INTRODUCTION:In low-resource settings, magnesium sulphate (MgSO4) for preeclampsia is administered majorly through an injection into the gluteal muscles 4-hourly for 24 hours. The repeated injections are very painful and may lead to infection, abscess formation, and reduced compliance. OBJECTIVE:To determine the acceptability of Springfusor® pump for the administration of Magnesium Sulphate in preeclampsia and eclampsia. DESIGN:Randomized Open Label Clinical Trial. METHODS:The study was conducted at Kawempe National Referral Hospital. Eligible women had a systolic blood pressure of ≥140mmHg and or diastolic blood pressure >90mmHg, proteinuria ≥+1, and the physician's decision to start on MgSO4. Four-hundred-ninety-six participants were randomized to a Springfusor® pump group (n = 248) or control (standard of care) (n = 248) administration of MgSO4. Intervention group had a loading dose (4gm of 50% MgSO4 intravenously over 20 minutes) and maintenance therapy (1gm of 50% MgSO4 intravenously per hour for 24 hours) administered using the Springfusor®. The standard of care (SOC) group received a loading dose of 4gm of 20% MgSO4 IV over 15-20 minutes, followed by 10gm of 50% MgSO4 intramuscular (5gm in each buttock) and a maintenance dose of 5gm of 50% MgSO4 was administered IM every 4 hours for 24 hours. Both arms received the rest of the care for preeclampsia/eclampsia as per the hospital guidelines. Acceptability of the method of administration was assessed using a Likert scale (1-5; 1 and 2: acceptable and 3-5: unacceptable). Pain at the site of MgSO4 administration was assessed using a Visual Analogue Scale 1-7, (1 minimal pain and 7 worst pain). Comparisons were assessed with the Chi-square test, Mann Whitney-Wilcoxon test, and Students' t-test. RESULTS:Intervention arm; was more acceptable than the standard of care arm, (95.3% vs70.3%; p<0.001), had a lower median pain score, (2(CI: 2-2), vs 4(CI: 4-5) p<0.001), and fewer side effects. Maternal mortality was comparable between groups (0.8% in the intervention arm vs 1.2% in the IM arm). TRIAL REGISTRATION:Trial No PACTR201712002887266 (https://pactr.samrc.ac.za/).

Objective: To assess whether, in those requiring ongoing uterine stimulation after cervical ripening with oral misoprostol and membrane rupture, augmentation with low dose oral misoprostol is superior to intravenous oxytocin. Design: Open-label, superiority randomised trial Setting: Government hospitals in India Population: Women induced with oral misoprostol for hypertensive disease in pregnancy and requiring ongoing induction after membrane rupture Methods: Participants received misoprostol (25mcg orally two hourly) or titrated oxytocin through an infusion pump. Main Outcome Measure: Caesarean birth Results: 520 women were randomised and the baseline characteristics were comparable between the groups. The caesarean section rate was not reduced by the use of misoprostol (misoprostol 32.3% vs oxytocin 27.3%; adjusted odds ratio 1.226 (95% CI 0.81-1.85, p=0.33)). There were no differences in rates of hyperstimulation, fetal heart rate abnormalities, or maternal side effects, although the geometric mean time from randomisation to birth was 31 minutes longer with misoprostol. Fewer babies in the misoprostol arm were admitted to the special care unit (10 vs 21 in the oxytocin group) and there were no neonatal deaths in the misoprostol group, compared to 3 in the oxytocin arm. Women’s acceptability ratings were high in both study groups. Conclusion: Following cervical preparation with oral misoprostol and membrane rupture, the use of ongoing oral misoprostol for augmentation did not significantly reduce caesarean rates compared to oxytocin. The method, however, was safe for both mother and baby.

Introduction: In the United States, there has been controversy over whether treatment of mild-to-moderate hypertension during pregnancy conveys more benefit than risk.Objective: The objective of the study was to compare risks and benefits of treatment of mild-to-moderate hypertension during pregnancy.Methods: This retrospective cohort study included 11,871 pregnant women with mild-to-moderate hypertension as defined by blood pressure (BP) values from three Kaiser Permanente regions between 2005 and 2014. Data were extracted from electronic health records. Dynamic marginal structural models with inverse probability weighting and informative censoring were used to compare risks of adverse outcomes when beginning antihypertensive medication treatment at four BP thresholds (>= 155/105, >= 150/100, >= 145/95, >= 140/90 mm Hg) compared with the recommended threshold in the United States at that time, >= 160/110 mm Hg. Outcomes included preeclampsia, preterm birth, small-for-gestational-age (SGA), Neonatal Intensive Care Unit (NICU) care, and stillbirth. Primary analyses allowed 2 weeks for medication initiation after an elevated BP. Several sensitivity and subgroup (i.e., race/ethnicity and pre-pregnancy body mass index) analyses were also conducted.Results: In primary analyses, medication initiation at lower BP thresholds was associated with greater risk of most outcomes. Comparing the lowest (& GE;140/90 mm Hg) to the highest BP threshold (>= 160/110 mm Hg), we found an excess risk of preeclampsia (adjusted Risk Difference (aRD) 38.6 per 100 births, 95% Confidence Interval (CI): 30.6, 46.6), SGA (aRD: 10.2 per 100 births, 95% CI: 2.6, 17.8), NICU admission (aRD: 20.2 per 100 births, 95% CI: 12.6, 27.9), and stillbirth (1.18 per 100 births, 95% CI: 0.27, 2.09). The findings did not reach statistical significance for preterm birth (aRD: 2.5 per 100 births, 95% CI: -0.4, 5.3). These relationships were attenuated and did not always reach statistically significance when comparing higher BP treatment thresholds to the highest threshold (i.e., >= 160/110 mm Hg). Sensitivity and subgroup analyses produced similar results.Conclusions: Initiation of antihypertensive medication at mild-to-moderate BP thresholds (140-155/90-105 mm Hg; with the largest risk consistently associated with treatment at 140/90 mm Hg) may be associated with adverse maternal and neonatal outcomes. Limitations include inability to measure medication adherence.

Hypertensive disorders of pregnancy are among the most serious conditions that pregnancy care providers face; however, little attention has been paid to the concept of tailoring clinical care to reduce associated adverse maternal and perinatal outcomes based on the underlying disease pathogenesis. This narrative review discusses the integration of phenotype-based clinical strategies in the management of high-risk pregnant patients that are currently not common clinical practice: real-time placental growth factor testing at Mount Sinai Hospital, Toronto and noninvasive hemodynamic monitoring to guide antihypertensive therapy at the University of Washington Medical Center, Seattle. Future work should focus on promoting more widespread integration of these novel strategies into obstetric care to improve outcomes of pregnancies at high risk of adverse maternal-fetal outcomes from these complications of pregnancy.

IntroductionStudies of hypertension in pregnancy that use electronic health care data generally identify hypertension using hospital diagnosis codes alone. We sought to compare results from this approach to an approach that included diagnosis codes, antihypertensive medications and blood pressure (BP) values.Materials and methodsWe conducted a retrospective cohort study of 1,45,739 pregnancies from 2009 to 2014 within an integrated healthcare system. Hypertensive pregnancies were identified using the “BP-Inclusive Definition” if at least one of three criteria were met: (1) two elevated outpatient BPs, (2) antihypertensive medication fill plus an outpatient hypertension diagnosis, or (3) hospital discharge diagnosis for preeclampsia or eclampsia. The “Traditional Definition” considered only delivery hospitalization discharge diagnoses. Outcome event analyses compared rates of preterm delivery and small for gestational age (SGA) between the two definitions.ResultsThe BP-Inclusive Definition identified 14,225 (9.8%) hypertensive pregnancies while the Traditional Definition identified 13,637 (9.4%); 10,809 women met both definitions. Preterm delivery occurred in 20.9% of BP-Inclusive Definition pregnancies, 21.8% of Traditional Definition pregnancies and 6.6% of non-hypertensive pregnancies; for SGA the numbers were 15.6, 16.3, and 8.6%, respectively (p < 0.001 for all events compared to non-hypertensive pregnancies). Analyses in women meeting only one hypertension definition (21–24% of positive cases) found much lower rates of both preterm delivery and SGA.ConclusionPrevalence of hypertension in pregnancy was similar between the two study definitions. However, a substantial number of women met only one of the study definitions. Women who met only one of the hypertension definitions had much lower rates of adverse neonatal events than women meeting both definitions.

OBJECTIVE:To compare maternal and infant outcomes with different antihypertensive medications in pregnancy.DESIGN:Retrospective cohort study.SETTING:Kaiser Permanente, a large healthcare system in the United States.POPULATION:Women aged 15-49 years with a singleton birth from 2005-2014 treated for hypertension.METHODS:We identified medication exposure from automated pharmacy data based on the earliest dispensing after the first prenatal visit. Using logistic regression, we calculated weighted outcome prevalences, adjusted odds ratios (aORs) and 95% confidence intervals, with inverse probability of treatment weighting to address confounding.MAIN OUTCOME MEASURES:Small for gestational age, preterm delivery, neonatal and maternal intensive care unit (ICU) admission, preeclampsia, and stillbirth or termination at > 20 weeks.RESULTS:Among 6346 deliveries, 87% with chronic hypertension, the risk of the infant being small for gestational age (birthweight < 10th percentile) was lower with methyldopa than labetalol (prevalence 13.6% vs. 16.6%; aOR 0.77, 95% CI 0.63 to 0.92). For birthweight < 3rd percentile the aOR was 0.57 (0.39 to 0.80). Compared with labetalol (26.0%), risk of preterm delivery was similar for methyldopa (26.5%; aOR 1.10 [0.95 to 1.27]) and slightly higher for nifedipine (28.5%; aOR 1.25 [1.06 to 1.46]) and other β-blockers (31.2%; aOR 1.58 [1.07 to 2.23]). Neonatal ICU admission was more common with nifedipine than labetalol (25.9% vs. 23.3%, aOR 1.21 [1.02 to 1.43]) but not elevated with methyldopa. Risks of other outcomes did not differ by medication.CONCLUSIONS:Risk of most outcomes was similar comparing labetalol, methyldopa and nifedipine. Risk of the infant being small for gestational age was substantially lower for methyldopa, suggesting this medication may warrant further consideration.

HomeHypertensionVol. 77, No. 6Individualized Management of Maternal Hemodynamics to Prevent Preeclampsia: Improvement in Maternal Outcomes Without Adverse Fetal Effects Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBIndividualized Management of Maternal Hemodynamics to Prevent Preeclampsia: Improvement in Maternal Outcomes Without Adverse Fetal Effects Thomas R. Easterling Thomas R. EasterlingThomas R. Easterling Correspondence to: Thomas R. Easterling, University of Washington, 1959 Pacific Ave NE, Box 356460, Seattle, WA. Email E-mail Address: [email protected] https://orcid.org/0000-0002-6015-5632 Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Washington, Seattle. Originally published12 May 2021https://doi.org/10.1161/HYPERTENSIONAHA.121.17202Hypertension. 2021;77:2054–2056This article is a commentary on the followingPreventing Recurrent Preeclampsia by Tailored Treatment of Nonphysiologic Hemodynamic Adjustments to PregnancySee related article, pp 2045–2053Hypertension in pregnancy remains a significant cause of maternal morbidity and mortality and contributes to preterm birth, stillbirth, and fetal growth restriction. For mothers and families affected by the severe forms of the condition, the impact can be devastating. Considerable effort has been made and success found in identifying and urgently treating severe hypertension when it occurs.1 Despite the ability to prevent severe hypertension with early antihypertensive therapy,2,3 lack of consensus remains regarding the blood pressure threshold for the initiation of medication, a target for treatment, and for choice of agents. The potential for adverse effects on the fetus, and in particular on fetal growth, remains a source of concern.The study by Mulder et al4 in the present issue of the journal addresses the dilemma of when and how to treat. The approach described recognizes that hemodynamic alterations are present before the onset of hypertension and adds weight to the position that high blood pressure and abnormal hemodynamics are a critical part of the pathway of maternal pathophysiology. An approach to care is described that moderates maternal morbidity without adversely impacting the fetus.The article reports a prospective cohort study of the management of abnormal maternal hemodynamics by a physiologically directed nomogram. Notably, the trial is not randomized but uses a control group from women who chose not to participate. The control group was effectively matched for maternal risk factors and risk adjusted for exposure to aspirin utilization and calcium supplementation. The aim of the study was to assess the impact of treatment directed at correcting hemodynamic abnormalities before the onset of hypertension on the recurrence preeclampsia.The intervention and control cohorts were composed of women with a history of preeclampsia in a prior pregnancy. The mean gestational age at diagnosis in the index pregnancy was 33 weeks; at delivery, 34 weeks. Just over half had early onset preeclampsia, 67% had HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and 26% to 27% delivered babies that were small for gestational age. When evaluated between pregnancies, the women had high rates of the components of metabolic syndrome including baseline proteinuria (17%–19%).Treatment in the experimental arm, the nomogram arm, was directed by abnormal maternal hemodynamics derived from Doppler based assessment of maternal cardiac output rather than an absolute blood pressure. Treatment with medications with β-blocking effect or vasodilatory effect was individualized to maternal parameters and adjusted over the course of pregnancy. Pharmacological therapy was initiated before the onset of hypertension. In general, the resulting blood pressures were in the range of 110s/60s (Table 2). Ongoing adjustment of medications was frequently needed. Women requiring more adjustments experienced higher rates of preeclampsia. Increased fetal surveillance was initiated when the addition of vasodilation was required.Women in the control arm received care as usual. Of note, outcomes in the control arm generally improved from index pregnancy—they regressed towards the mean. The gestational age at delivery increased from 34 to 38 weeks. The incidence of small for gestational age decreased from 26% to 14%. The incidence of HELLP syndrome decreased from 67% to 6%. These are important observations relevant to the design of subsequent trials.Maternal outcomes in the nomogram arm were better than in the control arm. The incidence of preeclampsia was lower (12% versus 22%), adjusted odds ratio, 0.47 (0.25–0.88) adjusted for aspirin and supplemental calcium exposure. The incidence of HELLP syndrome was markedly reduced (1% versus 6%), adjusted odds ratio, 0.11 (0.01–0.86) again adjusted for aspirin and supplemental calcium exposure. These findings are consistent with the CHIPs trial, where tight control of blood pressure resulted in a decreased incidence of severe hypertension, thrombocytopenia, and elevated liver enzymes.2 Notably, no clear fetal benefit was observed. There was no difference in gestational age at delivery (38 weeks), the incidence of preterm birth (12% versus 15%), mean birth weight (3143 versus 3170 g, P=0.5), or birth weight percentile (38 versus 41, P=0.36). Hemodynamic control and the associated low blood pressure improved maternal outcomes without adversely affecting the fetus. The marked reduction in the incidence of HELLP syndrome is particularly important in that HELLP is substantially more serious than the diagnosis of preeclampsia alone. It is often associated with severe morbidity—a condition to be avoided.This article contributes to the existing literature about the importance of maternal hemodynamics in our understanding and management of hypertensive conditions in pregnancy. At the University of Washington, we first described the longitudinal hemodynamics of nulliparous women who developed preeclampsia as characterized by an elevated cardiac output.5 We hypothesized a potential acute change in hemodynamics characterized by increasing vascular resistance as preeclampsia evolved but could not confirm the hypothesis due to women being delivered as they became ill. Bosio et al6 subsequently replicated the work in nulliparous women and confirmed what has been characterized as a cross-over in hemodynamics with increasing severity of disease. De Paco et al7 prospective evaluated a heterogeneous cohort of women at risk for preeclampsia at 11 to 13 weeks' gestation and found that those who developed preeclampsia had an elevated cardiac output compared to women who did not.Maternal therapy based on hemodynamics has been previously reported. In a cohort of women referred for management of risk for hypertension, we found that treatment based on hemodynamics resulted low rates of severe disease (0.43%) and low rates of preterm birth (4.7% < 34 weeks).8 Cardiac output that fell to less than the mean for gestational age or the development elevated resistance were strongly associated with the development of fetal growth restriction. Nevertheless, the overall incidence of birth weight <10th percentile was 19.8%, comparable to that of the tight control arm from CHIPS (the Control of Hypertension in Pregnancy Study).2 These events became less common as our experience and expertise evolved. Chaffin et al9 have reported the use of maternal hemodynamics derived from impedance cardiography to manage a cohort with chronic hypertension or a history of prior preeclampsia. The incidence of severe preeclampsia and delivery at <34 weeks in hyperdynamic women was 2.5% and 5.7%. For women with elevated vascular resistance the rates were 9.2% and 14.5%, respectively. Mean birth weight percentiles were the 52nd and the 44th.In a randomized controlled trial of nulliparous and diabetic women to prevent preeclampsia, we based therapy on abnormal hemodynamics and initiated treatment before the onset of overt hypertension, similar to the strategy used in this article.10 Women were enrolled based on a screening elevated cardiac output and managed with a fixed dose of β-blocker. Treatment resulted in a decreased incidence of preeclampsia (3.8% versus 18%) and a normalization of elevated renal blood flow and glomerular filtration rates. Although we did not observe a difference in the incidence of intrauterine growth restriction (4.7% versus 5.5%), we did observe a difference in mean birth weight due, in part, to an impact on macrosomia and, in part, to a downward shift in the birth weight distribution as a whole. The smallest babies in the treatment arm were observed to be born to mothers whose cardiac output fell below the mean for gestational age.The investigators have refined the approach with greater attention to the need for continuous medication adjustment than we did in our early experience with the approach. The ability to provide a matched control group strengthens the observations.What does this article do to add to our understanding of preeclampsia and hypertension in pregnancy? First, it contributes to a growing body of information that hypertension and the prehypertensive alterations in hemodynamics are more than a mere sign of preeclampsia—more than an epiphenomenon. The dramatic reduction in the recurrence of HELLP syndrome is particularly notable. Hemodynamic control is one of a number of candidate pathways for effective intervention. Second, normalization of blood pressure can be achieved without adverse impact on fetal growth if an adequate hemodynamic profile of adequate flow is maintained. The delivery of oxygen and nutrients to support growth are dependent on adequate flow rather than pressure. The potential effect of treatment on fetal growth appears to have been moderated by using β-blockers only when hemodynamically appropriate.This prospective cohort study is not a randomized trial and, therefore, should be viewed with some caution. That said, the matching of the control group as well as the strength of the findings adds credibility. Nevertheless, the potential for uncontrolled bias based on the patient choice to participate cannot be excluded. The results provide a strong basis for the design of a proper randomized trial which the authors have planned. These results suggest a trial based on serious maternal outcomes.11Can this model of care be scaled for broad utilization? Based on our experience and that described by the authors, the effort needed to provide this care is substantial. A committed core of providers, nurses, and technical support is required. The ability to noninvasively measure cardiac output at scale requires substantial training and effort at quality control. Although women with a history of preeclampsia are often highly motivated to avoid a recurrence, their commitment to this strategy must be recognized.Sources of FundingNone.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the American Heart Association.For Sources of Funding and Disclosures, see page 2056.Correspondence to: Thomas R. Easterling, University of Washington, 1959 Pacific Ave NE, Box 356460, Seattle, WA. Email [email protected]eduReferences1. Shields LE, Wiesner S, Klein C, Pelletreau B, Hedriana HL. Early standardized treatment of critical blood pressure elevations is associated with a reduction in eclampsia and severe maternal morbidity.Am J Obstet Gynecol. 2017; 216:415.e1–415.e5. doi: 10.1016/j.ajog.2017.01.008CrossrefGoogle Scholar2. Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE, Menzies J, Sanchez J, Singer J, Gafni A, et al.. Less-tight versus tight control of hypertension in pregnancy.N Engl J Med. 2015; 372:407–417. doi: 10.1056/NEJMoa1404595CrossrefMedlineGoogle Scholar3. Abalos A, Duley L, Steyn DW, Gialdini C. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy.Cochrane Database Syst Rev. 2018; 10:CD002252. doi: 10.1002/14651858.CD002252.pub4MedlineGoogle Scholar4. Mulder EG, Ghossein-Doha C, Cauffman E, Lopes van Balen VA, Schiffer VMMM, Alers R-J, Oben J, Smits L, van Kuijk SMJ, Spaanderman MEA. Preventing recurrent preeclampsia by tailored treatment of nonphysiologic hemodynamic adjustments to pregnancy.hypertension. 2021; 77:2045–2053. doi: 10.1161/HYPERTENSIONAHA.120.16502LinkGoogle Scholar5. Easterling TR, Benedetti TJ, Schmucker BC, Millard SP. Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study.Obstet Gynecol. 1990; 76:1061–1069.MedlineGoogle Scholar6. Bosio PM, McKenna PJ, Conroy R, O'Herlihy C. Maternal central hemodynamics in hypertensive disorders of pregnancy.Obstet Gynecol. 1999; 94:978–984. doi: 10.1016/s0029-7844(99)00430-5MedlineGoogle Scholar7. De Paco C, Kametas N, Rencoret G, Strobl I, Nicolaides KH. Maternal cardiac output between 11 and 13 weeks of gestation in the prediction of preeclampsia and small for gestational age.Obstet Gynecol. 2008; 111(2 pt 1):292–300. doi: 10.1097/01.AOG.0000298622.22494.0cCrossrefMedlineGoogle Scholar8. Easterling TR, Carr DB, Brateng D, Diederichs C, Schmucker B. Treatment of hypertension in pregnancy: effect of atenolol on maternal disease, preterm delivery, and fetal growth.Obstet Gynecol. 2001; 98:427–433. doi: 10.1016/s0029-7844(01)01477-6MedlineGoogle Scholar9. Chaffin DG, Webb DG. Outcomes of pregnancies at risk for hypertensive complications managed using impedance cardiography.Am J Perinatol. 2009; 26:717–721. doi: 10.1055/s-0029-1223283CrossrefMedlineGoogle Scholar10. Easterling TR, Brateng D, Schmucker B, Brown Z, Millard SP. Prevention of preeclampsia: a randomized trial of atenolol in hyperdynamic patients before onset of hypertension.Obstet Gynecol. 1999; 93(5 pt 1):725–733. doi: 10.1016/s0029-7844(98)00522-5MedlineGoogle Scholar11. Mulder E, Ghossein-Doha C, Appelman E, van Kuijk S, Smits L, van der Zanden R, van Drongelen J, Spaanderman M. Study protocol for the randomized controlled EVA (early vascular adjustments) trial: tailored treatment of mild hypertension in pregnancy to prevent severe hypertension and preeclampsia.BMC Pregnancy Childbirth. 2020; 20:775. doi: 10.1186/s12884-020-03475-wCrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesPreventing Recurrent Preeclampsia by Tailored Treatment of Nonphysiologic Hemodynamic Adjustments to PregnancyEva G. Mulder, et al. Hypertension. 2021;77:2045-2053 June 2021Vol 77, Issue 6Article InformationMetrics Download: 89 © 2021 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.121.17202PMID: 33979186 Originally publishedMay 12, 2021 PDF download SubjectsPreeclampsia

Objectives Induction of labour (IOL), or starting labour artificially, can be a lifesaving intervention for pregnant women and their babies, and rates are rising significantly globally. As rates increase, it becomes increasingly important to fully evaluate all available data, especially that from low income settings where the potential benefits and harms are greater. The goal of this paper is to describe the datasets collected as part of the Induction with Foley OR Misoprostol (INFORM) Study, a randomised trial comparing two of the recommended methods of cervical ripening for labour induction, oral misoprostol and Foley catheter, in women being induced for hypertension in pregnancy, at two sites in India during 2013–15. Data description This dataset includes comprehensive data on 602 women who underwent IOL for hypertensive disorders in pregnancy. Women were randomly assigned to cervical ripening with oral misoprostol or a transcervical Foley catheter in two government hospitals in India. The main dataset has 367 variables including monitoring during the induction of labour, medications administered, timing and mode of delivery, measures of neonatal morbidity and mortality, maternal mortality and morbidity, maternal satisfaction and health economic data. The dataset is anonymised and available on ReShare.

Background: Misfolded proteins in the urine of women with preeclampsia bind to Congo Red dye (urine congophilia). We evaluated a beta prototype of a point-of-care test for the identification of urine congophilia in preeclamptic women. Methods: Prospective diagnostic case-control study conducted in 409 pregnant women (n = 204 preeclampsia; n = 205 uncomplicated pregnancies) presenting for delivery in two tertiary level hospitals located in Bangladesh and Mexico. The GV-005, a beta prototype of a point-of-care test for detecting congophilia, was performed on fresh and refrigerated urine samples. The primary outcome was the prevalence of urine congophilia in each of the two groups. Secondary outcome was the likelihood of the GV-005 (index test) to confirm and rule-out preeclampsia based on an adjudicated diagnosis (reference standard). Findings: The GV-005 was positive in 85% of clinical cases (83/98) and negative in 81% of clinical controls (79/98) in the Bangladesh cohort. In the Mexico cohort, the GV-005 test was positive in 48% of clinical cases (51/106) and negative in 77% of clinical controls (82/107). Adjudication confirmed preeclampsia in 92% of Bangladesh clinical cases (90/98) and 61% of Mexico clinical cases (65/106). The odds ratio of a urine congophilia in adjudicated cases versus controls in the Bangladesh cohort was 34.5 (14.7 - 81.1) (p<0.001) compared to 4.2 (2.1 - 8.4; p<0.001) in the Mexico cohort. Interpretation: The GV-005, a beta prototype of a point-of-care test for detection of urine congophilia, is a promising tool for rapid identification of preeclampsia. (c) 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

OBJECTIVES:It is important to understand relationships of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension, given their high baseline risk of adverse outcomes. We assessed associations of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension by pre-pregnancy body mass index categories. STUDY DESIGN:We identified 14,369 women with chronic hypertension using electronic health records from 3 integrated health care delivery systems (2005-2014). Gestational weight gain-for-gestational age charts were used to calculate gestational weight gain z-scores, which account for gestational age. Modified Poisson regression models using generalized estimating equations were used to calculate relative risks and 95% confidence intervals, adjusted for sociodemographic and medical characteristics. MAIN OUTCOME MEASUREMENTS:Preeclampsia, preterm delivery, cesarean delivery, neonatal intensive care unit admission, birthweight (extracted from the electronic health record). RESULTS:In women with normal weight or overweight, low gestational weight gain (z-score < -1) was associated with 27-28% greater risk of preterm delivery and 48-82% greater risk of small-for-gestational age birthweight, while high gestational weight gain (z-score > 1) was associated with 40-90% greater risk of preeclampsia and 59-113% greater risk of large-for-gestational age birthweight. In women with obesity, low gestational weight gain was associated with 27-54% lower risk of several adverse pregnancy outcomes, including preeclampsia and cesarean delivery. CONCLUSIONS:In women with chronic hypertension and normal weight or overweight, moderate gestational weight gain may confer the lowest risk of adverse outcomes. In women with chronic hypertension and obesity, low gestational weight gain may be necessary for the lowest risk of adverse pregnancy outcomes.

BackgroundEvery year approximately 30,000 women die from hypertensive disease in pregnancy. Magnesium sulphate and anti-hypertensives reduce morbidity, but delivery is the only cure. Low dose oral misoprostol, a prostaglandin E1 analogue, is a highly effective method for labour induction. Usually, once active labour has commenced, the misoprostol is replaced with an intravenous oxytocin infusion if ongoing stimulation is required. However, some studies have shown that oral misoprostol can be continued into active labour, a simpler and potentially more acceptable protocol for women. To date, these two protocols have never been directly compared.MethodsThis pragmatic, open-label, randomised trial will compare a misoprostol alone labour induction protocol with the standard misoprostol plus oxytocin protocol in three Indian hospitals. The study will recruit 520 pregnant women being induced for hypertensive disease in pregnancy and requiring augmentation after membrane rupture. Participants will be randomised to receive either further oral misoprostol 25mcg every 2 h, or titrated intravenous oxytocin. The primary outcome will be caesarean birth. Secondary outcomes will assess the efficacy of the induction process, maternal and fetal/neonatal complications and patient acceptability. This protocol (version 1.04) adheres to the SPIRIT checklist. A cost-effectiveness analysis, situational analysis and formal qualitative assessment of women's experience are also planned.DiscussionAvoiding oxytocin and continuing low dose misoprostol into active labour may have a number of benefits for both women and the health care system. Misoprostol is heat stable, oral medication and thus easy to store, transport and administer; qualities particularly desirable in low resource settings. An oral medication protocol requires less equipment (e.g. electronic infusion pumps) and may free up health care providers to assist with other aspects of the woman's care. The simplicity of the protocol may also help to reduce human errors associated with the delivery of intravenous infusions. Finally, women may prefer to be mobile during labour and not restricted by an intravenous infusion. There is a need, therefore, to assess whether augmentation using oral misoprostol is superior clinically and economically to the standard protocol of intravenous oxytocin.Trial registrationClinical Trials.gov, NCT03749902, registered on 21(st) Nov 2018.

Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β-cell responsivity, and disposition index following a mixed-meal tolerance test utilizing a minimal model of glucose, insulin, and C-peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total β-cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed-meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age-dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P = .01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity.

Objective: To incorporate blood pressure (BP), diagnoses codes, and medication fills from electronic medical records (EMR) to identify pregnant women with hypertension. Study design: A retrospective cohort study of singleton pregnancies at three US integrated health delivery systems during 2005-2014. Main outcome measures: Women were considered hypertensive if they had any of the following: (1) >= 2 high BPs (>= 140/90 mmHg) within 30 days during pregnancy (High BP); (2) an antihypertensive medication fill in the 120 days before pregnancy and a hypertension diagnosis from 1 year prior to pregnancy through 20 weeks gestation (Treated Chronic Hypertension); or (3) a high BP, a hypertension diagnosis, and a prescription fill within 7 days during pregnancy (Rapid Treatment). We described characteristics of these pregnancies and conducted medical record review to understand hypertension presence and severity. Results: Of 566,624 pregnancies, 27,049 (4.8%) met our hypertension case definition: 24,140 (89.2%) with High BP, 5,409 (20.0%) with Treated Chronic Hypertension, and 5,363 (19.8%) with Rapid Treatment (not mutually exclusive). Of hypertensive pregnancies, 19,298 (71.3%) received a diagnosis, 9,762 (36.1%) received treatment and 11,226 (41.5%) had a BP >= 160/110. In a random sample (n = 55) of the 7,559 pregnancies meeting the High BP criterion with no hypertension diagnosis, clinical statements about hypertension were found in medical records for 58% of them. Conclusion: Incorporating EMR BP identified many pregnant women with hypertension who would have been missed by using diagnosis codes alone. Future studies should seek to incorporate BP to study treatment and outcomes of hypertension in pregnancy.

Introduction: Epidemiologic studies of hypertension in pregnancy traditionally rely on diagnosis codes to identify cases. Electronic medical records make it possible to incorporate measured blood pressures (BPs) into case definitions. Our aim was to examine hypertension trends in pregnancy comparing two methodologies: 1) Traditional and 2) BP-Augmented definitions. Methods: All pregnancies between 2009 -2014 were identified within an integrated healthcare delivery system. Hypertension case definitions were applied: 1) A Traditional definition based solely on delivery discharge diagnosis codes, and 2) A BP-Augmented definition using the following criteria during pregnancy: (a) two elevated outpatient BP measures (≥ 140/90 mmHg) on separate days, within 30 days of each other; (b) an antihypertensive medication fill plus a hypertension diagnosis code during pregnancy; or (c) a hospital discharge diagnosis of preeclampsia. Descriptive statistics were used to compare the two case definitions and temporal trends. Results: Of the 145,739 pregnancies, 13,637 [9.4%] met the Traditional definition and 14,225 [9.8%] met the BP-Augmented case definition (10,809 [7.4%] met both case definitions). There was a slight increase in hypertension prevalence over time based on both case definitions (figure). With the BP-Augmented definition, the prevalence increased from 9.5% of live births in 2009 to 9.8% of live births in 2014 (3% increase). For the traditional definition, the prevalence increased from 9.2% to 10.2% from 2009 to 2014 (11% increase). Conclusion: Results suggest that the prevalence of hypertension in pregnancy increased slightly from 2009-2014 with both case definitions. The two methods identified somewhat different populations with only 10,809 meeting both case definitions. Additional work is needed to validate the BP-Augmented definition’s predictive power to identify clinically important maternal and fetal outcomes.

In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β-cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed-meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β-cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β-cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.

This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy (n = 24) or a combination with glyburide (n = 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V β ), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V β /F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V β /F by 28%, weight-adjusted V β /F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy.

Objective We sought to evaluate associations between postpartum plasma adipokine concentrations among women with a history of preeclampsia ( PE) without severe features (MPE), PE with severe features (SPE), and no PE (NPE). We also investigated relationships between adipokines and computed tomography (CT)-quantified measures of visceral fat (VF) area (VFA) and subcutaneous fat area (SCFA). Study Design We performed a secondary analysis of data collected as part of a previously performed cross-sectional study at our institution. Women with and without a history of PE were recruited in 10 years after delivery. VFA and SCFA measures were performed by CT scan. Anthropometric data and peripheral blood samples from subjects were collected concurrently. Results Plasma adiponectin concentrations (mu g/mL) were significantly lower among MPE (18.5 +/- 7.1) compared with NPE ( 27.3 +/- 13.8) and SPE ( 25.7 +/- 9.6). Leptin (p = 0.32) and resistin (p = 0.93) concentrations were similar among the groups. Adiponectin concentrations more closely aligned with VFA (beta = -0.001, p = 0.03), while resistin concentrations trended toward correlating with SCFA (beta = 0.02, p = 0.05). Leptin was not preferential to VFA or SCFA. Conclusion VF distribution may contribute to the variation in PE phenotype. Adiponectin specifically may be a promising marker representing VFA.