Jan G. Aarnoudse

A genome-wide scan for preeclampsia in the Netherlands

Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia.

Anatomical and functional changes in the lower urinary tract during pregnancy

Objective To assess the prevalence and the development of urinary incontinence in nulliparous pregnant women, both subjectively and objectively, and to investigate the relation of incontinence with the mobility of the urethro‐vesical junction measured by perineal ultrasound.

Brain lesions several years after eclampsia

OBJECTIVE Eclampsia is thought to have no long-term neurological consequences. We aimed to delineate the neurostructural sequelae of eclampsia, in particular brain white matter lesions, utilizing high-resolution 3-Tesla magnetic resonance imaging (MRI). STUDY DESIGN Formerly eclamptic women were matched for age and year of index pregnancy with normotensive parous controls. The presence and volume of brain white matter lesions were compared between the groups. RESULTS MRI scans of 39 women who formerly had eclampsia and 29 control women were performed on average 6.4 +/- 5.6 years following the index pregnancy at a mean age of 38 years. Women with eclampsia demonstrated subcortical white matter lesions more than twice as often as compared with controls (41% vs 17 %; odds ratio, 3.3; 95% confidence interval, 1.05-10.61; P = .04). CONCLUSION Cerebral white matter lesions occur more often in women who formerly had eclampsia compared with women with normotensive pregnancies. The exact pathophysiology underlying these imaging changes and their clinical relevance remain to be elucidated.

Prospective validation and assessment of cardiovascular and offspring risk models for pregnant women with congenital heart disease

Objectives Adequate prepregnancy prediction of maternal cardiovascular and offspring risk is important for counselling and management of pregnancy in women with congenital heart disease (CHD). Therefore we performed a study to identify the optimal assessment strategy for estimating the risk of pregnancy in women with CHD. Methods In this prospective study, we determined the outcomes of 213 pregnancies in 203 women with CHD. The ZAHARA I (Zwangerschap bij Aangeboren HARtAfwijkingen I) and CARPREG (CARdiac disease in PREGnancy) risk scores were calculated for each pregnancy, as was the total number of cardiovascular (TPc) or offspring risk predictors (TPo) from these and other studies combined. Pregnancies were also classified according to the modified WHO classification of maternal cardiovascular risk and according to disease complexity (DC). Results Maternal cardiovascular events occurred during 22 pregnancies (10.3%). Offspring events occurred during 77 pregnancies in 81 children (37.3%). Cardiovascular and offspring event rates increased with higher risk scores, higher TPc or TPo, higher WHO class and greater DC. The highest area under the curve (AUC) for maternal cardiovascular risk was achieved by the WHO class (AUC: 0.77, p<0.0001). AUC for the ZAHARA I risk score was 0.71 (p=0.001), and for the CARPREG risk score 0.57 (p=0.32). All models performed insufficiently in predicting offspring events (AUC≤0.6). Conclusions The WHO classification is the best available risk assessment model for estimating cardiovascular risk in pregnant women with CHD. None of the offspring prediction models perform adequately in our cohort.

Long‐term cerebral imaging after pre‐eclampsia

Please cite this paper as: Aukes A, De Groot J, Wiegman M, Aarnoudse J, Sanwikarja G, Zeeman G. Long‐term cerebral imaging after pre‐eclampsia. BJOG 2012;119:1117–1122.

Increased Intima-Media Thickness After Early-Onset Preeclampsia

OBJECTIVE: Preeclampsia is associated with cardiovascular atherosclerotic events later in life. However, little is known about earlier subclinical signs of atherosclerosis. We aimed to investigate whether women who recently had preeclampsia show increased intima-media thickness (IMT), as marker of early atherosclerosis, compared with women with normal pregnancies or nulliparous women. METHODS: Intima-media thickness of carotid and femoral arteries measured by ultrasonography, and possible confounding risk factors as body mass index, blood pressure, serum lipids, smoking status, and family history of cardiovascular disease were compared among 22 nulliparous women, 22 primiparous women with normal pregnancy, and 22 primiparous women with early-onset preeclampsia at least 3 months postpartum and 6 weeks after ending lactation RESULTS: Except for slightly higher values for blood pressure, triglycerides, and homocysteine in the formerly preeclamptic women, no other clinical or biochemical differences were observed. The preeclampsia group showed an increased IMT (mean ± standard deviation, 0.63 ± 0.14 mm) of the common femoral artery compared with the normal pregnancy group (0.55 ± 0.06 mm, P = .005) and to the nulliparous group (0.52 ± 0.06 mm, P < .001). These differences remained significant after correction for possible confounders by multiple linear regression analyses. An increase in IMT of the common carotid artery between the normal pregnancy and the nulliparous group was observed, which became significant after adjustment for confounders. CONCLUSION: Preeclampsia and, to a lesser degree, normal pregnancy are associated with increased IMT. The association between increased IMT and (preeclamptic) pregnancy leads to the question of which comes first, which should be addressed in follow-up studies. LEVEL OF EVIDENCE: II-2

Anatomical and functional changes in the lower urinary tract following spontaneous vaginal delivery

Objective To assess the incidence of urinary incontinence in pregnancy and after spontaneous vaginal delivery and its relation with changes in the static and dynamic function of the pelvic floor.

Accuracy of serum uric acid as a predictive test for maternal complications in pre-eclampsia: Bivariate meta-analysis and decision analysis

The aim of this study is to determine the accuracy and clinical value of serum uric acid in predicting maternal complications in women with pre-eclampsia. An existing meta-analysis on the subject was updated. The accuracy of serum uric acid for the prediction of maternal complications was assessed with a bivariate model estimating a summary Receiver Operating Characteristic (sROC) curve. Subsequently, a clinical decision analysis was performed, in which three alternative strategies were modelled: (I) expectant management with monitoring until spontaneous labour; (II) induction of labour; (III) serum uric acid as test for predicting maternal complications. In the latter strategy, accuracy data of serum uric acid derived from the sROC curve were used to assess the value of serum uric acid in the management of women with pre-eclampsia. In this strategy, women with an increased serum uric acid were supposed to have labour induced, whereas women with serum uric acid levels below the threshold were managed expectantly. The decision whether to use the policy expectant management, to induce labour or to test serum uric acid levels, is based on the expected utility of each strategy. The expected utility depends on the probability of occurrence of severe maternal complications (i.e. severe hypertension, haemolysis, elevated liver enzymes and low platelet count (HELLP syndrome) or eclampsia) and the mode of delivery (caesarean section versus vaginal delivery). Valuation of the outcomes was performed using a distress ratio, which expresses how much worse a complication of pre-eclampsia is valued as compared to a caesarean section. Eight studies, testing 1565 women with pre-eclampsia, met the inclusion criteria. If the distress ratio was 10, the strategy regarding serum uric acid would be the preferred strategy when the probability of complications was between 2.9 and 6.3%. At higher complication rates induction of labour would be preferred, whereas at lower complication rates expectant management would be the best treatment option. These findings were stable in sensitivity analyses, using different distress ratios. Based on the decision analysis, serum uric acid seems to be a useful test in the management of pre-eclampsia under realistic assumptions.

Uteroplacental Blood Flow, Cardiac Function, and Pregnancy Outcome in Women With Congenital Heart Disease

Background— Pregnant women with congenital heart disease (CHD) are susceptible to cardiovascular, obstetric, and offspring complications. In women with CHD, cardiac dysfunction may compromise uteroplacental flow and contribute to the increased incidence of obstetric and offspring events. Methods and Results— We performed a prospective multicenter cohort study of pregnant women with CHD and healthy pregnant women. We compared clinical, laboratory, echocardiographic, and uteroplacental Doppler flow (UDF) parameters at 20 and 32 weeks gestation, and pregnancy outcome. We related cardiovascular parameters to UDF parameters and pregnancy outcome in women with CHD. We included 209 women with CHD and 70 healthy women. Cardiovascular parameters (N-terminal pro-B-type natriuretic peptide, left and right ventricular function) differed between both groups. UDF parameters were impaired in CHD women (umbilical artery pulsatility and resistance index at 32 weeks in CHD versus healthy women, P=0.0085 and P=0.017). The following cardiovascular parameters prepregnancy and at 20 weeks gestation were associated with UDF (umbilical artery resistance index) at 32 weeks at multivariable analysis: (1) right ventricular function (tricuspid annular plane systolic excursion) (P=0.002), (2) high N-terminal pro-B-type natriuretic peptide (P=0.085), (3) systemic (P=0.001), and (4) pulmonary (P=0.045) atrioventricular valve regurgitation. Women with CHD had more obstetric (58.9% versus 32.9%, P<0.0001) and offspring events (35.4% versus 18.6%, P=0.008) than healthy women. Impaired UDF was associated with adverse obstetric and offspring outcome. Conclusions— UDF parameters are abnormal in pregnant women with CHD. Cardiovascular function is associated with an abnormal pattern of UDF. Compromised UDF may be a key factor in the high incidence of offspring and obstetric complications in this population.

Enhancement of hepatic artery resistance to blood flow in preeclampsia in presence or absence of HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)

OBJECTIVE Our purpose was to test the hypothesis that the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is the result of excessive vasoconstriction of the hepatic arterial circulation. STUDY DESIGN Doppler ultrasonography was used to measure the pulsatility index of the common hepatic artery in 14 women with preeclampsia, 15 with preeclampsia complicated by HELLP syndrome, and 8 with HELLP syndrome but without proteinuria. Gestational age ranged from 24 to 38 weeks. The study group was compared with a reference group (n = 42). RESULTS Both in preeclampsia and in the HELLP syndrome the hepatic artery pulsatility index values were significantly increased compared with the reference group. However, no significant differences were found between the preeclamptic group, the HELLP group with proteinuria, and those with HELLP without proteinuria. CONCLUSIONS These findings indicate that hepatic artery resistance to blood flow is increased in preeclampsia in the presence or absence of the HELLP syndrome. The results also demonstrate that vasoconstriction of the hepatic arteries is not more pronounced in the HELLP syndrome than in other manifestations of preeclampsia. Therefore factors other than vasoconstriction are likely to be responsible for the development of the HELLP syndrome.