Mild to moderate hypertension during pregnancy is common. Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby ...improve the outcome.
To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy.
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2013) and reference lists of retrieved studies.
All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy defined, whenever possible, as systolic blood pressure 140 to 169 mmHg and diastolic blood pressure 90 to 109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days.
Two review authors independently extracted data.
Forty-nine trials (4723 women) were included. Twenty-nine trials compared an antihypertensive drug with placebo/no antihypertensive drug (3350 women). There is a halving in the risk of developing severe hypertension associated with the use of antihypertensive drug(s) (20 trials, 2558 women; risk ratio (RR) 0.49; 95% confidence interval (CI) 0.40 to 0.60; risk difference (RD) -0.10 (-0.13 to -0.07); number needed to treat to harm (NNTH) 10 (8 to 13)) but little evidence of a difference in the risk of pre-eclampsia (23 trials, 2851 women; RR 0.93; 95% CI 0.80 to 1.08). Similarly, there is no clear effect on the risk of the baby dying (27 trials, 3230 women; RR 0.71; 95% CI 0.49 to 1.02), preterm birth (15 trials, 2141 women; RR 0.96; 95% CI 0.85 to 1.10), or small-for-gestational-age babies (20 trials, 2586 women; RR 0.97; 95% CI 0.80 to 1.17). There were no clear differences in any other outcomes.Twenty-two trials (1723 women) compared one antihypertensive drug with another. Alternative drugs seem better than methyldopa for reducing the risk of severe hypertension (11 trials, 638 women; RR (random-effects) 0.54; 95% CI 0.30 to 0.95; RD -0.11 (-0.20 to -0.02); NNTH 7 (5 to 69)). There is also a reduction in the overall risk of developing proteinuria/pre-eclampsia when beta blockers and calcium channel blockers considered together are compared with methyldopa (11 trials, 997 women; RR 0.73; 95% CI 0.54 to 0.99). However, the effect on both severe hypertension and proteinuria is not seen in the individual drugs. Other outcomes were only reported by a small proportion of studies, and there were no clear differences.
It remains unclear whether antihypertensive drug therapy for mild to moderate hypertension during pregnancy is worthwhile.
Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby improve pregnancy outcome. This Cochrane Review is an ...updated review, first published in 2001 and subsequently updated in 2007 and 2014.
To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy.
We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 September 2017), and reference lists of retrieved studies.
All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy, defined as systolic blood pressure 140 to 169 mmHg and/or diastolic blood pressure 90 to 109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days.
Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy.
For this update, we included 63 trials (data from 58 trials, 5909 women), with moderate to high risk of bias overall.We carried out GRADE assessments for the main 'antihypertensive drug versus placebo/no antihypertensive drug' comparison only. Evidence was graded from very low to moderate certainty, with downgrading mainly due to design limitations and imprecision.For many outcomes, trials contributing data evaluated different hypertensive drugs; while we did not downgrade for this indirectness, results should be interpreted with caution.Antihypertensive drug versus placebo/no antihypertensive drug (31 trials, 3485 women)Primary outcomes: moderate-certainty evidence suggests that use of antihypertensive drug(s) probably halves the risk of developing severe hypertension (risk ratio (RR) 0.49; 95% confidence interval (CI) 0.40 to 0.60; 20 trials, 2558 women), but may have little or no effect on the risk of proteinuria/pre-eclampsia (average risk ratio (aRR) 0.92; 95% CI 0.75 to 1.14; 23 trials, 2851 women; low-certainty evidence). Moderate-certainty evidence also shows that antihypertensive drug(s) probably have little or no effect in the risk of total reported fetal or neonatal death (including miscarriage) (aRR 0.72; 95% CI 0.50 to 1.04; 29 trials, 3365 women), small-for-gestational-age babies (aRR 0.96; 95% CI 0.78 to 1.18; 21 trials, 2686 babies) or preterm birth less than 37 weeks (aRR 0.96; 95% CI 0.83 to 1.12; 15 trials, 2141 women).
we are uncertain of the effect of antihypertensive drug(s) on the risk of maternal death, severe pre-eclampsia, or eclampsia, orimpaired long-term growth and development of the baby in infancy and childhood, because the certainty of this evidence is very low. There may be little or no effect on the risk of changed/stopped drugs due to maternal side-effects, or admission to neonatal or intensive care nursery (low-certainty evidence). There is probably little or no difference in the risk of elective delivery (moderate-certainty evidence).Antihypertensive drug versus another antihypertensive drug (29 trials, 2774 women)Primary outcomes: beta blockers and calcium channel blockers together in the meta-analysis appear to be more effective than methyldopa in avoiding an episode of severe hypertension (RR 0.70; 95% CI 0.56 to 0.88; 11 trials, 638 women). There was also an increase in this risk when other antihypertensive drugs were compared with calcium channel blockers (RR 1.86; 95% CI 1.09 to 3.15; 5 trials, 223 women), but no evidence of a difference when methyldopa and calcium channel blockers together were compared with beta blockers (RR1.18, 95% CI 0.95 to 1.48; 10 trials, 692 women). No evidence of a difference in the risk of proteinuria/pre-eclampsia was found when alternative drugs were compared with methyldopa (aRR 0.78; 95% CI 0.58 to 1.06; 11 trials, 997 women), with calcium channel blockers (aRR: 1.24, 95% CI 0.70 to 2.19; 5 trials, 375 women), or with beta blockers (aRR 1.21, 95% CI 0.88 to 1.67; 12 trials, 1107 women).For the babies, we found no evidence of a difference in the risk oftotal reported fetal or neonatal death (including miscarriage) when comparing other antihypertensive drugs with methyldopa (aRR 0.77, 95% CI 0.52 to 1.14; 22 trials, 1791 babies), with calcium channel blockers (aRR 0.90, 95% CI 0.52 to 1.57; nine trials, 700 babies), or with beta blockers (aRR: 1.23, 95% CI 0.81 to 1.88; 19 trials, 1652 babies); nor in the risk for small-for-gestational age in the comparison with methyldopa (aRR 0.79, 95% CI 0.52 to 1.20; seven trials, 597 babies), with calcium channel blockers (aRR 1.05, 95% CI 0.64 to 1.73; four trials, 200 babies), or with beta blockers (average RR 1.13, 95% CI 0.80 to 1.60; 7 trials, 680 babies). No evidence of an overall difference among groups in the risk of preterm birth (less than 37 weeks) was found in the comparison with methyldopa (aRR: 0.91; 95% CI 0.68 to 1.22; 11 trials, 835 women), with calcium channel blockers (aRR 0.85, 95% CI 0.59 to 1.23; six trials, 330 women), or with beta blockers (aRR 1.22, 95% CI 0.90 to 1.66; 9 trials, 806 women).
There were no cases of maternal death andeclampsia. There is no evidence of a difference in the risk of severe pre-eclampsia, changed/stopped drug due to maternal side-effects, elective delivery, admission to neonatal or intensive care nursery when other antihypertensive drugs are compared with methyldopa, calcium channel blockers or beta blockers. Impaired long-term growth and development in infancy and childhood was not reported for these comparisons.
Antihypertensive drug therapy for mild to moderate hypertension during pregnancy reduces the risk of severe hypertension. The effect on other clinically important outcomes remains unclear. If antihypertensive drugs are used, beta blockers and calcium channel blockers appear to be more effective than the alternatives for preventing severe hypertension. High-quality large sample-sized randomised controlled trials are required in order to provide reliable estimates of the benefits and adverse effects of antihypertensive treatment for mild to moderate hypertension for both mother and baby, as well as costs to the health services, women and their families.
To investigate the impact of experimental interventions on living biological tissue, ex vivo rodent brain slices are often used as a more controllable alternative to a live animal model. However, for ...meaningful results, the biological sample must be known to be healthy and viable. One of the gold-standard approaches to identifying tissue viability status is to measure the rate of tissue oxygen consumption under specific controlled conditions. Here, we work with thin (400 μm) slices of mouse cortical brain tissue which are sustained by a steady flow of oxygenated artificial cerebralspinal fluid (aCSF) at room temperature. To quantify tissue oxygen consumption (
), we measure oxygen partial pressure (pO2) as a function of probe depth. The curvature of the obtained parabolic (or parabola-like) pO2 profiles can be used to extract
, providing one knows the Krogh coefficient Kt, for the tissue. The oxygen trends are well described by a Fick's law diffusion-consumption model developed by Ivanova and Simeonov, and expressed in terms of ratio (Q/K), being the rate of oxygen consumption in tissue divided by the Krogh coefficient (oxygen diffusivity × oxygen solubility) for tissue. If the fluid immediately adjacent to the tissue can be assumed to be stationary (i.e., nonflowing), one may invoke conservation of oxygen flux K·(∂P/∂x) across the interface to deduce (Kt/Kf), the ratio of Krogh coefficients for tissue and fluid. Using published interpolation formulas for the effect of salt content and temperature on oxygen diffusivity and solubility for pure water, we estimate Kf, the Krogh coefficient for aCSF, and hence deduce the Kt coefficient for tissue. We distinguish experimental uncertainty from natural biological variability by using pairs of repeated profiles at the same tissue location. We report a dimensionless Krogh ratio (Kt/Kf)=0.562±0.088 (mean ± SD), corresponding to a Krogh coefficient Kt=(1.29±0.21)×10-14 mol/(m·s·Pa) for mouse cortical tissue at room temperature, but acknowledge the experimental limitation of being unable to verify that the fluid boundary layer is truly stationary. We compare our results with those reported in the literature, and comment on the challenges and ambiguities caused by the extensive use of 'biologically convenient' non-SI units for tissue Krogh coefficient.
The benefits of breastfeeding are well known, and the World Health Organization recommends exclusive breastfeeding for the first six months of life and continuing breastfeeding to age two. However, ...many women stop breastfeeding due to lactational breast abscesses. A breast abscess is a localised accumulation of infected fluid in breast tissue. Abscesses are commonly treated with antibiotics, incision and drainage (I&D) or ultrasound-guided needle aspiration, but there is no consensus on the optimal treatment.
To assess the effects of different treatments for the management of breast abscesses in breastfeeding women.
We searched the Cochrane Pregnancy and Childbirth Group's Trial Register (27 February 2015). In addition we searched African Journals Online (27 February 2015), Google Scholar (27 February 2015), ProQuest Dissertations and Theses Databases (27 February 2015) and the WHO International Clinical Trials Registry Platform (ICTRP) search portal (27 February 2015). We also checked reference lists of retrieved studies and contacted experts in the field as well as relevant pharmaceutical companies.
Randomised controlled trials (RCTs) investigating any intervention for treating lactational breast abscesses compared with any other intervention. Studies published in abstract form, quasi-RCTs and cluster-RCTs were not eligible for inclusion.
Two review authors independently assessed studies for inclusion, assessed risk of bias and extracted data. Data were checked for accuracy.
We included six studies. Overall, trials had an unclear risk of bias for most domains due to poor reporting. Two studies did not stratify data for lactational and non-lactational breast abscesses, and these studies do not contribute to the results. This review is based on data from four studies involving 325 women. Needle aspiration (with and without ultrasound guidance) versus incision and drainage (I&D) Mean time (days) to complete resolution of breast abscess (three studies) - there was substantial heterogeneity among these data (Tau(2) = 47.63, I(2) = 97%) and a clear difference between subgroups (with or without ultrasound guidance; Chi(2) = 56.88, I(2) = 98.2%, P = < 0.00001). We did not pool these data in a meta-analysis. Two studies excluded women who had treatment failure when they calculated the mean time to complete resolution. One study found that the time to complete resolution of breast abscess favoured needle aspiration over I&D (mean difference (MD) -6.07; 95% confidence interval (CI) -7.81 to -4.33; n = 36), but excluded 9/22 (41%) women in the needle aspiration group due to treatment failure. Another study reported faster resolution in the needle aspiration group (MD -17.80; 95% CI -21.27 to -14.33; n = 64) but excluded 6/35 (17%) women in the needle aspiration group due to treatment failure. A third study also reported that needle aspiration was associated with a shorter time to complete resolution of breast abscess (MD -16.00; 95%CI -18.73 to -13.27; n = 60); however, the authors did not indicate the number of women who were lost to follow-up for either group, and it is unclear how many women contributed to this result. Considering the limitations of the available data, we do not consider the results to be informative. Continuation of breastfeeding, after treatment (success): results favoured the needle aspiration group, but we did not pool data from the two studies because of substantial unexplained heterogeneity (I(2) = 97%). One study reported that women in the needle aspiration group were more likely to continue breastfeeding (risk ratio (RR) 2.89; 95% CI 1.64 to 5.08; n = 60), whereas the other study found no clear difference (RR 1.09; 95% CI 0.97 to 1.22 n = 70). Treatment failure was more common among women treated with needle aspiration compared to those who underwent I&D (RR 16.12; 95% CI 2.21 to 117.73; two studies, n = 115, low quality evidence). In one study, treatment with needle aspiration failed in 9/22 women who subsequently underwent I&D to treat their breast abscess. In another study, treatment with needle aspiration failed in 6/35 women, who subsequently underwent I&D. All abscesses in the I&D group were successfully treated.The included studies provided limited data for the review's secondary outcomes. No data were reported for adverse events. One study (60 women) reported that women in the needle aspiration group were more satisfied with their treatment than women who received I&D to treat their breast abscesses. Incision and drainage (I&D) with or without antibioticsOne study (150 women) compared the value of adding a broad-spectrum cephalosporin (single dose or a course of treatment) to women who underwent I&D for breast abscesses.The mean time to resolution of breast abscess was reported as being similar in all groups (although women with infection were excluded). Mean time to resolution for women who received a course of antibiotics was reported as 7.3 days, 6.9 days for women who received a single dose of antibiotics and 7.4 days for women who did not receive antibiotics. Standard deviations, P values and CIs were not reported and prevented further analysis. No data were reported for any continuation of breastfeeding after treatment (success). For treatment failure, there was no clear difference between the groups of women who received antibiotics (either a single dose or a course of antibiotics) and those who did not (RR 1.00; 95% CI 0.36 to 2.76).Included studies rarely reported this review's secondary outcomes (including adverse events). For post-operative complications/morbidity, there was no difference in the risk of wound infections between the antibiotics and no antibiotics groups (RR 0.58; 95% CI 0.29 to 1.17), irrespective of whether women received a single dose or a course of antibiotics.
There is insufficient evidence to determine whether needle aspiration is a more effective option to I&D for lactational breast abscesses, or whether an antibiotic should be routinely added to women undergoing I&D for lactational breast abscesses. We graded the evidence for the primary outcome of treatment failure as low quality, with downgrading based on including small studies with few events and unclear risk of bias.
Growth of critical fluctuations prior to catastrophic state transition is generally regarded as a universal phenomenon, providing a valuable early warning signal in dynamical systems. Using an ...ecological fisheries model of three populations (juvenile prey J, adult prey A and predator P), a recent study has reported silent early warning signals obtained from P and A populations prior to saddle-node (SN) bifurcation, and thus concluded that early warning signals are not universal. By performing a full eigenvalue analysis of the same system we demonstrate that while J and P populations undergo SN bifurcation, A does not jump to a new state, so it is not expected to carry early warning signs. In contrast with the previous study, we capture a significant increase in the noise-induced fluctuations in the P population, but only on close approach to the bifurcation point; it is not clear why the P variance initially shows a decaying trend. Here we resolve this puzzle using observability measures from control theory. By computing the observability coefficient for the system from the recordings of each population considered one at a time, we are able to quantify their ability to describe changing internal dynamics. We demonstrate that precursor fluctuations are best observed using only the J variable, and also P variable if close to transition. Using observability analysis we are able to describe why a poorly observable variable (P) has poor forecasting capabilities although a full eigenvalue analysis shows that this variable undergoes a bifurcation. We conclude that observability analysis provides complementary information to identify the variables carrying early-warning signs about impending state transition.
Pre-eclampsia/eclampsia are leading causes of maternal mortality and morbidity, particularly in low- and middle- income countries (LMICs). We developed the miniPIERS risk prediction model to provide ...a simple, evidence-based tool to identify pregnant women in LMICs at increased risk of death or major hypertensive-related complications.
From 1 July 2008 to 31 March 2012, in five LMICs, data were collected prospectively on 2,081 women with any hypertensive disorder of pregnancy admitted to a participating centre. Candidate predictors collected within 24 hours of admission were entered into a step-wise backward elimination logistic regression model to predict a composite adverse maternal outcome within 48 hours of admission. Model internal validation was accomplished by bootstrapping and external validation was completed using data from 1,300 women in the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) dataset. Predictive performance was assessed for calibration, discrimination, and stratification capacity. The final miniPIERS model included: parity (nulliparous versus multiparous); gestational age on admission; headache/visual disturbances; chest pain/dyspnoea; vaginal bleeding with abdominal pain; systolic blood pressure; and dipstick proteinuria. The miniPIERS model was well-calibrated and had an area under the receiver operating characteristic curve (AUC ROC) of 0.768 (95% CI 0.735-0.801) with an average optimism of 0.037. External validation AUC ROC was 0.713 (95% CI 0.658-0.768). A predicted probability ≥25% to define a positive test classified women with 85.5% accuracy. Limitations of this study include the composite outcome and the broad inclusion criteria of any hypertensive disorder of pregnancy. This broad approach was used to optimize model generalizability.
The miniPIERS model shows reasonable ability to identify women at increased risk of adverse maternal outcomes associated with the hypertensive disorders of pregnancy. It could be used in LMICs to identify women who would benefit most from interventions such as magnesium sulphate, antihypertensives, or transportation to a higher level of care.
Many new chemical entities are discovered with high therapeutic potential, however, many of these compounds exhibit unfavorable pharmacokinetic properties due to poor solubility and/or poor membrane ...permeation characteristics. The latter is mainly due to the lipid-like barrier imposed by epithelial mucosal layers, which have to be crossed by drug molecules in order to exert a therapeutic effect. Another barrier is the pre-systemic metabolic degradation of drug molecules, mainly by cytochrome P450 enzymes located in the intestinal enterocytes and liver hepatocytes. Although the nasal, buccal and pulmonary routes of administration avoid the first-pass effect, they are still dependent on absorption of drug molecules across the mucosal surfaces to achieve systemic drug delivery. Bioenhancers (drug absorption enhancers of natural origin) have been identified that can increase the quantity of unchanged drug that appears in the systemic blood circulation by means of modulating membrane permeation and/or pre-systemic metabolism. The aim of this paper is to provide an overview of natural bioenhancers and their main mechanisms of action for the nasal, buccal, pulmonary and oral routes of drug administration. Poorly bioavailable drugs such as large, hydrophilic therapeutics are often administered by injections. Bioenhancers may potentially be used to benefit patients by making systemic delivery of these poorly bioavailable drugs possible via alternative routes of administration (i.e., oral, nasal, buccal or pulmonary routes of administration) and may also reduce dosages of small molecular drugs and thereby reduce treatment costs.
Transcranial magnetic stimulation (TMS) is a technique used to treat different neurological disorders non-invasively. A pulsed current to a coil generates a magnetic field (<inline-formula> <tex-math ...notation="LaTeX">B </tex-math></inline-formula>-field) which induces an electric field (<inline-formula> <tex-math notation="LaTeX">E </tex-math></inline-formula>-field). Underlying biophysical effects of TMS are unclear. Therefore, animal experiments are needed; however, making small TMS coils suitable for mice is difficult and their field strengths are typically much lower than for human sized coils. Objectives/Hypothesis . We aimed to design and demonstrate a mouse-specific coil that can generate high and focused <inline-formula> <tex-math notation="LaTeX">E </tex-math></inline-formula>-field. Methods . We designed a tapered TMS coil of 50 turns of 0.2 mm diameter copper wire around a 5 mm diameter tapered powdered iron core and discharged a <inline-formula> <tex-math notation="LaTeX">220~\mu \text{F} </tex-math></inline-formula> capacitor at 50 V through it. We measured <inline-formula> <tex-math notation="LaTeX">B </tex-math></inline-formula>-field with a Hall probe and induced <inline-formula> <tex-math notation="LaTeX">E </tex-math></inline-formula>-field with a wire loop. We measured temperature rise with a thermocouple. We applied 1200 pulses of continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) to mouse brain slices and analyzed how spontaneous electrical activity changed. Results . The coil gave maximum <inline-formula> <tex-math notation="LaTeX">B </tex-math></inline-formula>-field of 685 mT at the base of the coil and 340 mT at 2 mm below the coil, and maximum <inline-formula> <tex-math notation="LaTeX">E </tex-math></inline-formula>-field 2 mm below the coil of approximately 10 V/m, at 50 V power supply, with a temperature increase of 20 °C after 1200 pulses of cTBS. We observed no changes in <inline-formula> <tex-math notation="LaTeX">B </tex-math></inline-formula>-field with heating. cTBS reduced frequency of spontaneous population events in mouse brain slices up to 20 min after stimulation and iTBS increased frequency up to 20 min after stimulation. No frequency changes occurred after 20 min. No changes in amplitude of spontaneous events were found. Conclusion . The design generated fields strong enough to modulate brain activity in vitro .
Mild to moderate hypertension during pregnancy is common. Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby ...improve outcome.
To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy.
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 3), MEDLINE (1966 to November 2005), LILACS (1984 to November 2005) and EMBASE (1974 to November 2005).
All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy defined, whenever possible, as systolic blood pressure 140 to 169 mmHg and diastolic blood pressure 90 to 109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days.
Two review authors independently extracted data.
Forty-six trials (4282 women) were included. Twenty-eight trials compared an antihypertensive drug with placebo/no antihypertensive drug (3200 women). There is a halving in the risk of developing severe hypertension associated with the use of antihypertensive drug(s) (19 trials, 2409 women; relative risk (RR) 0.50; 95% confidence interval (CI) 0.41 to 0.61; risk difference (RD) -0.10 (-0.12 to -0.07); number needed to treat (NNT) 10 (8 to 13)) but little evidence of a difference in the risk of pre-eclampsia (22 trials, 2702 women; RR 0.97; 95% CI 0.83 to 1.13). Similarly, there is no clear effect on the risk of the baby dying (26 trials, 3081 women; RR 0.73; 95% CI 0.50 to 1.08), preterm birth (14 trials, 1992 women; RR 1.02; 95 % CI 0.89 to 1.16), or small-for-gestational-age babies (19 trials, 2437 women; RR 1.04; 95 % CI 0.84 to 1.27). There were no clear differences in any other outcomes. Nineteen trials (1282 women) compared one antihypertensive drug with another. Beta blockers seem better than methyldopa for reducing the risk of severe hypertension (10 trials, 539 women, RR 0.75 (95 % CI 0.59 to 0.94); RD -0.08 (-0.14 to 0.02); NNT 12 (6 to 275)). There is no clear difference between any of the alternative drugs in the risk of developing proteinuria/pre-eclampsia. Other outcomes were only reported by a small proportion of studies, and there were no clear differences.
It remains unclear whether antihypertensive drug therapy for mild to moderate hypertension during pregnancy is worthwhile.
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