Laura A. Magee

The classification, diagnosis and management of the hypertensive disorders of pregnancy: A revised statement from the ISSHP

There has never been a definite consensus on the classification and diagnostic criteria for the hypertensive disorders of pregnancy. This uncertainty is likely to have led to between-centre differences in rates of adverse maternal and foetal outcomes for the various hypertensive disorders in pregnancy, particularly pre-eclampsia. In 2000, the International Society for the Study of Hypertension in Pregnancy (ISSHP) recognised that this lack of consensus was one reason for controversies concerning counselling, management and documentation of immediate and remote pregnancy outcomes. Accordingly, the Society appointed a committee that reviewed available classifications and endorsed and published an international recommendation for how these disorders should be classified and diagnosed in pregnancy [1]. The major stumbling block remained whether or not proteinuria should be retained as a sine qua non for the diagnosis of pre-eclampsia; the Society recommended that a broad definition, at times not including proteinuria, could be applied for the clinical definition of pre-eclampsia whilst the inclusion of proteinuria would ensure more specificity around the diagnosis when reporting clinical criteria for patients enrolled in scientific research. The purpose of this document is to update ISSHP thinking on this subject.

Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis

BACKGROUND We investigated the relation between fetoplacental growth and the use of oral antihypertensive medication to treat mild-to-moderate pregnancy hypertension. METHODS The study design was a metaregression analysis of published data from randomised controlled trials. Data from a paper that was regarded as an extreme statistical outliner were excluded from primary analyses. The change in (group) mean arterial pressure (MAP) from enrolment to delivery was compared with indicators of fetoplacental growth. FINDINGS Greater mean difference in MAP with antihypertensive therapy was associated with the birth of a higher proportion of small-for-gestational-age (SGA) infants (slope: 0.09 [SD 0.03], r2=0.48, p=0.006, 14 trials) and lower mean birthweight significant after exclusion of data from another paper regarded as an extreme statistical outliner (slope: -14.49 [6.98] r=0.16, p=0.049, 27). No relation with mean placental weight was seen (slope -2.01 [1.62], r2=0.15, p=0.25, 11 trials). INTERPRETATION Treatment-induced falls in maternal blood pressure may adversely affect fetal growth. Given the small maternal benefits that are likely to be derived from therapy, new data are urgently needed to elucidate the relative maternal and fetal benefits and risks of oral antihypertensive drug treatment of mild-to-moderate pregnancy hypertension.

Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis

Abstract Objective To review outcomes in randomised controlled trials comparing hydralazine against other antihypertensives for severe hypertension in pregnancy. Study design Meta-analysis of randomised controlled trials (published between 1966 and September 2002) of short acting antihypertensives for severe hypertension in pregnancy. Independent data abstraction by two reviewers. Data were entered into RevMan software for analysis (fixed effects model, relative risk and 95% confidence interval); in a secondary analysis, risk difference was also calculated. Results Of 21 trials (893 women), eight compared hydralazine with nifedipine and five with labetalol. Hydralazine was associated with a trend towards less persistent severe hypertension than labetalol (relative risk 0.29 (95% confidence interval 0.08 to 1.04); two trials), but more severe hypertension than nifedipine or isradipine (1.41 (0.95 to 2.09); four trials); there was significant heterogeneity in outcome between trials and differences in methodological quality. Hydralazine was associated with more maternal hypotension (3.29 (1.50 to 7.23); 13 trials); more caesarean sections (1.30 (1.08 to 1.59); 14 trials); more placental abruption (4.17 (1.19 to 14.28); five trials); more maternal oliguria (4.00 (1.22 to 12.50); three trials); more adverse effects on fetal heart rate (2.04 (1.32 to 3.16); 12 trials); and more low Apgar scores at one minute (2.70 (1.27 to 5.88); three trials). For all but Apgar scores, analysis by risk difference showed heterogeneity between trials. Hydralazine was associated with more maternal side effects (1.50 (1.16 to 1.94); 12 trials) and with less neonatal bradycardia than labetalol (risk difference -0.24 (-0.42 to -0.06); three trials). Conclusions The results are not robust enough to guide clinical practice, but they do not support use of hydralazine as first line for treatment of severe hypertension in pregnancy. Adequately powered clinical trials are needed, with a comparison of labetalol and nifedipine showing the most promise.

Fortnightly review: Management of hypertension in pregnancy

Hypertension in pregnancy is not a single entity1 but comprises: ### Summary points Antihypertensive treatment is well tolerated in pregnancy, with few women needing to change drugs due to side effects Antihypertensive treatment for mild chronic hypertension benefits the mother, but the impact on perinatal outcomes is less clear, particularly for atenolol For hypertension presenting later in pregnancy, even near term, the available data do not allow for reliable conclusions to be made about the benefits and risks of restricted activity with or without admission to hospital Antihypertensive treatment for mild to moderate hypertension later in pregnancy benefits the mother, but the impact on perinatal outcomes may be harmful or beneficial Women with early, severe pre-eclampsia have better perinatal outcomes if they are managed “expectantly,” but data are insufficient to estimate risks to the mother For acute severe hypertension later in pregnancy, parenteral hydralazine is not the drug of choice as it is associated with more maternal and perinatal adverse effects than are other drugs, particularly intravenous labetalol or oral or sublingual nifedipine Antihypertensive treatment given antenatally should probably be reordered postnatally The types of hypertension in pregnancy differ primarily in the incidence, and not the nature, of maternal and perinatal complications. The UK confidential inquiries into maternal …

Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model

BACKGROUND Pre-eclampsia is a leading cause of maternal deaths. These deaths mainly result from eclampsia, uncontrolled hypertension, or systemic inflammation. We developed and validated the fullPIERS model with the aim of identifying the risk of fatal or life-threatening complications in women with pre-eclampsia within 48 h of hospital admission for the disorder. METHODS We developed and internally validated the fullPIERS model in a prospective, multicentre study in women who were admitted to tertiary obstetric centres with pre-eclampsia or who developed pre-eclampsia after admission. The outcome of interest was maternal mortality or other serious complications of pre-eclampsia. Routinely reported and informative variables were included in a stepwise backward elimination regression model to predict the adverse maternal outcome. We assessed performance using the area under the curve (AUC) of the receiver operating characteristic (ROC). Standard bootstrapping techniques were used to assess potential overfitting. FINDINGS 261 of 2023 women with pre-eclampsia had adverse outcomes at any time after hospital admission (106 [5%] within 48 h of admission). Predictors of adverse maternal outcome included gestational age, chest pain or dyspnoea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. The fullPIERS model predicted adverse maternal outcomes within 48 h of study eligibility (AUC ROC 0·88, 95% CI 0·84-0·92). There was no significant overfitting. fullPIERS performed well (AUC ROC >0·7) up to 7 days after eligibility. INTERPRETATION The fullPIERS model identifies women at increased risk of adverse outcomes up to 7 days before complications arise and can thereby modify direct patient care (eg, timing of delivery, place of care), improve the design of clinical trials, and inform biomedical investigations related to pre-eclampsia. FUNDING Canadian Institutes of Health Research; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction; Preeclampsia Foundation; International Federation of Obstetricians and Gynecologists; Michael Smith Foundation for Health Research; and Child and Family Research Institute.

Less-Tight versus Tight Control of Hypertension in Pregnancy

BACKGROUND The effects of less-tight versus tight control of hypertension on pregnancy complications are unclear. METHODS We performed an open, international, multicenter trial involving women at 14 weeks 0 days to 33 weeks 6 days of gestation who had nonproteinuric preexisting or gestational hypertension, office diastolic blood pressure of 90 to 105 mm Hg (or 85 to 105 mm Hg if the woman was taking antihypertensive medications), and a live fetus. Women were randomly assigned to less-tight control (target diastolic blood pressure, 100 mm Hg) or tight control (target diastolic blood pressure, 85 mm Hg). The composite primary outcome was pregnancy loss or high-level neonatal care for more than 48 hours during the first 28 postnatal days. The secondary outcome was serious maternal complications occurring up to 6 weeks post partum or until hospital discharge, whichever was later. RESULTS Included in the analysis were 987 women; 74.6% had preexisting hypertension. The primary-outcome rates were similar among 493 women assigned to less-tight control and 488 women assigned to tight control (31.4% and 30.7%, respectively; adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.77 to 1.35), as were the rates of serious maternal complications (3.7% and 2.0%, respectively; adjusted odds ratio, 1.74; 95% CI, 0.79 to 3.84), despite a mean diastolic blood pressure that was higher in the less-tight-control group by 4.6 mm Hg (95% CI, 3.7 to 5.4). Severe hypertension (≥160/110 mm Hg) developed in 40.6% of the women in the less-tight-control group and 27.5% of the women in the tight-control group (P<0.001). CONCLUSIONS We found no significant between-group differences in the risk of pregnancy loss, high-level neonatal care, or overall maternal complications, although less-tight control was associated with a significantly higher frequency of severe maternal hypertension. (Funded by the Canadian Institutes of Health Research; CHIPS Current Controlled Trials number, ISRCTN71416914; ClinicalTrials.gov number, NCT01192412.).

Diagnostic accuracy of urinary spot protein:creatinine ratio for proteinuria in hypertensive pregnant women: systematic review

Objective To review the spot protein:creatinine ratio and albumin:creatinine ratio as diagnostic tests for significant proteinuria in hypertensive pregnant women. Design Systematic review. Data sources Medline and Embase, the Cochrane Library, reference lists, and experts. Review methods Literature search (1980-2007) for articles of the spot protein:creatinine ratio or albumin:creatinine ratio in hypertensive pregnancy, with 24 hour proteinuria as the comparator. Results 13 studies concerned the spot protein:creatinine ratio (1214 women with primarily gestational hypertension). Nine studies reported sensitivity and specificity for eight cut-off points, median 24 mg/mmol (range 17-57 mg/mmol; 0.15-0.50 mg/mg). Laboratory assays were not well described. Diagnostic test characteristics were recalculated for a cut-off point of 30 mg/mmol. No significant heterogeneity in cut-off points was found between studies over a range of proteinuria. Pooled values gave a sensitivity of 83.6% (95% confidence interval 77.5% to 89.7%), specificity of 76.3% (72.6% to 80.0%), positive likelihood ratio of 3.53 (2.83 to 4.49), and negative likelihood ratio of 0.21 (0.13 to 0.31) (nine studies, 1003 women). Two studies of the spot albumin:creatinine ratio (225 women) found optimal cut-off points of 2 mg/mmol for proteinuria of 0.3 g/day or more and 27 mg/mmol for albuminuria. Conclusion The spot protein:creatinine ratio is a reasonable “rule-out” test for detecting proteinuria of 0.3 g/day or more in hypertensive pregnancy. Information on use of the albumin:creatinine ratio in these women is insufficient.

The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study.

OBJECTIVE Our purpose was to examine the potential teratogenicity of calcium channel blockers. STUDY DESIGN Six teratogen information services prospectively collected and followed up 78 women with first-trimester exposure to calcium channel blockers. Pregnancy outcome was compared (by paired t text of chi2 analysis) with that of a control group matched for maternal age and smoking. RESULTS There was no increase in major malformation (2/66=3.0% [calcium channel blockers] vs 0% [nonteratogenic controls], p=0.27); a fivefold increase was ruled out (baseline 2%, alpha = 0.05, beta = 0.20). The defects reported were attributable to maternal diabetes or coingestion of teratogens. The increase in preterm delivery 28% [calcium channel blockers] vs 9% [nonteratogenic controls], p=0.003), attributed to maternal disease by stepwise regression, was the most important factor responsible for the observed decrease in birth weight (mean -334 gm vs nonteratogenic controls, p=0.08). CONCLUSION This study suggests that calcium channel blockers do not represent a major teratogenic risk.

Could an infectious trigger explain the differential maternal response to the shared placental pathology of preeclampsia and normotensive intrauterine growth restriction

Preeclampsia/eclampsia remains an important cause of maternal and perinatal morbidity and mortality. Its origins lie in a mismatch between fetoplacental demands and the ability of the uteroplacental arteries to supply those demands, a situation that also arises in normotensive intrauterine growth restriction (the fetal syndrome of preeclampsia in isolation). Why is there this differential response to the same underlying pathology? This review summarises the evidence surrounding a potential trigger for the differential response, namely infection. This builds on the inflammatory model of preeclampsia for which there is increasing support. The evidence for an infectious trigger is principally indirect, linking the similarities between acute atherosis in preeclampsia and atherosclerosis, the increased likelihood of developing cardiovascular disease later in life following a preeclampsia pregnancy, and the association between chronic infection and atherogenesis. Also reviewed is the human and animal model evidence for an infectious trigger for preeclampsia. Perhaps preeclampsia truly is the ‘toxemia’ of pregnancy.

The effect of hypertensive disorders in pregnancy on small for gestational age and stillbirth: a population based study

BackgroundHypertensive disorders in pregnancy are leading causes of maternal, fetal and neonatal morbidity and mortality worldwide. However, studies attempting to quantify the effect of hypertension on adverse perinatal outcomes have been mostly conducted in tertiary centres. This population-based study explored the frequency of hypertensive disorders in pregnancy and the associated increase in small for gestational age (SGA) and stillbirth.MethodsWe used information on all pregnant women and births, in the Canadian province of Nova Scotia, between 1988 and 2000. Pregnancies were excluded if delivery occurred < 20 weeks, if birthweight was < 500 grams, if there was a high-order multiple pregnancy (greater than twin gestation), or a major fetal anomaly.ResultsThe study population included 135,466 pregnancies. Of these, 7.7% had mild pregnancy-induced hypertension (PIH), 1.3% had severe PIH, 0.2% had HELLP (hemolysis, elevated liver enzymes, low platelets), 0.02% had eclampsia, 0.6% had chronic hypertension, and 0.4% had chronic hypertension with superimposed PIH. Women with any hypertension in pregnancy were 1.6 (95% CI 1.5–1.6) times more likely to have a live birth with SGA and 1.4 (95% CI 1.1–1.8) times more likely to have a stillbirth as compared with normotensive women. Adjusted analyses showed that women with gestational hypertension without proteinuria (mild PIH) and with proteinuria (severe PIH, HELLP, or eclampsia) were more likely to have infants with SGA (RR 1.5, 95% CI 1.4–1.6 and RR 3.2, 95% CI 2.8–3.6, respectively). Women with pre-existing hypertension were also more likely to give birth to an infant with SGA (RR 2.5, 95% CI 2.2–3.0) or to have a stillbirth (RR 3.2, 95% CI 1.9–5.4).ConclusionsThis large, population-based study confirms and quantifies the magnitude of the excess risk of small for gestational age and stillbirth among births to women with hypertensive disease in pregnancy.