. Medication abortion was introduced in 2013, but its reach remains limited. We aimed to estimate the costs and cost effectiveness of providing first-trimester medication abortion and manual vacuum aspiration (MVA) services to inform planning for first-trimester service provision in South Africa and similar settings. METHODS: We obtained data on service provision and outcomes from an operations research study where medication abortion was introduced alongside existing MVA services in public hospitals in KwaZulu-Natal province. Clinical data were collected through interviews with first-trimester abortion clients and summaries completed by nurses performing the procedures. In parallel, we performed micro-costing at three of the study hospitals. Using a model built in Excel, we estimated the average cost per medical and surgical procedure and determined the cost per complete abortion performed. Results are presented in 2015 US dollars. RESULTS: A total of 1,129 women were eligible for a first trimester abortion at the three study sites. The majority (886, 78.5%) were eligible to choose their abortion procedure; 94.1% (n = 834) chose medication abortion. The total average cost per medication abortion was $63.91 (52.32-75.51). The total average cost per MVA was higher at $69.60 (52.62-86.57); though the cost ranges for the two procedures overlapped. Given average costs, the cost per complete medication abortion was lower than the cost per complete MVA despite three (0.4%) medication abortion women being hospitalized and two (0.3%) having ongoing pregnancies at study exit. Personnel costs were the largest component of the total average cost of both abortion methods. CONCLUSION: This analysis supports the scale-up of medication abortion alongside existing MVA services in South Africa. Women can be offered a choice of methods, including medication abortion with MVA as a back-up, without increasing costs.

Severe hypertension in pregnancy: Using dynamic checklists to save lives.

Severe hypertension is a major cause of morbidity and mortality. The South African Saving Mothers report (2011 - 2013) indicates that cerebral injury due to severe hypertension is resulting in avoidable maternal deaths. This demands that management of severe hypertension in pregnancy needs to be improved. A rapid-acting antihypertensive is recommended for the initial management of severe hypertension during pregnancy. A single dose of a rapid-acting agent may be ineffective, in which case incremental doses of the same medication or another antihypertensive may be required for adequate blood pressure control. To ensure that appropriate antihypertensives at the correct doses are administered, the use of a guideline in a dynamic checklist format is advocated and discussed in this article. It is envisaged that the use of dynamic checklists will be valuable to all healthcare professionals providing care during pregnancy and the puerperium.

Clinical awareness for health care professionals: Fatal encephalopathy complicating persistent vomiting in pregnancy.

Women with persistent vomiting during pregnancy need early referral to appropriate health facilities. Delayed referral and inappropriate management may lead to metabolic encephalopathy from a variety of causes, including electrolyte derangements or thiamine deficiency (Wernicke's encephalopathy) (WE). We present a case of persistent vomiting in pregnancy in which there was delayed referral, inappropriate treatment and failure to associate neurological signs such as terminal neck stiffness with WE, resulting in poor fetomaternal outcomes. In this report, we discuss the following lessons: (i) the need for early transfer of a patient with persistent vomiting and enigmatic clinical features to a higher healthcare facility; (ii) failure to associate neurological signs with complications of hyperemesis gravidarum/WE; (iii) lack of thiamine supplementation; and (iv) the advantages of magnetic resonance imaging over a computed tomography scan in the diagnosis of WE.

Introducing medication abortion into public sector facilities in KwaZulu-Natal, South Africa: an operations research study.

OBJECTIVES: Examine the feasibility of introducing mifepristone-misoprostol medication abortion into existing public sector surgical abortion services in KwaZulu-Natal, South Africa. STUDY DESIGN: Cohort study of women offered medication or surgical abortion in a larger medication abortion introduction study. The sample included 1167 women seeking first-trimester abortion at four public sector facilities; 923 women at ≤9 weeks' gestation were eligible for medication abortion. Women who chose medication abortion took 200 mg of mifepristone orally at the facility and 800 mcg of misoprostol buccally (or vaginally if they anticipated or experienced problems with buccal administration) 48 h later at home, based on international research and global safe abortion guidelines. Women who chose surgical abortion received 600 mg of misoprostol sublingually or vaginally on the day of their procedure followed by manual vacuum aspiration 4 h later. Main outcome measures included proportion of eligible women who chose each method, proportion with complete abortion and proportion reporting adverse events. RESULTS: Ninety-four percent of eligible women chose medication abortion. No adverse events were reported by women who chose surgical abortion; 3% of women in the medication abortion group reported adverse events and 0.4% reported a serious adverse event. Seventy-six percent of women received a family planning method at the facility where their received their abortion, with no difference based on procedure type. Medication abortion patients were significantly more likely to report they would choose this method again (94% vs. 78%, p<.001) and recommend the method to a friend (98% vs. 84%, p<.001). CONCLUSIONS: Medication abortion was successfully introduced with low and acceptable rates of adverse events; most women at study facilities chose this option. IMPLICATIONS: Mifepristone-misoprostol medication abortion was successfully integrated into public sector surgical abortion services in South Africa and was chosen by a large majority of women who were eligible and offered choice of early termination method; access to medication abortion should be expanded in South Africa and other similar settings.

The role of angiogenic, anti-angiogenic and vasoactive factors in pre-eclamptic African women: early- versus late-onset pre-eclampsia.

The pathogenesis and aetiology of pre-eclampsia (PE) is still unclear. We investigated the role of angiogenic, antiangiogenic and vasoactive factors in black South African women with early- and late-onset PE. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), soluble vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels were determined using the ELISA technique, and placental mRNA expression levels of sFlt-1, VEGF, PlGF and AT1 receptors were determined using real-time PCR. Serum sFlt-1 levels were significantly elevated and PlGF significantly reduced in early-onset PE compared to the normotensive group. Placental VEGF mRNA expression levels were significantly reduced in the late-onset preeclamptic group compared with the normotensives. The placental mRNA expression of AT1 receptor in the late-onset pre-eclamptic group was relatively raised compared to the normotensives, suggesting hypersensitivity to pressor agents. We believe that the excess of serum sFlt-1 and reduced VEGF and PlGF levels favour an anti-angiogenic state and endothelial dysfunction leading to PE, and that the aetiology and pathogenesis of early- and late-onset PE differ.

The Profile of Maternal Deaths in a District Hospital: A Five-Year Review of Maternal Deaths from 2006-2010

Objectives: The objectives were to determine the clinical and demographic profile of maternal deaths; determine the most common primary causes of maternal deaths at district hospital level; compare the causes of deaths at district hospital; provincial and national level; and to investigate the quality of care that was provided to maternal deaths patients and to make recommendations.Design: The design was a cross-sectional retrospective chart review.Setting and subjects: Subjects were all reported maternal deaths between January 2006 and December 2010 at Northdale Hospital; KwaZulu-Natal.Outcome measures: Outcome measures were the common characteristics and causes of maternal deaths; avoidable maternal deaths and quality of care.Results: The mean age of the 61 maternal deaths was 28 years. Thirty-three patients attended antenatal clinics. Of these; 57.6 booked at ? 20th week. Of the 28 (45.9) who died in the postpartum period; seven delivered at home and three died of anaesthetic complications. Thirty-nine patients (63.9) tested positive for human immunodeficiency virus. Only 10 were on highly active antiretroviral therapy. The five leading causes of deaths were non-pregnancy-related sepsis; miscarriage; acute collapse; pregnancy-related sepsis and anaesthetic complications. Thirty patients (49.3) received substandard care.Conclusion: The profile of maternal deaths at this district hospital differs from the national profile published in 2005-2007 Saving Mothers Report. While there was an increase in maternal deaths at national level; maternal death numbers decreased at this district hospital. Non-pregnancy-related sepsis remained the leading cause of deaths at national and facility level; but the other four major causes at the hospital level differed from those at the national level

Evaluation of standard and modified severity of illness scores in the obstetric patient.

PURPOSE: To test discrimination and calibration of APACHE-II and SAPS-II risk prediction scores in a cohort of obstetric patients, and to evaluate the effect of modifying these scores for the physiological changes in pregnancy. MATERIALS AND METHODS: A retrospective review of obstetric patients, 12 weeks gestation to 48 hours postpartum, admitted to the ICU for more than 24 hours. APACHE-II and SAPS-II, and versions modified for the physiological changes of pregnancy, were evaluated by receiver operating characteristic (ROC) curves and standardized mortality ratios (SMR). Multivariable analysis identified other parameters associated with mortality. RESULTS: Data were obtained from 332 patients from 5 countries, with a mortality rate of 12%. Mean (± SD) APACHE-II score was 16.8 ± 6.1 and SAPS-II score 26.5 ± 15.8. Good discrimination was demonstrated with area under the ROC curves of 0.82 and 0.78 respectively, with no improvement after modification for altered maternal physiology. APACHE-II overestimated mortality, with an SMR of 0.43 (0.52 after including diagnostic weighting) compared with 0.89 for SAPS-II. Bilirubin, albumin and Glasgow Coma Scale were independently associated with mortality. CONCLUSION: APACHE-II and SAPS-II are good discriminators of illness severity and may be valuable for comparing obstetric cohorts, but APACHE-II significantly over-estimates mortality.

Women living with HIV and AIDS: right to prevention, treatment, and health care.

Women living with HIV/AIDS not only bear the burden of this pandemic in under-resourced countries, but are faced with the human rights issues concerning the management of their condition, not only for their own health, but also for prevention of mother-to-child transmission of the virus and infertility investigation. This article tackles the issues of reproductive health rights pertaining to prevention of HIV, and rights regarding HIV testing including the ethical dilemmas associated with "opt in," "opt out," and mandatory testing. Accountability, rights to treatment and travel, and employment issues are also discussed.

Every death counts: use of mortality audit data for decision making to save the lives of mothers, babies, and children in South Africa.

South Africa is one of the few developing countries with a national confidential inquiry into maternal deaths. 164 health facilities obtain audit data for stillbirths and neonatal deaths, and a new audit network does so for child deaths. Three separate reports have been published, providing valuable information about avoidable causes of death for mothers, babies, and children. These reports make health-system recommendations, many of which overlap and are intertwined with the scarcity of progress in addressing HIV/AIDS. The leaders of these three reports have united to prioritise actions to save the lives of South Africa's mothers, babies, and children. The country is off-track for the health-related Millennium Development Goals. Mortality in children younger than 5 years has increased, whereas maternal and neonatal mortality remain constant. This situation indicates the challenge of strengthening the health system because of high inequity and HIV/AIDS. Coverage of services is fairly high, but addressing the gaps in quality and equity is essential to increasing the number of lives saved. Consistent leadership and accountability to address crosscutting health system and equity issues, and to prevent mother-to-child transmission of HIV, would save tens of thousands of lives every year. Audit is powerful, but only if the data lead to action.

HIV in pregnancy.

PURPOSE OF REVIEW: This review discusses recent articles on various aspects of the prevention of mother-to-child transmission during pregnancy and delivery. RECENT FINDINGS: Rapid human immunodeficiency virus (HIV) testing of women in labour whose status is not known allows the prompt treatment of mother and baby to reduce transmission risk. The feared clinical resistance in the mother after treatment with a single dose of nevirapine has been confirmed. Strategies are required to minimize this resistance and allow the use of nevirapine for treatment of the mother. There are new findings of mitochondrial toxicity in babies who have been exposed to anti-retroviral medicines during pregnancy or delivery, but the clinical implications are not clear. Long-term follow-up of exposed children is required. Resource-poor countries are starting to use multiple drugs to further reduce transmission to the infant. These efforts are reducing the rates of transmission to the level found in affluent countries. SUMMARY: Improvements in treatment continue to reduce the risk of HIV transmission from mother to child in resource-poor countries, but subsequent maternal resistance continues to be a problem since treatment for the mother's health is now possible. The long-term effects on the infant are still not understood.

Combined oral contraceptives and cervical cancer.

PURPOSE OF REVIEW: The issue of whether there might be an increased risk of cervical cancer associated with the use of oral contraceptives has been debated for decades. Early studies found a modest association with long-term use. A literature review was performed over the past 3 years, to establish whether there is any new evidence linking cervical cancer with the use of oral contraceptives. RECENT FINDINGS: A new analysis from eight studies conducted by the International Agency for Research on Cancer and a systematic review of cervical cancer and the use of hormonal contraceptives are two recent major epidemiological links strongly suggesting the increased risk of cervical cancer (up to twofold), but only for women who were both long-term users (5 years or more) and who had persistent human papilloma virus infections of the cervix. SUMMARY: These findings seem biologically plausible, but weighing the various risks and benefits, the World Health Organization does not recommend any change in oral contraceptive use or practice.

Methylenetetrahydrofolate reductase gene polymorphisms in black South Africans and the association with preeclampsia.

BACKGROUND: A methylenetetrahydrofolate reductase (MTHFR) polymorphism (1317T --> C) that occurs commonly in black African individuals prompted this study to establish whether this polymorphism, alone or in association with other MTHFR variants, is associated with preeclampsia in black South African women. METHODS: A group of 204 black women with preeclampsia was examined for the 677C --> T, 1298A --> C and 1317T --> C MTHFR polymorphic alleles using standard techniques. Also examined were women with early-onset preeclampsia (n = 67) and gestational hypertension (n = 78). Results were compared with 338 ethnically matched normotensive pregnant women who had normal full-term gestations. RESULTS: No differences in the 677T --> C or 1298A --> C MTHFR alleles were found between the study groups and controls; very few women were homozygous for either variant allele. Significant differences were observed for the 1317T --> C polymorphism: only 39% of preeclamptics were homozygous for the T allele compared with 52% of the control group [p = 0.002; 0.59 (0.42-0.83)]. Heterozygotes occurred significantly more frequently in preeclamptics (51%), compared with controls (41%) [p = 0.019; 1.49 (1.07-2.08)]. Allele frequencies also differed significantly between preeclamptics and controls [p = 0.003; 0.69 (0.53-0.88)]. Allele frequencies in women with gestational hypertension were statistically indistinguishable from those in controls. CONCLUSION: The low frequencies of the 677C --> T and 1298A --> C MTHFR variant alleles in black South Africans imply little or no role for these mutations in preeclampsia in this population group. However, significant differences in the 1317T --> C allele in preeclamptics suggest that the MTHFR gene, or a closely associated gene, may still have some role, as yet undefined, in the pathogenesis of preeclampsia.

Hypertension-related gene polymorphisms in pre-eclampsia, eclampsia and gestational hypertension in Black South African women.

OBJECTIVE: To examine whether polymorphisms in the renin-angiotensin system (RAS) are associated with pregnancy-related hypertensive disorders in a black South African population. DESIGN: The angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen M235T and angiotensin II receptor type 1 1166A<--C polymorphisms were assessed in study groups comprising 204 women with pre-eclampsia, 120 with eclampsia, 67 with early onset pre-eclampsia and 78 with gestational hypertension. METHODS: Using chi analysis, results were compared with those obtained from 338 ethnically matched normotensive pregnant women following normal full term pregnancies. No significant differences in the distribution of any of these polymorphisms were found between patients with pre-eclampsia or eclampsia and the normal control subjects. Patients with gestational hypertension were less frequently homozygous for the ACE insertion polymorphism compared with controls (5 versus 13%, respectively; P = 0.049; odds ratio 0.36 [95% confidence interval (CI) 0.09-1.04]). CONCLUSION: The commonly occurring RAS polymorphisms are not predictive of pre-eclampsia or eclampsia in the Black South African population.

Nitric oxide: does it have an etiological role in pre-eclampsia?

AIM: To determine evidence of nitric oxide (NO) in decidual biopsies and fetal membranes of preeclamptic women. BACKGROUND: Nitric oxide, a potent vasodilator, has been postulated to have a role in the etiology of preeclampsia. Investigations in peripheral blood have led to conflicting results. We therefore decided to study whether immunohistochemically detectable nitric oxide is produced in the decidua and within the fetal membranes. METHODS: Forty-two pregnant women at 28 weeks gestation or more were enrolled. Twenty were normotensive and 22 had preeclampsia. Women with chronic hypertension, diabetes and multiple pregnancies were excluded. Maternal blood samples prior to cesarean section (CS), decidual biopsies during CS, and fetal membrane specimens were obtained. The tissue specimens were fixed immediately (after delivery of the baby and placenta) in formalin, washed, and embedded in paraffin. Immunohistochemical staining for nitric oxide synthases (NOS) I, II, III was performed and reviewed in conjunction with routine hematoxylin and eosin sections, using light microscopy. RESULTS: There was no statistically significant difference in the level of immunostaining of nitric oxide synthases in both normotensive and hypertensive patients. DISCUSSION: The severity of blood pressure did not influence expression of nitric oxide synthases.

Plasminogen activator inhibitor type 1 (PAI1) and platelet glycoprotein IIIa (PGIIIa) polymorphisms in Black South Africans with pre-eclampsia.

BACKGROUND: Association of fibrin abnormalities with pre-eclampsia prompted this study to examine whether polymorphisms in the plasminogen activator inhibitor Type 1 and platelet glycoprotein IIIa genes constitute risk factors for this condition. METHODS: A group of 151 Black Zulu-speaking pre-eclamptics was examined for 4G/5G plasminogen activator inhibitor Type 1 and PlA1/A2 platelet glycoprotein IIIa polymorphic alleles using standard techniques. Results were compared with those found in 217 ethnically matched healthy normotensive pregnant women who had normal full-term gestations. RESULTS: Pre-eclamptic patients had a slightly higher frequency of the 4G plasminogen activator inhibitor Type 1 allele (15%) compared with the controls (12%); this was reflected also in the heterozygote frequency (28% and 22%) for the patients and the controls, respectively. These differences were not significant. Only 2% of this population was found to be homozygous for the 4G allele. No differences were observed in the platelet glycoprotein IIIa polymorphism genotype and allele frequency distribution between the patients and the controls. CONCLUSIONS: Neither the 4G allele of the plasminogen activator inhibitor Type 1 nor the PlA2 allele of the platelet glycoprotein IIIa have any significant role as risk factors in the patho-etiology of pre-eclampsia in Black South Africans, although these genes cannot yet be excluded as contributory to this disorder. It is possible that the underlying causes of pre-eclampsia may vary between different ethnic populations.