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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-score1) was associated with 40-90% greater risk of preeclampsia and 59-113% greater risk of LGA. In women with obesity, low GWG 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.

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.

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 Every 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. Methods This 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. Discussion Avoiding 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 registration Clinical Trials.gov, NCT03749902, registered on 21st Nov 2018.

Background: Hypertension is the most common medical disorder in pregnancy, complicating one in ten pregnancies. Treatment of severely increased blood pressure is widely recommended to reduce the risk for maternal complications. Regimens for the acute treatment of severe hypertension typically include intravenous medications. Although effective, these drugs require venous access and careful fetal monitoring and might not be feasible in busy or low-resource environments. We therefore aimed to compare the efficacy and safety of three oral drugs, labetalol, nifedipine retard, and methyldopa for the management of severe hypertension in pregnancy. Methods: In this multicentre, parallel-group, open-label, randomised controlled trial, we compared these oral antihypertensives in two public hospitals in Nagpur, India. Pregnant women were eligible for the trial if they were aged at least 18 years; they were pregnant with fetuses that had reached a gestational age of at least 28 weeks; they required pharmacological blood pressure control for severe hypertension (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg); and were able to swallow oral medications. Women were randomly assigned to receive 10 mg oral nifedipine, 200 mg oral labetalol (hourly, in both of which the dose could be escalated if hypertension was maintained), or 1000 mg methyldopa (a single dose, without dose escalation). Masking of participants, study investigators, and care providers to group allocation was not possible because of different escalation protocols in the study groups. The primary outcome was blood pressure control (defined as 120–150 mm Hg systolic blood pressure and 70–100 mm Hg diastolic blood pressure) within 6 h with no adverse outcomes. This study is registered with ClinicalTrials.gov, number NCT01912677, and the Clinical Trial Registry, India, number ctri/2013/08/003866. Findings: Between April 1, 2015, and Aug 21, 2017, we screened 2307 women for their inclusion in the study. We excluded 1413 (61%) women who were ineligible, declined to participate, had impending eclampsia, were in active labour, or had a combination of these factors. 11 (4%) women in the nifedipine group, ten (3%) women in the labetalol group, and 11 (4%) women in the methyldopa group were ineligible for treatment (because they had only one qualifying blood pressure measurement) or had treatment stopped (because of delivery or transfer elsewhere). 894 (39%) women were randomly assigned to a treatment group and were included in the intention-to-treat analysis: 298 (33%) women were assigned to receive nifedipine, 295 (33%) women were assigned to receive labetalol, and 301 (33%) women were assigned to receive methyldopa. The primary outcome was significantly more common in women in the nifedipine group than in those in the methyldopa group (249 [84%] women vs 230 [76%] women; p=0·03). However, the primary outcome did not differ between the nifedipine and labetalol groups (249 [84%] women vs 228 [77%] women; p=0·05) or the labetalol and methyldopa groups (p=0·80). Seven serious adverse events (1% of births) were reported during the study: one (Interpretation: All oral antihypertensives reduced blood pressure to the reference range in most women. As single drugs, nifedipine retard use resulted in a greater frequency of primary outcome attainment than labetalol or methyldopa use. All three oral drugs—methyldopa, nifedipine, and labetalol—are viable initial options for treating severe hypertension in low-resource settings. Funding: PREEMPT (University of British Columbia, Vancouver, BC, Canada; grantee of Bill & Melinda Gates Foundation).

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 (µg/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 (β = −0.001, p = 0.03), while resistin concentrations trended toward correlating with SCFA (β = 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.

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.

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

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.

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.

N1-methylnicotinamide (1-NMN) has been investigated as an endogenous probe for the renal transporter activity of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2-K (MATE1 and MATE2-K). As pregnancy increased the renal secretion of metformin, a substrate for OCT2, MATE1, and MATE2-K, we hypothesized that the renal secretion of 1-NMN would be similarly affected. Blood and urine samples collected from women prescribed metformin for type 2 diabetes, gestational diabetes, and polycystic ovarian syndrome during early, mid, and late pregnancy (n = 34 visits) and postpartum (n = 14 visits) were analyzed for 1-NMN using liquid chromatography-mass spectrometry. The renal clearance and secretion clearance, using creatinine clearance to correct for glomerular filtration, were estimated for 1-NMN and correlated with metformin renal clearance. 1-NMN renal clearance was higher in both mid (504 ± 293 ml/min, P < 0.01) and late pregnancy (557 ± 305 ml/min, P < 0.01) compared with postpartum (240 ± 106 ml/min). The renal secretion of 1-NMN was 3.5-fold higher in mid pregnancy (269± 267, P < 0.05) and 4.5-fold higher in late pregnancy compared with postpartum (342 ± 283 versus 76 ± 92 ml/min, P < 0.01). Because creatinine is also a substrate of OCT2, MATE1, and MATE2-K, creatinine clearance likely overestimates filtration clearance, whereas the calculated 1-NMN secretion clearance is likely underestimated. Metformin renal clearance and 1-NMN renal clearance were positively correlated (rs = 0.68, P < 0.0001). 1-NMN renal clearance increases during pregnancy due to increased glomerular filtration and net secretion by renal transporters.

Hydralazine, an antihypertensive agent used during pregnancy, undergoes N-acetylation primarily via N-acetyltransferase 2 (NAT2) to form 3-methyl-1,2,4-triazolo[3,4-a]phthalazine (MTP). To characterize the steady-state pharmacokinetics (PK) of hydralazine during pregnancy and evaluate the effects of NAT2 genotype on hydralazine and MTP PK during pregnancy, 12 pregnant subjects received oral hydralazine (5-25 mg every 6 hours) in mid- (n = 5) and/or late pregnancy (n = 8). Serial blood samples were collected over 1 dosing interval, and steady-state noncompartmental PK parameters were estimated. Subjects were classified as either (rapid acetylators, n = 6) or slow acetylators (SAs, n = 6) based on NAT2 genotype. During pregnancy, when compared with the SA group, the RA group had faster weight-adjusted hydralazine apparent oral clearance (70.0 ± 13.6 vs 20.1 ± 6.9 L/h, P < .05), lower dose-normalized area under the concentration-time curve (AUC; 1.5 ± 0.8 vs 5.9 ± 3.7 ng·h/mL, P < .05), lower dose-normalized peak concentrations (0.77 ± 0.51 vs 4.04 ± 3.18 ng/mL, P < .05), and larger weight-adjusted apparent oral volume of distribution (302 ± 112 vs 116 ± 45 L/kg, P < .05). Furthermore, the MTP/hydralazine AUC ratio was ∼10-fold higher in the RA group (78 ± 30 vs 8 ± 3, P < .05) than in the SA group. No gestational age or dose-dependent effects were observed, possibly because of the small sample size. This study describes for the first time, the PK of oral hydralazine and its metabolite, MTP, during pregnancy, and confirmed that the PK of oral hydralazine is NAT2 genotype dependent during pregnancy.

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.

The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25–750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was

Objective: Hypertension is a major risk factor for poor pregnancy outcomes. Many observational studies have relied on diagnosis codes, particularly from the delivery hospitalization, to identify hypertension in pregnancy. We augmented diagnosis codes with electronic blood pressure (BP) data to improve the identification of pregnant women with hypertension. Methods: We studied pregnant women aged 15-49 years enrolled in three Kaiser Permanente health plans who delivered during 2005-2014. Using diagnosis codes, BP values, and antihypertensive medication dispensings, we defined hypertension as: (1) ≥ 2 high BPs (≥ 140/90 mmHg) within 30 days of each other (2highBPs); or (2) ≥ 1 antihypertensive medication fill with ≥1 hypertension diagnosis code from 120 days prior to pregnancy through 20 weeks gestation (chronicHTN); or (3) ≥ 1 high BP, a hypertension diagnosis code, and an antihypertensive fill within 7 days (RapidTx). Among women meeting our study definition, we examined receipt of hypertension diagnosis codes and prevalence of severe hypertension (1+ BP ≥160/110 mmHg). Results: Among 553,477 eligible women, 29,933 (5%) met our definition of hypertension, including 26,855 identified via 2highBPs, 5,774 via chronicHTN and 6,198 via RapidTx (not mutually exclusive). Among women meeting our hypertension definition overall, only 64% had 1+ hypertension diagnosis code assigned during pregnancy, and 49% had one at delivery. Among hypertensive women identified via 2highBPs, only 60% (16,057/26,855) had a hypertension diagnosis code in pregnancy and 45% (12,131/ 26,855) at delivery. However, 53% of our hypertensive women (14,972/ 29,933) overall and 56% (14,972/ 26,855) of the 2highBPs women had severe hypertension at some time during pregnancy. Conclusion: Incorporating BP values identifies additional pregnant women with hypertension who would have been missed by approaches using diagnosis codes alone. Women identified by our method frequently had severely elevated BP, showing the importance of including these women in future studies of hypertension during pregnancy.

Objective: In the U.S., 1.3 million women of reproductive age take antihypertensive medications for chronic hypertension. However, some of these medications are considered unsafe during pregnancy. We evaluated the burden of switching and stopping medications during pregnancy among women receiving treatment for chronic hypertension. Study Design: We identified a population-based cohort of women with chronic hypertension who received antihypertensive medications within 120 days before pregnancy and gave birth to a singleton between 2005 and 2014 within three Kaiser Permanente regions. We characterized women’s antihypertensive medication use from 120 days before pregnancy through delivery. We ascertained the highest systolic and diastolic blood pressures in the 120 days before the start of pregnancy and supplemented these values with measures up through 8 weeks’ gestation when pre-pregnancy values were missing. Results: 5,782 pregnant women were included. Prior to pregnancy, the most commonly used medication classes were thiazide diuretics (2,370/5,782, 41%), beta-blockers (1,569/5,782, 27%) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) (1,391/5,782, 24%). In contrast, the predominant medications during pregnancy were labetalol (2,165/5,782, 37%) and methyldopa (1,593/5,782, 28%). During pregnancy, 18% of the cohort (1,037/5,782) had no antihypertensive medication fills. Women taking ACEI/ARBs or thiazides before pregnancy were the most likely to have no medication fills in pregnancy (23% and 20%, respectively). Many women (n=881) had at least one severe high BP (SBP ≥160 or DBP ≥110) before pregnancy, and in this group, 15% (132/881) filled no medications throughout pregnancy. Conclusion: Women with chronic hypertension frequently stop antihypertensive medications during pregnancy, even women with a severely high BP documented before pregnancy. Research is needed to understand impact of these treatment interruptions on pregnancy outcomes and women’s long-term health.

Background Maternal mortality and severe maternal morbidity are growing public health concerns in the United States. The Centers for Disease Control and Prevention Severe Maternal Morbidity measure provides insight into processes underlying maternal mortality and may highlight modifiable risk factors for adverse maternal health outcomes. Objective The primary objective of this study was to evaluate the association between hypertensive disorders and severe maternal morbidity at a regional perinatal referral center. We hypothesized that women with preeclampsia with severe features would have a higher rate of severe maternal morbidity compared to normotensive women. We also assessed the proportion of severe maternal morbidity diagnoses that were present on admission, in contrast to those arising during the delivery hospitalization. Study Design In this retrospective cross-sectional analysis, we assessed rates of severe maternal morbidity diagnoses (eg, renal insufficiency, shock, and sepsis) and procedures (eg, transfusion and hysterectomy) for all 7025 women who delivered at the University of Washington Medical Center from Oct. 1, 2013, through May 31, 2017. Severe maternal morbidity was determined from prespecified International Classification of Diseases diagnosis and procedure codes; all diagnoses were confirmed by chart review. Present-on-admission rates were calculated for each diagnosis through hospital administrative data provided by the Vizient University Health System Consortium. Maternal demographic and clinical characteristics were compared for women with and without severe maternal morbidity. The χ2 and Fisher exact tests were used to determine statistical significance. Odds ratios and 95% confidence intervals were calculated for the associations between maternal demographic and clinical characteristics and severe maternal morbidity. Results Of 7025 deliveries, 284 (4%) had severe maternal morbidity; 154 had transfusion only, 27 had other procedures, and 103 women had 149 severe maternal morbidity diagnoses (26 women had multiple diagnoses). Severe preeclampsia occurred in 438 deliveries (6.2%). Notably, hypertension was associated with severe maternal morbidity in a dose-dependent fashion, with the strongest association observed for preeclampsia with severe features (odds ratio, 5.4; 95% confidence interval, 3.9–7.3). Severe maternal morbidity was also significantly associated with preeclampsia without severe features, chronic hypertension, preterm delivery, pregestational diabetes, and multiple gestation. Among women with severe maternal morbidity, over one third of preterm births were associated with maternal hypertension. American Indian/Alaskan Native women had significantly higher severe maternal morbidity rates compared to other racial/ethnic groups (11.7% vs 3.9% for Whites, P Conclusion Hypertensive disorders in pregnancy are strongly associated with severe maternal morbidity in a dose-dependent relationship, suggesting that strategies to address rising maternal morbidity rates should include early recognition and management of hypertension. Prevention strategies focused on hypertension might also impact medically indicated preterm deliveries. The finding of increased severe maternal morbidity among American Indian/Alaskan Native women, a disadvantaged population in Washington State, underscores the role that socioeconomic factors may play in adverse maternal health outcomes. As 39% of severe maternal morbidity diagnoses were present on admission, this measure should be risk-adjusted if used as a quality metric for comparison between hospitals.

PURPOSE: The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites (5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)) during pregnancy (n=2) and postpartum (n=1). METHODS: Non-compartmental DTIC, MTIC, HMMTIC and AIC pharmacokinetics (PK) were estimated in one case at 29 weeks gestation and 18 days postpartum and a second case at 32 weeks gestation, in women receiving DTIC in combination with doxorubicin, bleomycin and vinblastine for treatment of Hodgkin’s Lymphoma. Drug concentrations were measured by HPLC. RESULTS: In the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration-time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 years follow-up, both subjects were in remission of their Hodgkin’s Lymphoma. CONCLUSIONS: Based on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both of these subjects experienced long-term remission of their Hodgkin’s Lymphoma.

To evaluate the steady-state pharmacokinetics of prednisone and its metabolite prednisolone in pregnant and lactating female subjects, 19 subjects received prednisone (4-40 mg/day orally) in early (n = 3), mid (n = 9), and late (n = 13) pregnancy as well as postpartum with (n = 2) and without (n = 5) lactation. Serial blood and urine samples were collected over 1 dosing interval. Prednisone and its metabolite, prednisolone, steady-state noncompartmental pharmacokinetic parameters were estimated. During pregnancy, prednisone apparent oral clearance increased with dose (35.1 ± 11.4 L/h with 5 mg, 52.6 ± 5.2 L/h with 10 mg, and 64.3 ± 6.9 L/h with 20 mg, P = .001). Similarly, unbound prednisone apparent oral clearance increased with dose. In addition, prednisolone renal clearance increased with dose (0.3 ± 0.3 L/h with 5 mg, 0.5 ± 0.4 L/h with 10 mg, and 1.3 ± 1.1 L/h with 20 mg, P = .002). Higher prednisone (r = 0.57, P ≤ .05) and prednisolone (r = 0.75, P ≤ .05) concentrations led to a higher percentage of unbound drug. Breast-milk/plasma area under the concentration-time curve ratios were 0.5-0.6 for prednisone and 0.02-0.03 for prednisolone. Relative infant doses were 0.35% to 0.53% and 0.09% to 0.18%, for prednisone and prednisolone, respectively. Prednisone and prednisolone exhibit dose- and concentration-dependent pharmacokinetics during pregnancy, and infant exposure to these agents via breast milk is minimal.

Aims Physiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy. Methods A multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration–time profiles were analyzed using both non-compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS. Results The systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19–36)% (P

Complications of portal hypertension, such as variceal hemorrhage and ascites, are associated with significant increases in both mortality and complications during pregnancy. Transjugular intrahepatic portosystemic shunt (TIPS) is a well-established procedure for treating portal hypertension, but the safety of TIPS during pregnancy is largely unknown. In this series, we review five patients who underwent TIPS placement while pregnant and describe their clinical outcomes. Five pregnant patients with cirrhosis and portal hypertension underwent elective TIPS for complications of portal hypertension (four for secondary prevention of variceal bleeding and one for refractory ascites). Outcomes measured were recurrent bleeding episodes or need for further paracenteses during pregnancy, estimated radiation dose to the fetus and gestational age at delivery. All patients were followed after delivery to evaluate technical and clinical success of the procedure. All five patients survived pregnancy and went on to deliver successfully. When TIPS was performed for secondary prevention of variceal bleeding (n = 4), no patients demonstrated variceal bleeding after TIPS placement. When TIPS was performed for refractory ascites (n = 1), no further paracenteses were required. All patients delivered successfully, albeit prematurely. Average radiation dose estimated to the fetus was 16.3 mGy. This series suggests that TIPS can be performed in selective pregnant patients with portal hypertension, with little added risk to the mother or fetus.

Hypertension in pregnancy remains a significant cause of maternal and neonatal morbidity and mortality. The structure of prenatal care with increasing frequency of visits near term is designed to identify generally asymptomatic women with hypertension or proteinuria and deliver them before the development of life-threatening hypertension. In the developed world, this strategy has been generally successful with marked reductions in the rates of maternal mortality and eclampsia. In low- and middle-income countries, where access and use of prenatal care are limited, maternal mortality and eclampsia remain commonplace. Treatment of severe hypertension (systolic blood pressure [DB], ≥160 mm Hg; or diastolic BP, ≥110 mm Hg) is broadly recommended.1,2 The California Maternal Quality Care Collaborative mandates initiation of treatment of severe hypertension within 1 hour of confirmation as minimal requirement for standard process.3 In contrast, the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on Hypertension in Pregnancy recommends withholding antihypertensive therapy for BPs 160/110 mm Hg seem logically inconsistent. The Control of Hypertension in Pregnancy Study (CHIPS) was a multicenter randomized, controlled trial of BP management in pregnancy.4 The trial was designed to evaluate what the authors described as tight control compared with less tight control. The trial was pragmatic in that pregnant women between 14 and 34 weeks of gestation with a diastolic BP of ≥90 mm Hg (≥85 mm Hg if on antihypertensive medication) were eligible without regard to classification of gestational or chronic hypertension; randomization was stratified to achieve a balance between groups. Seventy-five percent had chronic hypertension. Women with proteinuria, severe, uncontrolled hypertension, and comorbidities were …

Preeclampsia is a devastating complication of pregnancy. Soluble Fms-like tyrosine kinase-1 (sFlt-1) is an antiangiogenic protein believed to mediate the signs and symptoms of preeclampsia. We conducted an open pilot study to evaluate the safety and potential efficacy of therapeutic apheresis with a plasma-specific dextran sulfate column to remove circulating sFlt-1 in 11 pregnant women (20–38 years of age) with very preterm preeclampsia (23–32 weeks of gestation, systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, new onset protein/creatinine ratio >0.30 g/g, and sFlt-1/placental growth factor ratio >85). We evaluated the extent of sFlt-1 removal, proteinuria reduction, pregnancy continuation, and neonatal and fetal safety of apheresis after one (n=6), two (n=4), or three (n=1) apheresis treatments. Mean sFlt-1 levels were reduced by 18% (range 7%–28%) with concomitant reductions of 44% in protein/creatinine ratios. Pregnancy continued for 8 days (range 2–11) and 15 days (range 11–21) in women treated once and multiple times, respectively, compared with 3 days (range 0–14) in untreated contemporaneous preeclampsia controls (n=22). Transient maternal BP reduction during apheresis was managed by withholding pre-apheresis antihypertensive therapy, saline prehydration, and reducing blood flow through the apheresis column. Compared with infants born prematurely to untreated women with and without preeclampsia (n=22 per group), no adverse effects of apheresis were observed. In conclusion, therapeutic apheresis reduced circulating sFlt-1 and proteinuria in women with very preterm preeclampsia and appeared to prolong pregnancy without major adverse maternal or fetal consequences. A controlled trial is warranted to confirm these findings.

Introduction Management of severe hypertension in pregnancy requires prompt treatment – most commonly with intravenous medications. This strategy presents significant barriers to care, particularly in low resource environments. Objective To compare the effectiveness of three oral antihypertensive regimens in pregnant women with severe hypertension. Methods In an open-labeled trial in two hospitals in Nagpur, India, (NCT01912677), pregnant women ⩾28 weeks’ gestation with sBP ⩾160 mmHg or dBP ⩾110 mmHg were randomized to: (1) nifedipine 10 mg orally repeated hourly up to 2 additional doses for sBP >155 mmHg or dBP >105 mmHg, (2) labetalol 200 mg orally repeated hourly for 2 additional doses as above, or (3) methyldopa 1000 mg as a single dose. The primary outcome was achieving a sBP 120–150 mmHg and dBP 70-100mHg at 6 h without an adverse outcome or fetal compromise. Results 894 women were randomized: nifedipine (n = 298), 83.2% achieved primary outcome, (0.7% required additional drugs); labetalol (n = 295), 77.3% achieved primary outcome, (3.1% required additional drugs); methyldopa (n = 301), 76.4% achieved primary outcome, (18.3% required additional drugs), (NvsMD p = 0.04) X 2 ; (LvsMD p = 0.08), X 2 ; (NvsL p = 0.07) X 2. Without use of additional drugs, nifedipine and labetalol were superior to methyldopa, (P 0.001) X 2. Nifedipine was associated with maternal tachycardia, (p 0.001) X 2 ; persistence of headache, (p = 0.005) X 2 ; and a greater likelihood of neonatal admission to the NICU, (NvsMD p = 0.01) X 2 ; (LvsMD p = 0.6), X 2 ; (NvsL p = 0.06) X 2. MgSO 4 use was limited, 11.7%. The eclampsia rate was 0.1%. There were no maternal deaths or ICU admissions. 96% of infants were born alive; 95% of live-born were alive at discharge. Discussion Each regimen achieved some success. As a single agent, nifedipine and labetalol were superior to methyldopa. A structured approach of measuring BP and intervention with oral medications in a high risk environment achieved low rates of maternal and neonatal complications despite some differences in BP control across groups. This was achieved with a low rate of MgSO 4 utilization.

Aim(s) The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk. Methods Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject. Results Mean (±SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng ml−1) were 71 ± 18% (range 45–99%) of maternal concentrations (9.0 ± 3.4 ng ml−1). The mean umbilical cord venous plasma (0.09 ± 0.04 ng ml−1) and unbound drug concentrations (0.003 ± 0.001 ng ml−1) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. Conclusions Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant.

Objectives: Previously preeclamptic women may express cognitive difficulties, which have largely been unappreciated or attributed to stresses of a complicated pregnancy. This study aimed to explore the scope of perceived neurocognitive and psychosocial problems as well as quality of life following preeclampsia.Study design: Observational study. Through website promotion and e-mail, registrants of the USA-based Preeclampsia Foundation who experienced preeclampsia in the past 20 years were invited to complete a web-based survey. Participants were requested to ask an acquaintance that had a normotensive pregnancy to also complete the survey (controls).Main outcome measures: The Cognitive Failures Questionnaire (CFQ), abbreviated WHO Quality Of Life questionnaire (WHOQOL-BREF), Social Functioning Questionnaire (SFQ) and Breslau Short Screening Scale for DSM-IV Posttraumatic Stress Disorder were used in the survey. Analysis was performed using Mann-Whitney U tests and linear regression.Results: 966 cases and 342 controls completed the survey (median age 34, median time since first pregnancy 4 vs. 5 years). Cases scored significantly worse on CFQ (median 35 vs. 27), WHOQOL-BREF domains physical health (15 vs. 17), psychological (13 vs. 15), social relationships (13 vs. 15) and environment (15 vs. 16), and SFQ (8 vs. 7). All p Conclusions: Previously preeclamptic women appear to perceive more cognitive and social problems, and report poorer quality of life compared to a group of women with normotensive pregnancies. Research relating to the origin and management of these issues is needed. (C) 2013 International Society for the Study of Hypertension in Pregnancy Published by Elsevier B.V. All rights reserved.

Objective To compare magnesium sulphate concentrations achieved by intramuscular and intravenous regimens used for the prevention of eclampsia. Setting Low-resource obstetric hospitals in Nagpur and Vellore, India. Population Pregnant women at risk for eclampsia due to hypertensive disease. Methods A pharmacokinetic study was performed as part of a randomised trial that enrolled 300 women comparing intramuscular and intravenous maintenance regimens of magnesium dosing. Data from 258 enrolled women were analysed in the pharmacokinetic study. A single sample was drawn per woman with the expectation of using samples in a pooled data analysis. Main outcome measures Pharmacokinetic parameters of magnesium distribution and clearance. Results Magnesium clearance was estimated to be 48.1 dl/hour, volume of distribution to be 156 dl and intramuscular bioavailability to be 86.2%. The intramuscular regimen produced higher initial serum concentrations, consistent with a substantially larger loading dose. At steady state, magnesium concentrations in the intramuscular and intravenous groups were comparable. With either regimen, a substantial number of women would be expected to have serum concentrations lower than those generally held to be therapeutic. Conclusions Clinical implications were that a larger loading dose for the intravenous regimen should be considered; where feasible, individualised dosing of magnesium sulphate would reduce the variability in serum concentrations and might result in more women with clinically effective magnesium concentrations; and lower dose magnesium suphate regimens should be considered with caution.

Information on the pharmacokinetics of tacrolimus during pregnancy is limited to case reports despite the increasing number of pregnant women being prescribed tacrolimus for immunosuppression.Blood, plasma, and urine samples were collected over 1 steady-state dosing interval from women treated with oral tacrolimus during early to late pregnancy (n = 10) and postpartum (n = 5). Total and unbound tacrolimus as well as metabolite concentrations in blood and plasma were assayed by a validated liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. A mixed-effect linear model was used for comparison across gestational age and using postpartum as the reference group.The mean oral clearance (CL/F) based on whole-blood tacrolimus concentration was 39% higher during mid-pregnancy and late pregnancy compared with postpartum (47.4 ± 12.6 vs. 34.2 ± 14.8 L/h, P0.03). Tacrolimus-free fraction increased by 91% in plasma (f(P)) and by 100% in blood (f(B)) during pregnancy (P = 0.0007 and 0.002, respectively). Increased fP was inversely associated with serum albumin concentration (r = -0.7, P = 0.003), which decreased by 27% during pregnancy. Pregnancy-related changes in f(P) and f(B) contributed significantly to the observed gestational increase in tacrolimus whole-blood CL/F (r² = 0.36 and 0.47, respectively, P0.01). In addition, tacrolimus whole-blood CL/F was inversely correlated with both hematocrit and red blood cell counts, suggesting that binding of tacrolimus to erythrocytes restricts its availability for metabolism. Treating physicians increased tacrolimus dosages in study participants during pregnancy by an average of 45% to maintain tacrolimus whole-blood trough concentrations in the therapeutic range. This led to striking increases in unbound tacrolimus trough concentrations and unbound area under the concentration-time curve, by 112% and 173%, respectively, during pregnancy (P = 0.02 and 0.03, respectively).Tacrolimus pharmacokinetics are altered during pregnancy. Dose adjustment to maintain whole-blood tacrolimus concentration in the usual therapeutic range during pregnancy increases circulating free drug concentrations, which may impact clinical outcomes.

N1-methylnicotinamide (1-NMN) has been investigated as an endogenous probe for the renal transporter activity of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2-K (MATE1 and MATE2-K). As pregnancy increased the renal secretion of metformin, a substrate for OCT2, MATE1, and MATE2-K, we hypothesized that the renal secretion of 1-NMN would be similarly affected. Blood and urine samples collected from women prescribed metformin for type 2 diabetes, gestational diabetes, and polycystic ovarian syndrome during early, mid, and late pregnancy (n = 34 visits) and postpartum (n = 14 visits) were analyzed for 1-NMN using liquid chromatography-mass spectrometry. The renal clearance and secretion clearance, using creatinine clearance to correct for glomerular filtration, were estimated for 1-NMN and correlated with metformin renal clearance. 1-NMN renal clearance was higher in both mid (504 ± 293 ml/min, P < 0.01) and late pregnancy (557 ± 305 ml/min, P < 0.01) compared with postpartum (240 ± 106 ml/min). The renal secretion of 1-NMN was 3.5-fold higher in mid pregnancy (269± 267, P < 0.05) and 4.5-fold higher in late pregnancy compared with postpartum (342 ± 283 versus 76 ± 92 ml/min, P < 0.01). Because creatinine is also a substrate of OCT2, MATE1, and MATE2-K, creatinine clearance likely overestimates filtration clearance, whereas the calculated 1-NMN secretion clearance is likely underestimated. Metformin renal clearance and 1-NMN renal clearance were positively correlated (rs = 0.68, P < 0.0001). 1-NMN renal clearance increases during pregnancy due to increased glomerular filtration and net secretion by renal transporters.

In the absence of uncontrolled hypertension or renal insufficiency, many consider the perinatal outcomes in pregnant women with nephrotic syndrome to be good. To further investigate this we performed a retrospective chart review of women with biopsy-proven nephrotic syndrome due to primary glomerular disease during pregnancy at a single tertiary center. Our review determined characteristics, presentation, management, pathologic diagnoses, and associated renal and maternal-fetal outcomes of 19 individuals with 26 pregnancies and 26 offspring. The mean age was 27.6 years, the mean gestational age at the presentation of nephrotic syndrome was 18.6 weeks, the mean creatinine was 0.85 mg/dL, mean serum albumin was 1.98 g/dL, and the mean proteinuria was 8.33 g/24 hours. The mean cardiac output was 8.6 L/minute, which was elevated compared to normal pregnancy. A kidney biopsy was performed during pregnancy in 8 individuals (median gestational age at time of biopsy was 21 weeks), changing management in six. Of the 26 pregnancies, maternal complications included preeclampsia in seven, acute kidney injury in six, premature rupture of membranes in two, and cellulitis in three. The mean age of gestation at delivery was 35.5 weeks. Fetal complications included low birth weight (under 2,500 g) in 14, intra-uterine growth restriction in three, and neonatal intensive care unit admission in eight. Thus, pregnant women with nephrotic syndrome are at high risk for developing both maternal and fetal complications, even in the absence of significant renal impairment or uncontrolled hypertension at the time of presentation of nephrotic syndrome.

Objective To test the safety, efficacy, and acceptability of a simple, mechanically flow-controlled pump (Springfusor®) for the delivery of magnesium sulfate for the treatment of preeclampsia. Design Eligible women ( n =300) had blood pressure ⩾140/100mmHg, and proteinuria ⩾1+ (30mgdL); the clinic team determined that they were likely to benefit from magnesium sulfate. Women were randomized to 24h of magnesium sulfate by either IV administered by the Springfusor® pump ( n =147) or standard hospital practice – IV loading dose administered manually followed by maintenance therapy using an IM route of administration ( n =153). Main outcome measures Our primary outcome of interest was the safety and efficacy of the Springfusor pump including the side and adverse effects experienced during drug administration. Data on side effects, patient acceptability, delivery complications, and maternal and neonatal outcomes were collected. Results Fewer women stopped treatment due to side effects, toxicity, oliguria or renal failure, or women's request in the Springfusor arm (4% or 6 of 147 women) compared to the Standard of Care arm (6.5% or 10 of 153 women). Women in the Springfusor arm reported significantly less nausea, headache, and pain than women in the Standard of Care arm. Almost all women (97%) in the Springfusor arm reported their pain level as ‘acceptable' or ‘very acceptable' compared to only 30% of women given the Standard of Care. Conclusion The Springfusor pump may offer an alternative to intramuscular administration of magnesium sulfate where electronic pumps are not available.

Objective. We evaluated the association of 1-h oral glucose challenge test (OGCT) and 3-h oral glucose tolerance test (OGTT) results with preeclampsia. Methods. A retrospective cohort study was performed among 26,105 women. Results. Preeclampsia was associated with the upper OGCT quartiles [114–132 mg/dL: odds ratio (OR) = 1.25, 95% confidence interval (CI) 1.09–1.44; >132 mg/dL: OR = 1.40, 95% CI 1.21–1.61] compared with

Between 62,000 and 77,000 women die annually from pre-eclampsia/eclampsia. Prompt delivery, preferably by the vaginal route, is vital for good maternal and neonatal outcomes. Two low cost interventions -low dose oral misoprostol tablets and transcervical Foley catheterisation- are already used in low resource settings. In this open label, parallel randomised study, our objective was to compare their relative risks and benefits. 602 women with a live fetus requiring delivery for pre-eclampsia or hypertension were randomly assigned to labour induction with oral misoprostol 25 micrograms every 2 h (maximum of 12 doses) or a transcervical Foley catheter (size 18 F with 30 ml balloon) which remained until active labour started, the Foley catheter fell out, or 12 h elapsed. Randomisation was computer-generated with allocation concealment by opaque sequentially numbered sealed envelopes. Induction continued with artificial membrane rupture and oxytocin, administered through a micro-drip gravity infusion set. Fetal monitoring was by intermittent auscultation. The primary outcome was vaginal birth within 24 h, and trial registration as with ClinicalTrials.gov (NCT01801410). 302 women were allocated to misoprostol and 300 women to Foley catheter; all were analysed. More women in the misoprostol arm had a vaginal birth within 24 h (57.0% vs. 47.0%; absolute risk difference (RD) 10.0%, with 95%CI 2.0% to 17.9%). Rates of uterine hyperstimulation were very low in both groups (0.7% vs 0.3%; RD 0.3%; −0.8% to 1.5%) and no differences were seen in neonatal morbidity. More women in the misoprostol group would use the same method in the future should they require another induction (82.8% vs. 72.0%; RD 10.8%; 4.2% to 17.4%). Oral misoprostol 25 micrograms was more effective and more acceptable to women than a transcervical Foley catheter for induction of labour in women requiring delivery because of pre-eclampsia or hypertension. MRC/DFID/Wellcome Trust Joint Global Health Trials Scheme (Ref. G1100686/1).

BACKGROUND Clonidine, a centrally acting antihypertensive agent, has been used successfully in pregnancy. We sought to describe the pharmacodynamic effects of clonidine in pregnancy and the associated impact on fetal growth. METHODS A retrospective cohort study was performed. Maternal hemodynamics were measured before and after treatment. Responses to clonidine were categorized by the predominant hemodynamic effect: decreased vascular resistance, decreased cardiac output (CO), or mixed. Multinomial logistic regression was used to evaluate predictors of hemodynamic response to clonidine and association between response group and birth weight. RESULTS Sixty-six pregnant women were studied. Treatment was associated with a reduction of mean arterial pressure (MAP) (-9.2 mm Hg, P < 0.001), a reduction in total peripheral resistance (TPR) (-194 dyne·cm·sec⁻⁵, P < 0.001), and an increase in CO (+0.5 l/min, P < 0.001). The hemodynamic response was characterized by decreased resistance in 34 women; decreased CO in 22; and mixed effect in 10. No maternal demographic characteristics were associated with a reduction in CO. Mean birth weight percentile was lower in the group that experienced a reduction in CO compared to the group with a reduction in vascular resistance (26.1 vs. 43.6, P = 0.02). The rate of birth weight

Clonidine is a centrally acting, alpha-2 adrenergic agonist used for the treatment of hypertension during pregnancy. The metabolic pathways of clonidine are poorly understood, and the quantitative contribution of specific human cytochrome P450 (P450) isoforms has not been systematically assessed. In this study, 17 cDNA-expressed P450 enzymes, in addition to pooled human liver microsomes, were evaluated for clonidine 4-hydroxylation activity in vitro. Five P450 enzymes-CYP2D6, 1A2, 3A4, 1A1, and 3A5-catalyzed measurable formation of 4-hydroxyclonidine. Selective inhibition studies in human liver microsomes confirmed that these isoforms are jointly responsible for 4-hydroxylation of clonidine in vitro, and CYP2D6 accounted for approximately two-thirds of the activity. The major role of CYP2D6 in clonidine metabolism might explain the increase in its nonrenal clearance during pregnancy.

Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n = 35) and postpartum (n = 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 +/- 243 ml/min, P < 0.01) and late pregnancy (625 +/- 130 ml/min, P < 0.01) compared with postpartum (477 +/- 132 ml/min). These changes reflected significant increases in creatinine clearance (240 +/- 70 ml/min, P < 0.01 and 207 +/- 56 ml/min, P < 0.05 versus 165 +/- 44 ml/min) and in metformin net secretion clearance (480 +/- 190 ml/min, P < 0.01 and 419 +/- 78 ml/min, P < 0.01 versus 313 +/- 98 ml/min) in mid and late pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (

Cardiac output and sFlt-1 are elevated prior to clinical evidence of preeclampsia. Early treatment of high cardiac output with atenolol decreases the risk for preeclampsia. We hypothesized that atenolol would impact circulating sFlt-1.Cardiac output and plasma sFlt-1 were measuredor=24 weeks' gestation and every 6 to 8 weeks in a longitudinal pilot study of: 1) women with risk factors for preeclampsia (high-risk group; n=46) who were treated with atenolol, and 2) low-risk group (control, n=25) who were not treated.The groups were similar in maternal age (mean+/-SD: high-risk 28.3+/-5.4 versus control 30.3+/-5.5 years) and enrollment gestational age (17.3+/-4.3 versus 16.1+/-4.2 weeks). The high-risk group had higher cardiac output (9.7+/-1.7 versus 7.3+/-1.7 L/min; p0.001) and mean arterial pressure (91.8+/-10.6 versus 79.6+/-7.3 mm Hg; p0.001). Cardiac output and mean arterial pressure decreased while sFlt-1 levels rose less in the high-risk group compared with controls (p=0.001 for all using GEE) even after adjusting for preeclampsia risk factors (age, weight, and primigravida status).Atenolol in high-risk women was associated with a lower rise in sFlt-1, suggesting an effect of hemodynamically directed treatment on the anti-angiogenic state.

Amoxicillin is recommended for anthrax prevention in pregnancy. The objective of this study was to evaluate the pharmacokinetics of amoxicillin during pregnancy and postpartum (PP). Sixteen women received amoxicillin during gestation (18-22 weeks (T2) and 30-34 weeks (T3)) as well as 3 months postpartum (PP) to evaluate single-dose pharmacokinetics. Amoxicillin compartmental pharmacokinetic parameters were used to simulate amoxicillin concentration-time profiles following different dosage strategies. Amoxicillin CL(renal) (T2: 24.8+/-6.7 l/h, P

Background Preeclampsia complicates approximately 3–5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking. Objective As an initial step in evaluating the utility of pravastatin in preventing preeclampsia and after consultation with the US Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia. Study Design We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12 0/7 and 16 6/7 weeks' gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (clinicaltrials.gov identifier NCT01717586). Results Ten women assigned to pravastatin and 10 to placebo completed the trial. There were no differences between the 2 groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared with postpartum. Four subjects in the placebo group developed preeclampsia compared with none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile. Conclusion This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.

Introduction Previously preeclamptic women may express cognitive difficulties, which have largely been ignored or attributed to the stresses of a complicated pregnancy. Objectives This study aimed to identify the scope of neurocognitive and psychosocial problems following preeclampsia. Methods Through website promotion and a mass e-mail members of the USA-based Preeclampsia Foundation who experienced preeclampsia in the past 20 years were invited to complete a web-based survey, consisting of a questionnaire about current and past medical health, the Cognitive Failures Questionnaire (CFQ), the abbreviated WHO Quality Of Life questionnaire (WHOQOL-BREF), and the Social Functioning Questionnaire (SFQ). Participants were stimulated to ask a friend who had a normotensive pregnancy to complete the survey as well (controls). Women with current or past neurological conditions were excluded. Analysis was performed using Mann Whitney U test and linear regression. Results 966 cases and 342 controls were included. Median age was 34, median time since first pregnancy 4 and 5 years respectively. Cases scored significantly worse on all three questionnaires, and more often underwent psychiatric therapy, currently or in the past. There was a significant effect of migraine on all questionnaires and of eclampsia on CFQ score. Cronbach's alphas were >0.7, indicating good internal consistency of the questionnaires. Cases (n=966)Controls (n=342)CFQTotal score35 (3;69)27 (5;62) ∗ WHOQOL-BREFQuality of life4 (1;5)4 (2;5) ∗ Satisfaction with health3 (1;5)4 (1;5) ∗ Physical health domain15 (5;20)17 (9;20) ∗ Psychological domain13 (4;19)15 (6;20) ∗ Social relationships domain13 (4;20)15 (4;20) ∗ Environment domain15 (7;20)16 (8;20) ∗ SFQTotal score8 (0;22)7 (0;19) ∗ Results are expressed as median (range) or number (percentage) ∗ p Conclusion Previously preeclamptic women report more cognitive and social problems, and worse quality of life compared to women who had normotensive pregnancies. Health care providers and patients should be aware of this so that affected women may receive recognition, psychological care and escape from the ignorance of their environment. Our findings may stimulate research relating to the origin and management of these important issues.

Nephropathy complicates 5% to 10% of pregnancies in women with diabetes and is associated with adverse outcomes. Given the importance of blood pressure (BP) control in reducing cardiovascular and renal complications outside of pregnancy, we hypothesized that poorly controlled hypertension in early pregnancy among women with diabetic nephropathy would be associated with adverse outcomes.To examine the impact of hypertensive control in early pregnancy on perinatal outcomes, we performed a retrospective cohort study of pregnancies complicated by diabetic nephropathy with "Above Target" mean arterial pressure (or = 100 mm Hg; N = 21) and "Below Target" mean arterial pressure (100 mm Hg; N = 22), which approximates the American Diabetes Association and the Seventh Report of the Joint National Committee recommended target of 130/80 mm Hg, measured at20 weeks' gestation.There were no differences in maternal age (mean +/- SEM: 27.2 +/- 1.2 v 29.5 +/- 1.0 years), duration of diabetes (median, range: 17.5, 13 to 24 v 16, 1 to 25 years), or glucose control (glycosylated hemoglobin [HbA1c] 8.0% +/- 0.3% v 8.1% +/- 0.4%) between the Above and Below Target groups. The Above Target group had more proteinuria (4.69 +/- 1.08 v 1.65 +/- 0.43 g/24 h; P = .007) and higher serum creatinine levels (1.23 +/- 0.17 v 0.85 +/- 0.06 mg/dL; P = .02). The Above Target group was more likely to deliver at32 weeks' gestation (38.1% v 4.6%; P = .007). The increased risk of preterm delivery remained significant after adjusting for duration of diabetes and glucose control.Suboptimal control of hypertension in early pregnancy in women with diabetic nephropathy is associated with a significant risk of preterm delivery. Improved preconceptional control of hypertension may reduce adverse perinatal outcomes in women with diabetic nephropathy.

Women who develop preeclampsia have a higher risk of future cardiovascular disease and diabetes compared to women who have uncomplicated pregnancies. We hypothesized that women with prior preeclampsia would have increased visceral adiposity that would be a major determinant of their metabolic and cardiovascular risk factors.We compared intraabdominal fat (IAF) area, insulin sensitivity index (SI), fasting lipids, low-density lipoprotein relative flotation rate, and brachial artery flow-mediated dilatation in 49 women with prior preeclampsia and 22 controls who were at least 8 months postpartum and matched for age, parity, body mass index, and months postpartum. Women were eligible if they did not smoke tobacco, use hormonal contraception, have chronic hypertension, or have a history of gestational diabetes.The groups were similar for age (mean ± SD: prior preeclampsia 33.4 ± 6.6 vs control 34.6 ± 4.3 years), parity (median: 1 for both), body mass index (26.7 ± 5.9 vs 24.0 ± 7.3 kg/m(2)), and months postpartum (median [25th-75th percentile]: 16 [13-38] vs 16.5 [13-25]). There were no significant differences in IAF area and SI. Despite this, women with preeclampsia had lower high-density lipoprotein (46.0 ± 10.7 vs 51.3 ± 9.3 mg/dL; P.05), smaller/denser low-density lipoprotein relative flotation rate (0.276 ± 0.022 vs 0.289 ± 0.016; P = .02), higher systolic (114.6 ± 10.9 vs 102.3 ± 7.5 mm Hg) and diastolic (67.6 ± 7.5 vs 60.9 ± 3.6 mm Hg; P.001) blood pressures, and impaired flow-mediated dilatation (4.5 [2-6.7] vs 8.8 [4.5-9.1] percent change, P.05) compared to controls. In a subgroup analysis, women with nonsevere preeclampsia (n = 17) had increased IAF (98.3 [60.1-122.2]) vs 63.1 [40.1-70.7] cm(2); P = .02) and decreased SI (4.18 [2.43-5.25] vs 5.5 [3.9-8.3] × 10(-5) min(-1)/pmol/L; P = .035) compared to the controls, whereas women with severe preeclampsia (n = 32) were not different for IAF and SI. IAF was negatively associated with SI and positively associated with cardiovascular risk factors even after adjusting for the matching variables and total body fat.Women with prior preeclampsia have an atherogenic lipid profile and endothelial dysfunction compared to matched control subjects despite having similar adiposity and insulin sensitivity, suggesting that there are mechanisms separate from obesity and insulin resistance that lead to their cardiovascular risk factors. Visceral adiposity may have a role in contributing to these risk factors in the subgroup of women who have preeclampsia without severe features.

Small for gestational age (SGA) infants are at increased risk for morbidity and mortality. The objective of this study was to develop a birthweight for gestational age reference that more accurately represents the Washington state population, focusing on SGA. Washington state birth certificate files of singleton births in 1989 to 1998 were used to develop the 3rd, 10th, 50th, and 90th percentiles of birthweight for gestational age for males and females. The Washington state 10th percentile curve most closely approximates a nationally representative reference, whereas an earlier but widely used California-based reference had the lowest centiles across gestational age with few exceptions. Using the Washington reference, 8.4% of Washington births would be classified as SGA (