Chronic hypertension and superimposed preeclampsia: screening and diagnosis.

Superimposed preeclampsia complicates about 20% of pregnancies in women with chronic hypertension and is associated with increased maternal and perinatal morbidity compared with preeclampsia alone. Distinguishing superimposed preeclampsia from chronic hypertension can be challenging because, in chronic hypertension, the traditional criteria for the diagnosis of preeclampsia, hypertension, and significant proteinuria can often predate the pregnancy. Furthermore, the prevalence of superimposed preeclampsia is unlikely to be uniformly distributed across this high-risk group but is related to the severity of preexisting endothelial dysfunction. This has led to interest in identifying biomarkers that could help in screening and diagnosis of superimposed preeclampsia and in the stratification of risk in women with chronic hypertension. Elevated levels of uric acid and suppression of other renal biomarkers, such as the renin-angiotensin aldosterone system, have been demonstrated in women with superimposed preeclampsia but perform only modestly in its prediction. In addition, central to the pathogenesis of preeclampsia is a tendency toward an antiangiogenic state thought to be triggered by an impaired placenta and, ultimately, contributing to the endothelial dysfunction pathognomonic of the disease. In the general obstetrical population, angiogenic factors, such as soluble fms-like tyrosine kinase-1 and placental growth factor, have shown promise in the prediction of preeclampsia. However, soluble fms-like tyrosine kinase-1 and placental growth factor are impaired in women with chronic hypertension irrespective of whether they develop superimposed preeclampsia. Therefore, the differences in levels are less discriminatory in the prediction of superimposed preeclampsia compared with the general obstetrical population. Alternative biomarkers to the angiogenic and renal factors include those of endothelial dysfunction. A characteristic of both preeclampsia and chronic hypertension is an exaggerated systemic inflammatory response causing or augmenting endothelial dysfunction. Thus, proinflammatory mediators, such as tumor necrosis factor-α, interleukin-6, cell adhesion molecules, and endothelin, have been investigated for their role in the screening and diagnosis of superimposed preeclampsia in women with chronic hypertension. To date, the existing limited evidence suggests that the differences between those who develop superimposed preeclampsia and those who do not are, as with angiogenic factors, also modest and not clinically useful for the stratification of women with chronic hypertension. Finally, pro-B-type natriuretic peptide is regarded as a sensitive marker of early cardiac dysfunction that, in women with chronic hypertension, may predate the pregnancy. Thus, it has been proposed that pro-B-type natriuretic peptide could give insight as to the ability of women with chronic hypertension to adapt to the hemodynamic requirements of pregnancy and, subsequently, their risk of developing superimposed preeclampsia. Although higher levels of pro-B-type natriuretic peptide have been demonstrated in women with superimposed preeclampsia compared with those without, current evidence suggests that pro-B-type natriuretic peptide is not a predictor for the disease. The objectives of this review are to, first, discuss the current criteria for the diagnosis of superimposed preeclampsia and, second, to summarize the evidence for these potential biomarkers that may assist in the diagnosis of superimposed preeclampsia.

Ophthalmic artery peak systolic velocity ratio distinguishes pre-eclampsia from chronic and gestational hypertension: A prospective cohort study.

OBJECTIVE: To examine whether the ophthalmic artery peak systolic velocity ratio (OA PSV-ratio) is higher in women with pre-eclampsia compared with gestational hypertension (GH) and chronic hypertension (CH), after controlling for confounding variables. DESIGN: Prospective cohort. SETTING: Specialist hypertension clinic in a tertiary referral centre. POPULATION: Singleton pregnancies presenting between 32+0 and 36+6  weeks of gestation with pre-eclampsia (n = 50), GH (n = 54) and CH (n = 56). METHODS: Paired measurements of maternal mean arterial pressure (MAP) and OA PSV-ratio were performed by trained sonographers. Multiple linear regression was fitted to the OA PSV-ratio, including maternal characteristics and medical history, GH, pre-eclampsia and MAP and use of antihypertensive medication. MAIN OUTCOME MEASURE: Whether pre-eclampsia is independently associated with higher OA PSV-ratio. RESULTS: MAP was significantly higher in both GH (p = 0.0015) and pre-eclampsia (p = 0.008) than in CH pregnancies. There was no significant difference between pre-eclampsia and GH (0.670). The OA PSV-ratio was significantly higher in pre-eclampsia than CH (p = 0.0008) and GH (p = 0.015). There was no significant difference between the OA PSV-ratio in CH and GH (p = 0.352). Multiple linear regression modelling showed that the OA PSV-ratio was influenced by maternal weight (p = 0.005), maternal age (p = 0.014), antihypertensive medications (p = 0.007) and MAP (p < 0.0001). After controlling for these variables, the OA PSV-ratio was still significantly higher in those with pre-eclampsia (p = 0.0002). CONCLUSIONS: The OA PSV-ratio is influenced by maternal weight, age, antihypertensive medications and MAP. Pre-eclampsia is an independent predictor of OA PSV-ratio, which therefore may be a useful point-of-care test when assessing women presenting with hypertension.

Maternal cardiac adaptation and fetal growth.

BACKGROUND: Pregnancies with small-for-gestational-age fetuses are at increased risk of adverse maternal-fetal outcomes. Previous studies examining the relationship between maternal hemodynamics and fetal growth were mainly focused on high-risk pregnancies and those with fetuses with extreme birthweights, such as less than the 3rd or 10th percentile and assumed a similar growth pattern in fetuses above the 10th percentile throughout gestation. OBJECTIVE: This study aimed to evaluate the trends in maternal cardiac function, fetal growth, and oxygenation with advancing gestational age in a routine obstetrical population and all ranges of birthweight percentiles. STUDY DESIGN: This was a prospective, longitudinal study assessing maternal cardiac output and peripheral vascular resistance by bioreactance at 11+0 to 13+6, 19+0 to 24+0, 30+0 to 34+0, and 35+0 to 37+0 weeks' gestation, sonographic estimated fetal weight in the last 3 visits and the ratio of the middle cerebral artery by umbilical artery pulsatility indices or cerebroplacental ratio in the last 2 visits. Women were divided into the following 5 groups according to birthweight percentile: group 1, <10th percentile (n=261); group 2, 10 to 19.9 percentile (n=180); group 3, 20 to 29.9 percentile (n=189); group 4, 30 to 69.9 percentile (n=651); and group 5, ≥70th percentile (n=508). The multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables and z scores of the estimated fetal weight and cerebroplacental ratio. RESULTS: In visit 2, compared with visit 1, in all groups, cardiac output increased, and peripheral vascular resistance decreased. At visit 3, groups 1, 2, and 3, compared with 4 and 5, demonstrated an abrupt decrease in cardiac output and increase in peripheral vascular resistance. From visit 2, group 1 had a constant decline in estimated fetal weight, coinciding with the steepest decline in maternal cardiac output and rise in peripheral vascular resistance. In contrast, in groups 4 and 5, the estimated fetal weight had a stable or accelerative pattern, coinciding with the greatest increase in cardiac output and lowest peripheral vascular resistance. Groups 2 and 3 showed a stable growth pattern with intermediate cardiac output and peripheral vascular resistance. Increasing birthweight was associated with higher cerebroplacental ratio. Groups 3, 4, and 5 had stable cerebroplacental ratio across visits 3 and 4, whereas groups 1 and 2 demonstrated a significant decline (P<.001). CONCLUSION: In a general obstetrical population, maternal cardiac adaptation at 32 weeks' gestation parallels the pattern of fetal growth and oxygenation; babies with birthweight<20th percentile have progressive decline in fetal cerebroplacental ratio, decline in maternal cardiac output, and increase in peripheral vascular resistance.

Chronic hypertension in pregnancy stratified by first-trimester blood pressure control and adverse perinatal outcomes: A prospective observational study.

INTRODUCTION: The aim of this study was to assess perinatal outcomes in women with chronic hypertension (CH) stratified into four groups according to their blood pressure (BP) control in the first trimester of pregnancy. MATERIAL AND METHODS: This was a prospective cohort study between January 2011 and June 2017, based in a university hospital in London, UK. The population consisted of four groups: group 1 included women without history of CH, presenting in the first trimester with BP >140/90 mmHg (n = 100). Groups 2-4 had prepregnancy CH; group 2 had BP <140/90 mmHg without antihypertensives (n = 234), group 3 had BP <140/90 mmHg with antihypertensives (n = 272), and group 4 had BP ≥140/90 mmHg despite antihypertensives (n = 194). The main outcome measures were: fetal growth restriction, admission to neonatal (NNU) or neonatal intensive care unit (NICU) for ≥2 days, composite neonatal morbidity, and composite serious adverse neonatal outcome. Outcomes were collected from the hospital databases and for up to 6 weeks postnatally. Differences between groups were assessed using chi-squared test and multivariate logistic regression was used to assess the independent contribution of the four groups to the prediction of pertinent outcomes, after controlling for maternal characteristics. RESULTS: There was a higher incidence of fetal growth restriction in groups 3 (17.6%) and 4 (18.2%), compared with groups 1 (10.0%) and 2 (11.1%) (P = .04). There were more admissions to the NNU for ≥2 days in groups 3 (23.2%) and 4 (25.0%), compared with groups 1 (17.0%) and 2 (13.2%) (P = .008); and more admissions to NICU for ≥2 days in groups 3 (9.2%) and 4 (9.4%), compared with groups 1 (3.0%) and 2 (3.4%) (P = .01). Composite neonatal morbidity was higher in groups 3 (22.4%) and 4 (21.4%), compared with groups 1 (17.0%) and 2 (11.5%) (P = .009). Composite serious adverse postnatal outcome was higher in groups 3 (3.3%) and 4 (4.2%), compared with groups 1 (1.0%) and 2 (0.9%) but the difference did not reach statistical significance (P = .09). These results were also observed when values were adjusted for maternal characteristics. CONCLUSIONS: In CH adverse perinatal outcomes are worse in women who are known to have CH and need antihypertensives in the first trimester of pregnancy. Women with newly diagnosed CH in the first trimester have similar outcomes to those with known CH who have antihypertensive treatment discontinued.

Pregnancy in Liver Transplantation.

Pregnancy after liver transplantation (LT) is increasingly common and is a frequent scenario that transplant physicians, obstetricians, and midwives encounter. This review summarizes the key issues surrounding preconception, pregnancy-related outcomes, immunosuppression, and breastfeeding in female LT recipients. Prepregnancy counseling in these patients should include recommendations to delay conception for at least 1-2 years after LT and discussions about effective methods of contraception. Female LT recipients are generally recommended to continue immunosuppression during pregnancy to prevent allograft rejection; however, individual regimens may need to be altered. Although pregnancy outcomes are overall favorable, there is an increased risk of maternal and fetal complications. Pregnancy in this cohort remains high risk and should be managed vigilantly in a multidisciplinary setting. We aim to review the available evidence from national registries, population-based studies, and case series and to provide recommendations for attending clinicians.

First trimester serum angiogenic and anti-angiogenic factors in women with chronic hypertension for the prediction of preeclampsia.

BACKGROUND: An imbalance between angiogenic and antiangiogenic factors is thought to be a central pathogenetic mechanism in preeclampsia. In pregnancies that subsequently experience preeclampsia, the maternal serum concentration of the angiogenic placental growth factor is decreased from as early as the first trimester of pregnancy, and the concentration of the antiangiogenic soluble fms-like tyrosine kinase-1 is increased in the last few weeks before the clinical presentation of the disease. Chronic hypertension, which complicates 1-2% of pregnancies, is the highest risk factor for the development of preeclampsia among all other factors in maternal demographic characteristics and medical history. Two previous studies in women with chronic hypertension reported that first-trimester serum placental growth factor and soluble fms-like tyrosine kinase-1 levels were not significantly different between those who experienced superimposed preeclampsia and those who did not, whereas a third study reported that concentrations of placental growth factor were decreased. OBJECTIVE: The purpose of this study was to investigate whether, in women with chronic hypertension, serum concentrations of placental growth factor and soluble fms-like tyrosine kinase-1 and soluble fms-like tyrosine kinase-1/placental growth factor ratio at 11+0-13+6 weeks gestation are different between those women who experienced superimposed preeclampsia and those who did not and to compare these values with those in normotensive control subjects. STUDY DESIGN: The study population comprised 650 women with chronic hypertension, which included 202 women who experienced superimposed preeclampsia and 448 women who did not experience preeclampsia, and 142 normotensive control subjects. Maternal serum concentration of placental growth factor and soluble fms-like tyrosine kinase-1 were measured by an automated biochemical analyzer and converted into multiples of the expected median with the use of multivariate regression analysis in the control group. Comparisons of placental growth factor and soluble fms-like tyrosine kinase-1 levels and soluble fms-like tyrosine kinase-1/placental growth factor ratio in multiples of the expected median values between the 2 groups of chronic hypertension and the control subjects were made with the analysis of variance or the Kruskal-Wallis test. RESULTS: In the group of women with chronic hypertension who experienced preeclampsia compared with those women who did not experience preeclampsia, there were significantly lower median concentrations of serum placental growth factor multiples of the expected median (0.904 [interquartile range, 0.771-1.052] vs 0.948 [interquartile range, 0.814-1.093]; P=.014) and soluble fms-like tyrosine kinase-1 multiples of the expected median (0.895 [interquartile range, 0.760-1.033] vs 0.938 [interquartile range, 0.807-1.095]; P=.013); they were both lower than in the normotensive control subjects (1.009 [interquartile range, 0.901-1.111] and 0.991 [interquartile range, 0.861-1.159], respectively; P<.01 for both). There were no significant differences among the 3 groups in soluble fms-like tyrosine kinase-1/placental growth factor ratios. In women with chronic hypertension, serum placental growth factor and soluble fms-like tyrosine kinase-1 levels provided poor prediction of superimposed preeclampsia (area under the curve, 0.567 [95% confidence interval, 0.537-0.615] and 0.546 [95% confidence interval, 0.507-0.585], respectively). CONCLUSION: Women with chronic hypertension, and particularly those who subsequently experienced preeclampsia, have reduced first-trimester concentrations of both placental growth factor and soluble fms-like tyrosine kinase-1.

First trimester inflammatory mediators in women with chronic hypertension.

INTRODUCTION: Chronic hypertension complicates 1%-2% of pregnancies and is one of the most significant risk factors for the development of preeclampsia. Inflammatory mediators, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule (VCAM) and endothelin have been implicated in the endothelial dysfunction that is pathognomonic of preeclampsia and may serve as useful first trimester biomarkers for the prediction of preeclampsia. The objectives of this study are: first, to investigate differences in serum levels of IL-6, TNF-α, VCAM and endothelin at 11+0 to 13+6 weeks' gestation in women with chronic hypertension who developed superimposed preeclampsia with those who did not and normotensive controls and, second, to evaluate the performance of these biomarkers in the prediction of preeclampsia. MATERIAL AND METHODS: The study population was comprised of 650 women with chronic hypertension, including 202 who developed superimposed preeclampsia and 448 who did not, and 142 normotensive controls matched to the chronic hypertension group for storage time and racial origin. Serum concentrations of IL-6, TNF-α, VCAM and endothelin were measured and the values were converted into multiples of the expected median using multivariate regression analysis in the control group. The multiples of the median values of the biomarkers between the two groups of women with chronic hypertension and the controls were compared, and the receiver operating characteristic curve (ROC) was used to assess the performance of these variables for the prediction of preeclampsia. RESULTS: In women with chronic hypertension, compared with the normotensive controls, there was a significantly higher first trimester median concentration of endothelin but not of VCAM, IL-6 or TNF-α. Within the cohort of women with chronic hypertension, those who developed superimposed preeclampsia, compared with those who did not, had higher first trimester serum concentration of VCAM but not of endothelin, IL-6 or TNF-α. However, serum VCAM provided a poor prediction of superimposed preeclampsia (area under the ROC curve 0.537, 95% CI 0.487-0.587). CONCLUSIONS: Women with chronic hypertension have increased serum endothelin in the first trimester of pregnancy and those who develop superimposed preeclampsia have higher levels of VCAM. None of the inflammatory mediators performed well in the first trimester in the prediction of preeclampsia.

The effect of parity on longitudinal maternal hemodynamics.

BACKGROUND: Parous women have a lower risk for pregnancy complications, such as preeclampsia or delivery of small-for-gestational-age neonates. However, parous women are a heterogeneous group of patients because they contain a low-risk cohort with previously uncomplicated pregnancies and a high-risk cohort with previous pregnancies complicated by preeclampsia and/or small for gestational age. Previous studies examining the effect of parity on maternal hemodynamics, including cardiac output and peripheral vascular resistance, did not distinguish between parous women with and without a history of preeclampsia or small for gestational age and reported contradictory results. OBJECTIVE: The objective of the study was to compare maternal hemodynamics in nulliparous women and in parous women with and without previous preeclampsia and/or small for gestational age. STUDY DESIGN: This was a prospective, longitudinal study of maternal hemodynamics, assessed by a bioreactance method, measured at 11+0 to 13+6, 19+0 to 24+0, 30+0 to 34+0, and 35+0 to 37+0 weeks' gestation in 3 groups of women. Group 1 was composed of parous women without a history of preeclampsia and/or small for gestational age (n = 632), group 2 was composed of nulliparous women (n = 829), and group 3 was composed of parous women with a history of preeclampsia and/or small for gestational age (n = 113). A multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables controlling for maternal characteristics, medical history, and development of preeclampsia or small for gestational age in the current pregnancy. RESULTS: In groups 1 and 2, cardiac output increased with gestational age to a peak at 32 weeks and peripheral vascular resistance showed a reversed pattern with its nadir at 32 weeks; in group 1, compared with group 2, there was better cardiac adaptation, reflected in higher cardiac output and lower peripheral vascular resistance. In group 3 there was a hyperdynamic profile of higher cardiac output and lower peripheral vascular resistance at the first trimester followed by an earlier sharp decline of cardiac output and increase of peripheral vascular resistance from midgestation. The incidence of preeclampsia and small for gestational age was highest in group 3 and lowest in group 1. CONCLUSION: There are parity-specific differences in maternal cardiac adaptation in pregnancy.

Chronic hypertension: first-trimester blood pressure control and likelihood of severe hypertension, preeclampsia, and small for gestational age.

BACKGROUND: There is extensive evidence that prepregnancy chronic hypertension is associated with a high risk of development of severe hypertension and preeclampsia and birth of small-for-gestational-age neonates. However, previous studies have not reported whether antihypertensive use, blood pressure control, or normalization of blood pressure during early pregnancy influences the rates of these pregnancy complications. OBJECTIVE: The purpose of this study was to stratify women with prepregnancy chronic hypertension according to the use of antihypertensive medications and level of blood pressure control at the first hospital visit during the first trimester of pregnancy and to examine the rates of severe hypertension, preeclampsia, and birth of small-for-gestational-age neonates according to such stratification. STUDY DESIGN: We conducted a prospective study of 586 women with prepregnancy chronic hypertension, in the absence of renal or liver disease, that was booked at a dedicated clinic for the management of hypertension in pregnancy. The patients had singleton pregnancies and were subdivided according to findings in their first visit: group 1 (n=199), blood pressure <140/90 mm Hg without antihypertensive medication; group 2 (n=220), blood pressure <140/90 mm Hg with antihypertensive medication; and group 3 (n=167), systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg, despite antihypertensive medication. In the subsequent management of these pregnancies, our policy was to maintain the blood pressure at 130-140/80-90 mm Hg with the use of antihypertensive medication; antihypertensive drugs were stopped if the blood pressure was persistently <130/80 mm Hg. The outcome measures were severe hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥110 mm Hg), preterm and term preeclampsia (in addition to hypertension at least 1 of renal involvement, liver impairment, neurologic complications, or thrombocytopenia), and birth of small-for-gestational-age neonates (birthweight <5th percentile for gestational age). The incidence of these complications was compared in the 3 strata. RESULTS: The median gestational age at presentation was 10.0 weeks (interquartile range, 9.1-11.0 weeks). In groups 2 and 3, compared with group 1, there was a significantly higher body mass index, incidence of black racial origin, and history of preeclampsia in a previous pregnancy. There was a significant increase from group 1 to group 3 in the incidence of severe hypertension (10.6%, 22.2%, and 52.1%), preterm preeclampsia with onset at <37 weeks of gestation (7.0%, 15.9%, and 20.4%), and small for gestational age (13.1%, 17.7%, and 21.1%), but not term preeclampsia with onset at ≥37 weeks of gestation (9.5%, 9.1%, and 6.6%). CONCLUSIONS: In women with prepregnancy chronic hypertension, the rates of development of severe hypertension, preterm preeclampsia, and small for gestational age are related to the use of antihypertensive medications and the level of blood pressure control at the first hospital visit during the first trimester of pregnancy.

The effect of ethnicity on the performance of protein-creatinine ratio in the prediction of significant proteinuria in pregnancies at risk of or with established hypertension: an implementation audit and cost implications.

INTRODUCTION: The replacement of 24-h urine collection by protein-creatinine ratio (PCR) for the diagnosis of preeclampsia has been recently recommended. However, the literature is conflicting and there are concerns about the impact of demographic characteristics on the performance of PCR. MATERIAL AND METHODS: This was an implementation audit of the introduction of PCR in a London Tertiary obstetric unit. The performance of PCR in the prediction of proteinuria ≥300 mg/day was assessed in 476 women with suspected preeclampsia who completed a 24-h urine collection and an untimed urine sample for PCR calculation. Multivariate logistic regression was used to assess the independent predictors of significant proteinuria. RESULTS: In a pregnant population, ethnicity and PCR are the main predictors of ≥300 mg proteinuria in a 24-h urine collection. A PCR cut-off of 30 mg/mmol would have incorrectly classified as non-proteinuric, 41.4% and 22.9% of black and non-black women, respectively. Sensitivity of 100% is achieved at cut-offs of 8.67 and 20.56 mg/mmol for black and non-black women, respectively. Applying these levels as a screening tool to inform the need to perform a 24-h urine collection in 1000 women, would lead to a financial saving of €2911 in non-black women and to an additional cost of €3269 in black women. CONCLUSIONS: Our data suggest that a move from screening for proteinuria with a 24-h urine collection to screening with urine PCR is not appropriate for black populations. However, the move may lead to cost-saving if used in the white population with a PCR cut-off of 20.5.

Maternal demographics and hemodynamics for the prediction of fetal growth restriction at booking, in pregnancies at high risk for placental insufficiency.

INTRODUCTION: Fetal growth restriction (FGR) is associated with poor perinatal outcomes. Screening and prevention tools for FGR, such as uterine artery Doppler imaging and aspirin, underperform in high-risk groups, compared with general antenatal populations. There is a paucity of sensitive screening tests for the early prediction of FGR in high-risk pregnancies. MATERIALS AND METHODS: This was a prospective observational study based in a dedicated antenatal hypertension clinic at a tertiary UK hospital. We assessed maternal demographic and central hemodynamic variables as predictors for FGR in a group of women at high risk for placental insufficiency due to chronic hypertension (n = 55) or a history of hypertension in a previous pregnancy (n = 71). Outcome variables were birthweight z-score as well as development of FGR (defined as birthweight below the 5th or 3rd centile). Maternal hemodynamics were assessed using a noninvasive transthoracic bioreactance monitor (Cheetah NICOM). RESULTS: The mean gestation at presentation was 13.6 (range: 8.5-19.5) weeks. Sixteen women delivered babies below the 5th centile. Ten of these were below the 3rd centile. Independent predictors of birthweight z-score were body surface area, peripheral vascular resistance and white ethnicity (R(2) = 0.26, p < 0.0001). Independent predictors of FGR were maternal height and cardiac output. The area under the receiver operator characteristic curve for prediction of FGR was 0.915 (95% CI 0.859-0.972) and 0.9079 (95% CI 0.823-0.990) for FGR below the 5th and 3rd centiles, respectively. CONCLUSION: In women with chronic hypertension or a history of hypertension in a previous pregnancy, maternal size and cardiac output at booking provide a sensitive screening tool for FGR.

Longitudinal maternal cardiac function in hypertensive disorders of pregnancy.

BACKGROUND: Compared with gestational hypertension, preeclampsia has traditionally been considered the worse end of the spectrum of hypertensive disorders of pregnancy. It is associated with worse pregnancy outcomes and future cardiovascular morbidities. Both hypertensive disorders may be associated with cardiac maladaptation in pregnancy. However, previous studies were limited by small numbers and a paucity of longitudinal data and unaccounted for the contribution of maternal characteristics that can affect hemodynamics. OBJECTIVE: This study aimed to assess, in an unselected population, the maternal cardiac adaptation in normotensive and hypertensive pregnancies after controlling for important maternal characteristics that affect maternal cardiac function and the interaction among these covariates. STUDY DESIGN: This was a prospective, multicenter longitudinal study of maternal hemodynamics, assessed by a noninvasive bioreactance technology, measured at 11 0/7 to 13 6/7, 19 0/7 to 24 0/7, 30 0/7 to 34 0/7, and 35 0/7 to 37 0/7 weeks of gestation in 3 groups of women. Group 1 was composed of women with preeclampsia (n=45), group 2 was composed of women with gestational hypertension (n=61), and group 3 was composed of normotensive women (n=1643). A multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables controlling for maternal age, height, weight, weight gain, race, previous obstetrical history, and birthweight. RESULTS: After adjusting for confounders that significantly affect maternal hemodynamics, both group 1 and group 2, compared with group 3, had pathologic cardiac adaptation. Group 1, compared with group 3, demonstrated hyperdynamic circulation with significantly higher cardiac output driven by greater stroke volume in the first trimester of pregnancy. As the pregnancies progressed to after 20 0/7 weeks of gestation, this hyperdynamic state transitioned to hypodynamic state with low cardiac output and high peripheral vascular resistance. Group 2, compared with group 3, had no significant differences in cardiac output, stroke volume, and heart rate before 20 0/7 weeks of gestation but thereafter demonstrated a continuous decline in cardiac output and stroke volume, similar to group 1. Both groups 1 and 2, compared with group 3, had persistently elevated mean arterial pressure and uterine artery pulsatility index throughout pregnancy. CONCLUSION: After adjusting for confounders that affect maternal hemodynamics in an unselected pregnant population, women with preeclampsia and gestational hypertension, compared with normotensive women, demonstrated similar cardiac maladaptation. This pathologic profile was evident after 20 0/7 weeks of gestation and at least 10 weeks before the clinical manifestation of the disease.

Prediction of adverse outcome by ophthalmic artery Doppler and angiogenic markers in pregnancies with new onset hypertension.

OBJECTIVES: To compare the ophthalmic artery Doppler peak systolic velocity ratio (OA PSV-ratio) and soluble fms-like tyrosine kinase-1/placental growth factor ratio (sFlt-1/PlGF ratio) in predicting adverse maternal and perinatal outcomes in women presenting with new onset hypertension. STUDY DESIGN: Prospective cohort study in a specialist hypertension clinic, within a tertiary referral centre. MAIN OUTCOME MEASURES: Comparison between the OA PSV-ratio and sFlt-1/PlGF ratio in predicting delivery within one week from presentation and adverse maternal and perinatal outcomes e.g. severe hypertension, neonatal unit admission, small for gestational age. RESULTS: Women who delivered within one week, compared to those who did not, had a higher OA PSV-ratio (0.82 vs 0.71, p < 0.01) and sFlt-1/PlGF ratio (93.3 vs 40.5, p = 0.08). Independent predictors of the OA PSV-ratio included mean arterial pressure and maternal weight and predictors of the sFlt-1/PlGF ratio included diastolic blood pressure and use of antihypertensive medications. Prediction of adverse outcomes with both ratios were similar and only modest e.g. AUROC for predicting delivery within one week for OA PSV-ratio was 0.57 (95% CI 0.47-0.67) and for sFlt-1/PlGF ratio was 0.61 (95% CI 0.52-0.70) (p = 0.53). CONCLUSIONS: In women presenting with new onset hypertension, the OA PSV-ratio and sFlt-1/PlGF ratio have similar and modest performance in predicting adverse outcomes.

Postnatal assessment for renal dysfunction in women with hypertensive disorders of pregnancy : A prospective observational study.

BACKGROUND: Hypertensive disorders of pregnancy are associated with chronic kidney disease. Early detection of renal dysfunction enables implementation of strategies to prevent progression. International guidelines recommend review at 6-8 weeks postpartum to identify persistent hypertension and abnormal renal function, but evidence for the efficacy of this review is limited. METHODS: All women attending a specialist fetal-maternal medicine clinic for hypertensive disorders of pregnancy (pre-eclampsia, chronic hypertension, gestational hypertension) were invited for a 6-8 weeks postpartum review of their blood pressure and renal function in order to establish the prevalence and independent predictors of renal dysfunction. Renal dysfunction was defined as low estimated Glomerular Filtration Rate (eGFR < 60 ml/min/1.73 m2) or proteinuria (24-h protein excretion > 150 mg or urinary albumin-to-creatinine ratio > 3 mg/mmol). All women attending a specialist clinic for hypertensive disorders were invited for a 6-8 weeks postpartum review of their blood pressure and renal function. Demographics, pregnancy and renal outcomes were prospectively collected. RESULTS: Between 2013 and 2019, 740 of 1050 (70.4%) women who had a pregnancy complicated by a hypertensive disorder attended their 6-8 weeks postpartum visit. Renal dysfunction was present in 32% of the total cohort and in 46% and 22% of women with and without pre-eclampsia, respectively. Multivariate logistic regression demonstrated that independent predictors were pre-eclampsia, chronic hypertension, highest measured antenatal serum creatinine, highest measured antenatal 24-h urinary protein, and blood pressure ≥ 140/90 mmHg at the postnatal visit. CONCLUSIONS: Renal dysfunction was present in one in three women with hypertensive disorders of pregnancy at 6-8 weeks postpartum. This includes women with gestational hypertension and chronic hypertension without superimposed pre-eclampsia, and thus these women should also be offered postnatal review.

Maternal thyroid function at 11 to 13 weeks of gestation and subsequent development of preeclampsia.

OBJECTIVE: To determine if maternal thyroid function in the first trimester is altered in pregnancies that subsequently develop preeclampsia (PE). METHODS: Mean arterial pressure (MAP), uterine artery pulsatility index (PI) maternal serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) at 11 to 13 weeks of gestation were measured in 102 singleton pregnancies that subsequently developed PE, and the values were compared to the results of 4318 normal pregnancies. RESULTS: In both the PE groups that required delivery before 34 weeks (early-PE) and the late-PE group, compared with the unaffected group, the median MAP multiple of the normal median (MoM) and uterine artery PI MoM were significantly increased. In late-PE but not in early-PE, compared with the unaffected group, the median TSH MoM was significantly increased and the median FT4 MoM was decreased. Logistic regression analysis demonstrated that TSH MoM provided a significant contribution in the prediction of late-PE. CONCLUSION: Impaired thyroid function may predispose to the development of late-PE, and measurement of maternal serum TSH can improve the prediction of late-PE provided by a combination of factors in the maternal history and the measurements of MAP and uterine artery PI.

Maternal thyroid function at 11-13 weeks of gestation in women with hypothyroidism treated by thyroxine.

OBJECTIVE: The aim of this study in pregnant women with hypothyroidism treated by levothyroxine is to examine the interrelations between thyroid-stimulating hormone (TSH), free thyroxine (FT(4)) and free tri-iodothyronine (FT(3)), and examine whether in such patients the treatment is adequate. METHODS: This was a retrospective cross-sectional study. Maternal serum concentrations of FT(3), FT(4) and TSH were measured at 11-13 weeks in 164 singleton pregnancies from women with hypothyroidism before pregnancy receiving treatment with thyroxine. The values were compared to the results in 4,318 normal singleton pregnancies. RESULTS: In the hypothyroid group, compared to the normal group, there was an increase in median TSH (1.990 vs. 1.007 MoM) and FT(4) (1.052 vs. 0.992 MoM) and decrease in FT(3) (0.901 vs. 0.991 MoM). Serum FT(4) was at or above the 2.5th centile in 158 (96.3%) cases but TSH was above the 97.5th centile in 48 (29.3%) and FT(3) was below the 2.5th centile in 49 (29.9%) cases. In both the hypothyroid and unaffected groups there were significant associations between TSH and FT(4), TSH and FT(3) and between FT(3) and FT(4). CONCLUSIONS: In a high proportion of pregnant women with hypothyroidism treated with levothyroxine there is evidence of persistent hypothyroidism because the treatment is inadequate in correcting the levels of FT(3).

Maternal thyroid function at 11-13 weeks of gestation.

OBJECTIVE: To establish normal ranges of maternal serum thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) at 11-13 weeks of gestation. METHODS: Maternal serum concentrations of FT3, FT4, TSH, anti-thyroperoxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were measured at 11-13 weeks. Normal ranges were constructed from the data of singleton pregnancies with no anti-thyroid antibodies resulting in live births after 34 weeks of phenotypically normal neonates with birth weight above the 5th percentile. Adjustments were made for maternal characteristics found by multiple regression analysis to affect the levels of TSH, FT3 and FT4. RESULTS: 3,592 of the 4,318 pregnancies examined were antibody negative, and in this group serum TSH increased whereas FT3 and FT4 decreased with gestation, and all three were lower in black than in white women. Serum FT3 and FT4 decreased but TSH did not change significantly with maternal age; TSH and FT3 increased whereas FT4 decreased with body mass index; TSH decreased whereas FT3 and FT4 increased with serum free beta-hCG. In the antibody-positive group, compared to the negative group, median TSH was higher and median FT3 and FT4 were lower. CONCLUSION: The study established normal ranges for maternal thyroid function at 11-13 weeks.

Admissions for hypoglycaemia after 35 weeks of gestation: perinatal predictors of cost of stay.

BACKGROUND: Hypoglycaemia accounts for approximately one-tenth of term admissions to neonatal units can cause long-term neurodevelopmental impairment and is associated with the significant burden to the affected infants, families and the health system. OBJECTIVE: To define the prevalence, length and cost of admissions for hypoglycaemia in infants born at greater than 35 weeks gestation and to identify antenatal and perinatal predictors of those outcomes. MATERIALS AND METHODS: This was a retrospective audit of infants admitted for hypoglycaemia between 1 January 2012 and 31 December 2015, in a level three neonatal intensive care unit at King's College Hospital NHS Foundation Trust, London. The main outcome measures were the prevalence, length and cost of admissions for hypoglycaemia and antenatal and postnatal predictors of the length and cost of the stay. RESULTS: There were 474 admissions for hypoglycaemia (17.8% of total admissions). Their median (IQR) blood glucose on admission was 2.1 (1.7-2.4) mmol/l, gestation at delivery 38.1 (36.7-39.3) weeks, birthweight percentile 31.4 (5.4-68.9), their length of stay was 3.0 (2.0-5.0). Admissions equated to a total of 2107 hospital days. The total cost of the stay was 1,316,591 Great Britain pound. The antenatal factors associated with admission for hypoglycaemia were maternal hypertension (19.8%), maternal diabetes (24.5%), foetal growth restriction (FGR) (25.9%) and pathological intrapartum cardiotocograph (23.4%). In 13.7% of cases, there was no associated pregnancy complication. Multivariate logistic regression analysis demonstrated lower gestational age, z-score birthweight squared, exclusive breastfeeding and maternal prescribed nifedipine were independently associated with the length and cost of the stay. CONCLUSION: Hypoglycaemia accounted for approximately one-fifth of admissions after 35-week gestation. Lower gestational age and admission blood glucose, low and high z-score birthweight, maternal nifedipine and exclusive breastfeeding are associated with longer duration of stay.

Severe hypertension, preeclampsia and small for gestational age in women with chronic hypertension diagnosed before and during pregnancy.

OBJECTIVES: To compare rates of severe hypertension (SH), preeclampsia (PE) birth of small for gestational age (SGA) neonates between women with chronic hypertension (CH) diagnosed during the first trimester of pregnancy and those with pre-pregnancy CH. STUDY DESIGN: Prospective cohort study of women with CH and singleton pregnancies referred to an Antenatal Hypertension Clinic at 8-14 weeks' gestation. At presentation the patients were subdivided into four groups based on blood pressure (BP) control. Group 1 included women without a preceding history of CH presenting with BP of ≥140/90 mmHg (n = 86). Groups 2-4 had pre-pregnancy CH; in group 2 the BP was <140/90 mmHg without antihypertensive medication (n = 200), in group 3 the BP was <140/90 mmHg with antihypertensive medication (n = 231) and in group 4 the BP was ≥140/90 mmHg despite antihypertensive medication (n = 173). MAIN OUTCOME MEASURES: PE, SH (BP ≥ 160/110 mmHg), SGA (birthweight < 10th percentile). RESULTS: In group 1, the rate of SH (15.1%), was similar to that in group 2 (10.5%) and group 3 (23.8%) but significantly lower than in group 4 (52.6%). In group 1, the rate of PE (12.8%) and SGA <10th centile (18.6%) were similar to those in group 2 (16.5% and 21.0%) and significantly lower than in group 3 (26.0 and 30.7%) and group 4 (26.6% and 31.8). CONCLUSION: In women diagnosed with CH in the first trimester of pregnancy, the rates of SH, PE and SGA are similar to those with pre-pregnancy CH who present with BP below 140/90 without the need for antihypertensive medication.

Pregnancy outcomes in women with previous gestational hypertension: A cohort study to guide counselling and management.

OBJECTIVES: In pregnant women with previous gestational hypertension: to compare the prevalence of preeclampsia as defined by the 2001 versus the 2014 International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria, to determine the rates of fetal growth restriction (FGR) as defined, not only by birthweight centile, but in combination with fetal ultrasound studies and, finally, to determine rates of other related outcomes such as gestational diabetes (GDM) and obstetric cholestasis (OC). STUDY DESIGN: This was a retrospective observational study based at the Antenatal Hypertension Clinic, Kings College Hospital, London. Routinely collected data of 773 women booked between 2011 and 2016 with a history of gestational hypertension was analysed. All women were normotensive at booking and those with chronic hypertension were excluded. MAIN OUTCOMES MEASURES: Hypertensive disorders of pregnancy (ISSHP-2014), FGR, GDM. RESULTS: Forty-nine percent developed one or more pregnancy complications, of which 72% were hypertensive disorders of pregnancy, 25.8% preeclampsia, 25% GDM and 19% FGR. Overall recurrence rate of preeclampsia was 12.5% (ISSHP-2014). Higher blood pressure and body mass index at booking were associated with higher risk of preeclampsia and GDM. Earlier gestation of previous hypertension was associated with higher risk of preeclampsia and FGR. The ISSHP-2014 compared to the 2001 guidelines classified 56% more women as having preeclampsia. CONCLUSION: Pregnant women with a history of gestational hypertension have a 49% chance of developing a complication related to a hypertensive disorder, GDM and OC. The rate of preeclampsia was more than doubled if the updated ISSHP-2014 definition was used.