Thesis
Reference
Prevalence des differents phenotypes d'hypertension arterielle apres une pre-eclampsie
DITISHEIM, Agnès
Abstract
La pré-éclampsie (PE) est un trouble hypertensif gravidique qui touche 3-5% des grossesses.
Elle s'associe à un risque d'hypertension artérielle (HTA) 4 fois supérieur à la population générale. L'objectif de cette étude prospective contrôlée est d'évaluer la prévalence des différents phénotypes d'hypertension par la mesure de la pression artérielle de 24 heures (MAPA) dans le post-partum. Des MAPA sur 24 heures ont été effectuées 6-12 semaines après l'accouchement, chez 115 femmes ayant fait une PE et 41 femmes ayant eu une grossesse normale. Les valeurs de MAPA diurne et nocturne étaient significativement plus élevées après une PE. Cinquante % des patientes avec PE présentaient une HTA persistante, 17.9% une HTA de la blouse blanche, 11.6% une HTA masquée et 62.3% étaient non-dippers. La MAPA après une PE permet l'identification des patientes à risque cardiovasculaire élevé et l'implémentation précoce de mesures préventives.
DITISHEIM, Agnès. Prevalence des differents phenotypes d'hypertension arterielle apres une pre-eclampsie. Thèse de doctorat : Univ. Genève, 2017, no. Méd. 10846
URN : urn:nbn:ch:unige-1010636
DOI : 10.13097/archive-ouverte/unige:101063
Available at:
http://archive-ouverte.unige.ch/unige:101063
Disclaimer: layout of this document may differ from the published version.
1 / 1
Section de médecine Clinique
Département des Spécialités de Médecine Service d’Endocrinologie, Diabétologie, Hypertension et Nutrition
Thèse préparée sous la direction du Professeur Antoinette Pechère-Bertschi
" PREVALENCE DES DIFFERENTS PHENOTYPES D’HYPERTENSION ARTERIELLE APRES UNE PRE-
ECLAMPSIE "
Thèse
présentée à la Faculté de Médecine de l'Université de Genève
pour obtenir le grade de Docteur en médecine par
Agnès Julia Ditisheim
de
La Chaux-de-Fonds (NE)
Thèse n° 10846
Genève
2017
2 Table des matières
Résumé ... 3
Introduction ... 4
Risque cardiovasculaire et rénal après une pré-éclampsie ... 5
Mesure ambulatoire de la pression artérielle ... 6
Rythme circadien de la pression artérielle dans la pré-éclampsie ... 7
Sensibilité au sel après une pré-éclampsie ... 8
Suivi médical après une pré-éclampsie ... 9
Rationnel de l’étude ... 10
Manuscrit original, soumis au journal Hypertension ... 12
Discussion ... 29
Perspectives ... 38
Bibliographie ... 39
Annexes ... 45
3 Résumé
La pré-éclampsie est un trouble hypertensif gravidique qui touche 3-5% des grossesses. Elle se grève d’une morbidité à court et à long terme majeure, notamment par un risque
d’hypertension à long terme quatre fois supérieur à celui de la population générale.
Récemment, les recommandations internationales ont souligné l’importance du dépistage et du contrôle des facteurs de risque cardiovasculaires chez les femmes ayant présenté une pré- éclampsie. Cette étude prospective contrôlée, a pour objectif d’évaluer la prévalence des différents phénotypes d’hypertension artérielle (HTA) par mesure de la pression artérielle de 24 heures (MAPA) et d’estimer la classe de risque de sensibilité au sel, dérivée des
paramètres de cet examen. Des MAPA sur 24 heures ont été effectuées 6 à 12 semaines après l’accouchement, auprès de 115 femmes ayant fait une pré-éclampsie et 41 femmes ayant eu une grossesse normale. Les valeurs de pression artérielle ambulatoire diurne était
significativement plus élevées dans le groupe des pré-éclampsies (118.9±15.0 / 83.2±10.4 mmHg) comparées aux contrôles (104.8±7.9 / 71.6±5.3 mmHg, p<0.01). Il en était de même pour les valeurs nocturnes (111.2±17.6 / 74.8±11.0 mmHg), pour les pré-éclampsies, versus les contrôles (94.3±7.6 / 61.7±4.6 mmHg, p<0.01). Trente % des patientes avec pré-
éclampsie présentaient une HTA confirmée à la MAPA (MAPA moyenne diurne
≥135/85mmHg), 17.9% avaient une HTA dite de la blouse blanche, 11.6% une HTA
masquée et 62.5% étaient non-dippers. Le patiente ayant présenté une pré-éclampsie étaient à plus haut risque d’être sensibles au sel. En effet, 58.6% d’entre elles étaient catégorisée à
« haut-risque » (17.7% chez les contrôles, p<0.01). L’utilisation de la MAPA est un outil précieux pour le suivi post-partum d’une pré-éclampsie. Elle permet d’identifier précocement les patientes à risque d’HTA chronique et l’identification des différents phénotypes
d’hypertension. Elle aide à cibler les patientes à haut-risque qui bénéficieront d’un suivi médical rigoureux et de la mise en place de mesures préventives.
4 Introduction
La pré-éclampsie est un syndrome unique à la grossesse. Elle affecte 3-5% des grossesses et représente l’une des premières causes de mortalité maternelle et fœtale à l’échelle mondiale.
Elle se grève d’une morbidité à court et à long terme, tant pour la mère que l’enfant.1-3 La pré- éclampsie se définit par l’apparition d’une hypertension artérielle (HTA) nouvelle dès 20 semaines d’aménorrhée, associée à au moins une atteinte d’organe cible pouvant se
manifester par une protéinurie, une thrombopénie, une anomalie de la fonction hépatique, un œdème pulmonaire ou des symptômes neurologiques.4, 5
Sa physiopathologie, seulement partiellement élucidée, débuterait tôt dans la grossesse. Elle implique un développement anormal de la vascularisation placentaire, résultat d’une
implantation superficielle du placenta et d’un défaut de transformation des artères utérines spiralées. L’insuffisance vasculaire qui en découle induit des phénomènes d’hypoxie et d’ischémie placentaire. Le placenta en souffrance libèrera différents facteurs dans la circulation maternelle, dont des cytokines pro-inflammatoires, des microparticules de syncytiotrophoblaste et des radicaux libres, induisant une dysfonction endothéliale diffuse, une augmentation des résistances vasculaires et de l’agrégation plaquettaire chez la mère.6, 7 Il n’existe aucun traitement curatif de la pré-éclampsie et seul l’accouchement avec la délivrance placentaire, permet d’arrêter la progression de la maladie.
S’il a longtemps été enseigné que la pré-éclampsie se guérissait par l’accouchement, on sait désormais qu’elle s’accompagne d’une augmentation du risque cardiovasculaire, rénal et métabolique à long terme chez la mère. Bien qu’il soit admis qu’un suivi médical après une pré-éclampsie est nécessaire, les évidences manquent quant aux modalités de ce suivi et aux mesures de prévention devant s’appliquer.8, 9
5 Risque cardiovasculaire et rénal après une pré-éclampsie
Les premières études observant une augmentation du risque cardiovasculaire après une pré- éclampsie ont été publiées dans les années 80. Ce sont deux méta-analyses publiées en 2007 dans le British Medical Journal par Bellamy et al.1, et en 2008, dans l’American Heart Journal par McDonald et al.3, qui ont consolidé et validé ces données publiées, et largement contribué à sensibiliser la communauté scientifique et médicale à la problématique. Il ressort de ces travaux, que les femmes ayant fait une pré-éclampsie ont un risque de faire de
l’hypertension quatre fois plus élevé que la population générale (Risque relatif (RR): 3,7 ; intervalle de confiance (IC) 95% : 2,7-5,05 ; suivis de 14,1 ans; 13 études) et elles sont deux fois plus susceptibles d’avoir un événement ischémique cardiaque (RR : 2,16 ; IC 95% : 1,86 to 2,52 ; suivi de 11,7 ans ; 8 études).1 La méta-régression effectuée par McDonald et al. est en accord avec ces résultats et démontre un risque de maladies cardiaques futures échelonné selon la gravité de la pré-éclampsie (pré-éclampsie sévère : RR 5,36 (IC 95% 3,96- 7,27).3 La mortalité cardiovasculaire est plus du double chez les femmes ayant présenté une pré-
éclampsie (RR 2,29, IC 95% 1,73-3,04 ; 7 études).3
L’atteinte rénale est centrale dans la pathogénie de la pré-éclampsie et est caractérisée par une endothéliose glomérulaire. Une étude de cohorte rétrospective norvégienne, a révélé un risque accru de d’insuffisance rénale terminale ultérieure, après une pré-éclampsie.10 Bien qu’en absolu, le nombre de femme présentant une insuffisance rénale terminale après une pré- éclampsie soit faible (0.10% 30 ans après la première naissance), il n’en demeure pas moins 5 fois plus élevé que la population générale (RR 4,7 (IC 95% : 3,6-6,1). Ce risque augmente en cas d’épisodes répétés de pré-éclampsie.
6 Prévention cardiovasculaire après une pré-éclampsie
Les maladies cardiovasculaires demeurent la principale cause de décès des femmes dans le monde.11, 12 Historiquement considérée comme une maladie « d’homme », les femmes ont longtemps été ignorées des études cliniques. Toutefois, les complications hypertensives de la grossesse, la ménopause et l’usage des traitements hormonaux semblent contribuer aux différences entre les genres, dans le développement et l’évolution clinique des maladies cardiovasculaires.13 Les premières recommandations cliniques destinées aux femmes ont été publiées en 1999 par l’American Heart Association (AHA). Il faut attendre 2011 pour que la pré-éclampsie et le diabète gestationnel soient considérés comme des facteurs de risque cardiovasculaire indépendants et que l’obtention d’information sur l’histoire de la grossesse intègre les recommandations de l’AHA.11 Les Sociétés Européenne d’Hypertension et de Cardiologie ont intégré dans leurs recommandations de 2013 un paragraphe dédié aux conséquences cardiovasculaires à long-terme après un trouble hypertensif de la grossesse. Ils recommandent une modification des habitudes de vie ainsi qu’un suivi régulier de la tension artérielle et des facteurs métaboliques après l’accouchement.12 Aucune évidence ne soutient ces recommandations. Si les sociétés d’experts s’accordent pour souligner l’importance d’effectuer un dépistage et un traitement des facteurs de risque cardiovasculaire après une pré-éclampsie, il n’existe, à ce jour, aucune directive clinique structurant cette prise en charge.
Mesure ambulatoire de la pression artérielle
La mesure de la pression artérielle de 24 heures (MAPA) est une technique de mesure automatique de la pression artérielle qui permet l’enregistrement de valeurs sériées sur une journée. Son usage tant en pratique clinique qu’en recherche a augmenté, puisqu’elle permet une évaluation exhaustive de la pression artérielle sur 24 heures. La MAPA offre plusieurs avantages par rapport à la mesure manuelle classique au cabinet. Tout d’abord, elle permet
7 d’éliminer toute élévation de la pression artérielle induite par l’effet « blouse blanche ». Les mesures fournies sont plus précises, en limitant les variations inter-observateurs et en utilisant des techniques de mesures standardisées par l’appareil.14 La MAPA permet l’étude des
variations circadiennes de la pression artérielle et de distinguer différents phénotype
d’hypertension artérielle, tel que l’HTA nocturne, l’HTA masquée et l’identification de l’effet
« blouse blanche ».14
Le diagnostic d’hypertension de la blouse blanche ou l’hypertension isolée du cabinet,
s’applique aux patients qui présentent de valeurs de pression artérielle systolique ≥140 mmHg et ou diastolique ≥ 90 au cabinet, avec des mesures fiables de la pression artérielle à domicile
< 135/85 mmHg.15 Il s’agit d’un phénomène fréquent, avec une incidence variant de 12-50%
selon la définition utilisée, qui s’explique en partie par le stress éprouvé par le patient lors de la consultation médicale et un état anxieux plus prononcé que les sujets normotensifs.15, 16 Cet effet serait atténué lorsque la pression artérielle est mesurée par une infirmière.17 Le risque cardiovasculaire associé à l’hypertension de la blouse blanche serait légèrement supérieur à celui de la population générale, toute fois, bien en dessous du risque associé à l’HTA chronique.18-20
L’hypertension masquée est le phénomène inverse où la tension artérielle mesurée au cabinet est < 140/90 mmHg, alors que les valeurs prises en ambulatoire sont élevées. Dans ce cas de figure, les conséquences en terme de risque cardiovasculaire à long terme et d’atteinte d’organe, sont similaires à celles observées en cas d’hypertension artérielle chronique.20-23
Rythme circadien de la pression artérielle dans la pré-éclampsie
Le rythme circadien physiologique de tension artérielle est caractérisé par un abaissement nocturne de 10 % des valeurs diurnes. Le terme « non-dipper », faire référence à la perte de l’abaissement tensionnel nocturne. Ce phénomène s’associe à une augmentation du risque cardiovasculaire, tant dans la population générale que chez les patients hypertendus.14
8 L’émoussement du rythme nycthéméral de la pression artérielle a été décrit dans la pré-
éclampsie et dans les pré-éclampsies sévères, une inversion du rythme ainsi qu’une hypertension artérielle nocturne ont été observés (revue en annexe).24-27 Les conséquences obstétricales et cardiovasculaires à long terme de cette perte du dipping nocturne ne sont pas connues. Une étude rapporte cependant une association entre l’hypertension nocturne durant la grossesse et un taux plus élevé d’insuffisance rénale, de dysfonction hépatique, de
thrombocytopénie, d’épisode d’hypertension artérielle sévère et de bébés de petits poids à la naissance.26 Cette observation peut être le reflet d’un degré plus sévère de pré-éclampsie, qui comme décrit dans d’autres publications, peut s’associer à une inversion du rythme
nycthéméral. Ici encore, les évidences manquent pour guider l’emploi des thérapies anti- hypertensives dans l’hypertension nocturne ainsi que la décision de déclencher
l’accouchement.26
Sensibilité au sel après une pré-éclampsie
La sensibilité au sel représente le degré de réponse de la tension artérielle aux variations de la consommation de sel. Elle se définit par une augmentation de 5-10% de la pression artérielle mesurée au cabinet ou une élévation de ≥ 4mmHg de la pression ambulatoire moyenne en cas d’apport sodiques élevés.28 C’est un facteur de risque de mortalité et de morbidité
cardiovasculaire indépendant de l’hypertension.29, 30 La sensibilité au sel est déterminée par différents facteurs, tels que la génétique, le genre, la fonction rénale et les hormones
sexuelles.13, 31-33 Le protocole d’évaluation de la sensibilité au sel ne s’applique pas à la
pratique clinique quotidienne. Un outil d’estimation du risque de sensibilité au sel, dérivant de paramètres de la MAPA, a été développé et validé chez le patient hypertendu.34 Cet outil détermine 3 classes de risque (bas, intermédiaire et haut) sur la base de la perte ou non du dipping nocturne et de la fréquence cardiaque moyenne. Nous avons ensuite validé ce modèle chez les patientes ayant présenté une pré-éclampsie, dans le cadre d’un suivi à 10 ans
9 (publication originale en annexe).31 Nous avons pu démontrer que 10 ans après un épisode de pré-éclampsie sévère, les patientes présentaient une sensibilité au sel avant la ménopause.
Cette sensibilité au sel s’associait avec un émoussement de l’abaissement tensionnel nocturne à la MAPA.
Suivi médical après une pré-éclampsie
Comme mentionné ci-dessus, les sociétés d’experts ont progressivement intégré les troubles hypertensifs de la grossesse, en particulier la pré-éclampsie, comme facteurs de risque dans leurs recommandations. Cependant, les évidences dont nous disposons actuellement sont insuffisantes pour éditer des directive cliniques claires quant aux modalités pratiques de ce suivi. En effet, les scores de risque ne s’appliquent pas aux femmes en âge de procréer. La pré-éclampsie étant une maladie de la primipare, elle affecte majoritairement des femmes de moins de 40 ans, désirant des grossesses ultérieures. De plus, si les praticiens sont largement sensibilisés aux séquelles maternelles de la pré-éclampsie, les études montrent que
l’identification et le suivi de routine des parturientes à risque est insuffisant. Un audit réalisé auprès de 21 maternités en Grande-Bretagne (n=257) a révélé que 6% des parturientes n’avaient pas eu de mesure de leur pression artérielle 6 semaines après leur pré-éclampsie et 68% ne se souvenaient pas d’avoir eu une analyse d’urine. Par ailleurs, 11% des participantes présentaient soit une hypertension artérielle persistante, soit une protéinurie non résolue, soit les deux, à 6 semaines.35 Une étude rétrospective cas-témoin néerlandaise rapportait que 42,9
% des patientes avec pré-éclampsie n’avaient pas de contrôle de leur pression artérielle dans le post-partum. La glycémie et le profil lipidique n’étaient que rarement effectués, malgré la présence de facteurs de risques cardiovasculaire avant la grossesse d’intérêt.36 Une enquête canadienne effectuée auprès des obstétriciens, sages-femmes et médecins de famille de la province d’Ontario, a montré que 54,3 % des soignants pouvaient correctement affirmer que
10 la pré-éclampsie s’associait à un risque plus élevé de développer une hypertension. Cette étude a mis en évidence des manquements au niveau de la communication entre les différents intervenants, ainsi que de l’information donnée aux patientes.37
Rationnel de l’étude
A Genève et en Suisse, le suivi des patientes ayant souffert de pré-éclampsie est actuellement peu structuré, diffère entre les institutions du pays, voire, est inexistant. Reflet d’une prise en charge fragmentée entre l’obstétrique et la médecine interne, la prévention et le dépistage de la maladie cardiovasculaire est souvent omis. La consultation spécialisée postpartum de la pré-éclampsie a vu le jour en décembre 2012 aux Hôpitaux Universitaires de Genève, au sein de l’Unité d’Hypertension. Officialisant ainsi l’usage qui voulait que ces patientes soient vues par les spécialistes en hypertension, la création de la consultation a été l’occasion de repenser le suivi proposé à ces patientes et de le structurer.
C’est dans ce contexte que nous avons mené cette étude portant sur l’utilité de la mesure ambulatoire de la pression artérielle de 24 heures dans le suivi après une pré-éclampsie. Il n’y a actuellement pas de données sur l’usage de la MAPA dans le suivi post-partum de la pré- éclampsie et nous ne disposons pas de valeurs de référence normales. Les patientes ayant présenté une pré-éclampsie avec et sans critères de gravité ont été évaluées à l’Unité d’Hypertension des Hôpitaux Universitaires de Genève, 6 à 12 semaines après
l’accouchement. Une MAPA était effectuée en présence d’une HTA au cabinet avec ou sans albuminurie persistante. Afin d’évaluer la prévalence de l’HTA masquée, des MAPA on été effectuées dans un sous-groupe de patiente normotendues à 6-12 semaines d’un épisode de pré-éclampsie. En contrôle, des MAPA ont été effectuées à la même période du post-partum chez des patientes en bonne santé habituelle, ayant mené à terme une grossesse sans
11 complication hypertensive. L’objectif de l’étude était d’évaluer les différents phénotypes d’hypertension artérielle ambulatoire après une pré-éclampsie, la prévalence du status « non- dipper » et d’estimer la classe de risque de sensibilité au sel dérivée de paramètres de la MAPA.
12 Manuscrit original, soumis au journal Hypertension
PREVALENCE OF HYPERTENSIVE PHENOTYPES AFTER A PREECLAMPSIA:
A PROSPECTIVE CONTROLLED STUDY
Agnès Ditisheim1,5, Grégoire Wuerzner2, Belen Ponte3,1,Yvan Vial4, Olivier Irion5, Michel Burnier2, Michel Boulvain5, Antoinette Pechère-Bertschi1
1Hypertension Centre, University Hospitals of Geneva, Switzerland
2Service of Nephrology and Hypertension, University Hospital of Lausanne, Switzerland
3Service of Nephrology, University Hospitals of Geneva, Switzerland
4Service of Obstetrics, University Hospital of Lausanne, Switzerland
5Service of Obstetrics, University Hospitals of Geneva, Switzerland
Short title: 24h-ambulatory blood pressure monitoring after a preeclampsia
Words count of the manuscript: 3715 words Words count of the abstract: 250 words
Total number of figure and table: 4 figures and 3 tables
Correspondence to:
Pechère-Bertschi Antoinette
Service of Endocrinology, Diabetology, Hypertension and Nutrition University Hospitals of Geneva
Rue Gabrielle-Perret-Gentil 4 1211 Geneva 4 - Switzerland
e-mail: [email protected]
Abstract
Preeclampsia (PE) is associated with an increased cardiovascular and renal risk later in life.
The aim of this prospective controlled study was to assess the prevalence of the different hypertensive phenotypes using 24h ambulatory blood pressure monitoring (ABPM) 6-12 weeks after a PE, to estimate the risk of salt sensitivity (RSS) and variability of the BP derived from ABPM parameters. Women with PE (n=115) were compared to 41 control women. Overall daytime ambulatory systolic and diastolic blood pressures (BP) were
significantly higher in the PE group (118.9 ± 15.0/83.2 ± 10.4 mmHg) than in controls (104.8
± 7.9/71.6 ± 5.3 mmHg, p<0.01), so were the nocturnal BP values (111.2 ± 17.6/74.8 ± 11.0 mmHg in PE, 94.3 ± 7.6/61.7 ± 4.6 mmHg in controls, p<0.01). Thirty percent of
preeclamptic women remained hypertensive on ABPM (diurnal ABP ≥135/85 mmHg) at 6-12 weeks post-partum (0.0% in controls, p< 0.01); 17.9 % a white coat hypertension (2.8% in controls, p<0.01) and 11.6 % a masked hypertension (0.0% in controls, p<0.01). The prevalence of non-dippers was similar in both groups (46.6% in PE vs 41.2%, in controls, p=NS). High RSS class was more frequent in women with PE (58.6%
vs 17.7%, in controls, p<0.01). The standard deviation of ABP was significantly augmented in PE women (p<0.01). ABPM early in the post-partum enables diagnosis of sustained ambulatory hypertension and the identification of women with masked hypertension who are at high cardiovascular risk. It helps targeting women who will need a careful follow- up and preventive measures.
2 Introduction
Cardiovascular diseases are the principal cause of death in women worldwide and are greatly enhanced by hypertension. Preeclampsia is a hypertensive disorder specific to gestation that affects 5-8 % of all pregnancies.38 It remains one of the leading causes of maternal death worldwide and is associated with a greater lifetime risk for cardiovascular and renal diseases.2, 3
In the general clinical practice, a wider use of the 24h ambulatory blood pressure monitoring (ABPM) has been promoted by the European as well as the British Hypertension Societies. It provides a more comprehensive evaluation of the blood pressure (BP) over 24 hours and allows to detect different hypertension phenotypes associated with an increased
cardiovascular risk such as masked hypertension or a non-dipping pattern during nighttime which could not be identified by measuring office BP only.14 Thus, several studies have now demonstrated that masked hypertension is associated with a risk of cardiovascular
complications as high as patients with sustained daytime hypertension.39 A non-dipping status is also associated with an unfavorable cardiovascular outcome in a hypertensive population.14 A blunted nocturnal dip of BP has been described in hypertensive disorders of pregnancy and seems to correlate with the severity of the disease 24, 25 Nocturnal hypertension in pregnancy has been associated with more maternal and fetal adverse outcome, such as preeclampsia, renal insufficiency, severe hypertension and low birth weight babies.26 However, whether the non-dipping pattern of BP persists during the post-partum period has never been investigated systematically.
Recently, different international guidelines have underlined that women who had a hypertensive disorder of the pregnancy should benefit from a post-partum screening and management for cardiovascular risk factors, but with no precise recommendations.5, 40-42 The prevalence of hypertensive phenotypes after a preeclampsia, especially masked hypertension,
3 is not known and the place of ABPM in the follow-up after a preeclampsia needs to be
defined. We hypothesized that part of the elevated risk of cardiovascular disease in women with a history of preeclampsia may be related to lack of early established diagnosis of hypertension and/or abnormal circadian profile. As an abnormal circadian profile has been shown to be linked with salt sensitivity of the BP43, we also estimated the risk of salt sensitivity (RSS) and the variability of the BP from ABPM parameters. To this purpose, we performed prospectively a 24h ABPM 6 to 12 weeks after delivery in preeclamptic women and in a group of women with uncomplicated pregnancies to assess the different hypertension phenotypes and the prevalence of the non-dipping pattern after preeclampsia.
Methods
Study type and population
This prospective controlled study enrolled women with preeclampsia and a control group of women with an uncomplicated pregnancy at time of discharge from the Maternity of the University Hospitals of Geneva (HUG) and the University Hospital of Lausanne (CHUV), Switzerland, from July 2010 to December 2013.
Inclusion criteria for women with preeclampsia were: consenting women with persisting office hypertension (≥140/90 mmHg, with or without antihypertensive medication) at 6-12 weeks post-partum. Exclusion criteria were the use of anti-inflammatory drugs, or any cardiac, endocrinologic or known renal diseases.
Inclusion criteria for the control group were women without known medical condition who underwent an uncomplicated normotensive pregnancy and delivered spontaneously a term and healthy baby.
The Ethics Committee of both institutions approved this study and written informed consent was obtained from each participant. Study was registered (Clinical Trials Identifier:
NCT01095939) and performed according to Helsinki declaration.
4 Study procedure
Women were evaluated either at the Hypertension Unit of the University Hospital of Geneva, or the Service of Nephrology and Hypertension of Lausanne University Hospital,
Switzerland, at 6 to 12 weeks post-partum. The participants came in the morning after a light snack. Height and weight were measured and body mass index calculated. Relevant maternal and infant medical histories and family factors were collected and a complete physical examination was performed. Blood pressure was assessed as described below. ABPM was performed in preeclamptic women who presented with office high BP (≥140/90 mmHg) or who still required antihypertensive therapy. To identify masked hypertension, an ABPM was performed in a subgroup of normotensive women after preeclampsia (office BP
<140/90mmHg) with or without an increased urinary albumin/creatinine ratio (spot ≥3.5 mg/mmol). Plasma creatinine, spot urine albumin, creatinine were measured and kidney function was estimated using the CKD-EPI formula.44
Definitions
Preeclampsia was defined as new-onset hypertension after 20 weeks of gestation associated with at least one end-organ damage.4 Birth weight percentiles were determined according to the Swiss Society of Pediatrics standards and small for gestational age infant were defined as a birth weight < 10th percentile for gestational age at birth.
Hypertension phenotypes were defined as follow. Masked hypertension was defined as normal office BP (<140/90 mmHg) with an abnormally high diurnal ABP (≥135/85 mm Hg).12 Conversely, white-coat hypertension referred to high office BP (≥ 140/90 mmHg) with normal awake ABP measurement (<135/85 mm Hg).12 Sustained hypertension and true normotension described situations where both types of BP measurements were consistent.
Normal dipping was defined as nocturnal drop of ≥10-20% of mean ABP. Non-dippers were subjects with 0-9 % nocturnal fall of mean ABP, extreme dippers with > 20% nocturnal fall of
5 mean ABP and reverse dippers included patients with a nocturnal increase of mean ABP.14 Nocturnal hypertension was defined as night ABP ≥120/70 mmHg and/or a nocturnal dip <
10%.
When treatment was still required at 6-12 weeks post-partum, patients who had a high office BP with normal diurnal ABP were designed as having a “white-coat effect”14. Patients who presented with a masked uncontrolled hypertension, with normal office BP and high awake ABP, were referred as having a “masked phenomena”.14 The terms “controlled hypertension”
and “uncontrolled hypertension” were used when both BP measurements were concordant.
Blood pressure measurement methods
Office BP was measured with the patient seated, relaxed, arm rested on a table at the level of the heart and uncrossed legs. Arm cuff was adjusted to the arm circumference by tape
measurement. After 5 minutes of rest, two BP measurements were taken at 1-2 minutes intervals, on the same arm, with a validated automated device (Omron HEM-907-E, Kyoto, Japan. British Hypertension Society Grade A/A). Arithmetic mean of the two BP values was used for the present analysis.
A 24-hour ABPM was performed with a validated device (Diasys Integra, Physicor,
Switzerland) and programmed to perform a BP measurement every 20 minutes from 07.00 to 22.59 hour and every 30 minutes from 23.00 to 06.59 hour. Calibration of the device was made by two simultaneous auscultatory BP measurements, using a calibrated mercury sphygmomanometer connected to the ambulatory device by a Y tube. A difference of less than 5 mmHg was considered as acceptable. Subjects were instructed not to smoke nor drink alcohol or any caffeine-containing beverage, to record their time of sleep and awakening as well as their activities in a diary. According to the European Society of Hypertension
recommendations, ABPM was considered valid and was included in the analysis when at least 14 BP measurements during the day and 7 readings during the night were recorded.45
6 Assessment of salt sensitivity risk using ABPM data
We also estimated the risk of salt sensitivity with the formula of Castiglioni et al. which was validated previously in women with a history of severe preeclampsia by ourselves.31, 34 Three classes of risk of salt sensitivity (RSS) graded as low, intermediate and high, were defined based on the dipping status and the mean heart rate (HR) over 24 hours.
Patients were defined as « dippers » when the nocturnal drop of mean arterial pressure (MAP) was ≥ 10% and « non-dippers » otherwise. They were then classified as high heart rate (HR) and low HR when the 24 hours mean HR was respectively over or under 70 bpm. Low RSS class included subjects classified as « dippers » and low mean HR. Patients identified as
« non-dippers » and high HR were considered as high RSS class and the intermediate RSS included all other subject not otherwise classified.
Statistical analysis
Results are reported as mean (standard deviation) for continuous variables and in percentage (absolute number) for the categorical variables. Normality of the distribution was tested by drawing a histogram and Q-Q plot. The statistical difference between three groups was tested by a Student’s t-test or Kruskal-Wallis test for the continuous variables and by the Chi2 or the Fishertestfor proportions. A two-sided p value ≤ 0.05 was considered as statistically
significant. All data analyses were performed with Stata software, version 12.1.
Results
We screened 250 women 6-12 weeks after a preeclampsia between July 2010 and December 2013. We enrolled 35 women with a high office BP as defined previously and 31 with a high office BP and albuminuria. We included an additional 49 preeclamptic women who were normotensive after their delivery with or without albuminuria in order to detect masked hypertension. Twenty-seven patients (24.1%) were still under anti-hypertensive therapy after
7 preeclampsia at time of recruitment. We performed an ABPM in 156 women i.e. 115 women with preeclampsia and 41 control women (figure 1). Eight patients discontinued the ABPM recording or had less than 14 valid measurements and were excluded (3 in the preeclampsia group and 5 in the controls). Thus, in total, the data of 146 women were available for the analysis. The baseline characteristics of the 2 defined groups are shown in table 1. There were no significant differences between women with preeclampsia and controls for the age,
primiparity, prevalence of pregestational diabetes and twin pregnancies. Several
characteristics were significantly more prevalent or increased in the group of preeclamptic women: Afro-Caribbean origin (p<0.01), body mass index (p<0.01), chronic hypertension before the index pregnancy (p=0.01) and smokers (p<0.01). All women were breastfeeding.
As expected, preterm delivery was more frequent among women with preeclampsia
compared to normal pregnancy (mean gestational age at birth 36.0 ± 3.9 weeks vs 39.4 ± 1.6 in controls, p<0.01). Accordingly, birth weight of the newborns in the preeclampsia group was significantly lower (2525.6 ± 898.1grams versus 3230 ± 449.9, p<0.01). However, there was no significant difference between groups in term of small for gestational age infants (birth weight < 10th percentile for gestational age). Seven neonatal deaths occurred in the group with preeclampsia.
Office BP and 24h ABPM values are shown in Table 2. Office BP was significantly higher among women who had preeclampsia. Daytime systolic and diastolic ABP were significantly higher in the preeclampsia group (118.9 ± 15.0/83.2 ± 10.4) than in the control group (104.8 ± 7.9/71.6 ± 5.3, p<0.01). Nighttime ABPM was also significantly higher in the preeclampsia group (111.2 ± 17.6/74.8 ± 11.0) compared to the control group (94.3 ± 7.6/61.7 ± 4.6). The standard deviation (SD) of the systolic and diastolic daytime ABP, a proxy of the variability of the BP, were significantly higher in the preeclampsia group (13.8 ± 4.7/11.4 ± 6.1) than in the control group (10.8 ± 4.5/8.7±2.4, p<0.01). The diastolic nighttime standard deviation of
8 the ABP was also higher in the preeclampsia group (9.8 ± 3.3) compared to the control group (8.0±2.0, p<0.01).
Table 3 presents the different BP phenotypes considering the need for anti-hypertensive therapy. Altogether, 34 patients with preeclampsia (30.4%) had a confirmed diurnal ambulatory hypertension (ABP ≥135/85 mmHg) at 6-12 weeks post-partum (0.0% in the controls, p<0.01). Prevalence of white coat hypertension or white coat effect was significantly increased in the preeclampsia group (17.9 %) compared to controls (2.8 %, p<0.01). We found a significantly more frequent masked HTN or masked phenomena in the preeclampsia groups (11.6 %) than in the controls (0.0 % p<0.01). Results are illustrated in figures 2 and 3.
Nocturnal hypertension (night time ABP ≥120/70 mm Hg and/or dipping < 10%) was only found in women who had preeclampsia. Normal nocturnal dipping was lost in 62.5% of women who had preeclampsia, of whom 46.6 % were non-dippers, 2.9 % extreme dipper and 9.7 % were reversed dippers. In the control group, 53 % were non-dippers. Although the non- dipper proportion was similar between the 2 groups, the ambulatory BP measurements were significantly lower, in the normal range, in the control group.
We also calculated the salt sensitivity risk index31 and showed that women who had a
preeclampsia were at higher risk to be salt-sensitive than the controls. Indeed, 58.6% percent of women with a recent episode of preeclampsia were categorized as “high-risk” for salt- sensitivity compared to only 17.7% of the control group (p<0.01).
Discussion
The main finding of this study is that women who had preeclampsia have a high prevalence of persistent diurnal and nocturnal ambulatory hypertension 6-12 weeks after delivery when compared to controls with normal pregnancies. In addition, a recent preeclampsia is associated with an increased prevalence of masked hypertension (11.6%) and white coat
9 hypertension (17.9%). The index of salt-sensitivity risk and the variability of ambulatory BP as reflected by the standard deviations, a proxy of variability, were significantly increased in preeclampsia compared to controls.
Preeclampsia is associated with an increased long-term risk of hypertension, cardiovascular and renal diseases and diabetes.1 Recently, guidelines of the American Heart Association and of the European Societies of Hypertension and Cardiology emphasized the need for an appropriate post-partum screening and control of the cardiovascular risk factors for women with a history of hypertensive disorder of pregnancy.11, 12 However, data on the management of the early follow-up after a preeclampsia are lacking and ABPM in the post partum period has never been evaluated. In the general clinical practice, ABPM has been shown to be a useful and cost effective tool for establishing true diagnosis of HTN as well as detecting masked and white coat HTN. Its use has now integrated the recommendations on the
management of hypertension in adult the European and British guidelines (ESH and NICE).14,
46
Our study shows that ABPM detects a large diversity of phenotypes of blood pressures early after a preeclampsia. It allows early identification of high-risk women with true ambulatory or masked HTN. It enables the assessment of the efficacy of the treatment or the necessity of stopping it. The right timing to perform the cardiovascular screening after a hypertensive disorder of the pregnancy is a matter of debate. The consensual time is usually 3 months, but some women will still be hypertensive 9 or 12 months after the delivery or will remain definitely hypertensive. The challenge for the clinician is not to lose the women that will remain definitely hypertensive at follow-up.
Our results show that in women who had a preeclampsia that remain with a high office blood pressure 6-12wk post-partum, 30-42 % of them have respectively a persistent diurnal and nocturnal true ambulatory hypertension. Studies on hypertensive disorders of pregnancy have
10 focused on ante-partum period, and unfortunately only few data addressed the issue of
hypertension in the post partum47.
Recently, Goel A et al. showed a high incidence of post partum hypertension (18.6%) in 988 women admitted for cesarean section.48 It is known that the frequency of hemorrhagic strokes is rising concurrently with the increase in the prevalence of maternal hypertension, especially in the post-partum period.49 So, the right timing to perform ABPM has to be determined. In our experience, an early follow up is a good timing to start patient education. Soon after delivery, preeclamptic women have to learn how to manage a hypertension and most of them have questions or anxiety about the future. They are avid for explanation on what happened and are very receptive to health messages and prevention. For many of these young and healthy women, it represents a first medical contact and it is an opportunity to settle an appropriate follow-up.
In our study, 17.9 % of women who had a preeclampsia presented with a white-coat
hypertension or a white-coat effect. In some studies, but not all, white-coat hypertension was associated with an increased risk of stroke in the general population.19, 20, 50 In the particular condition of pregnancy, white-coat hypertension identified early during pregnancy has been associated with a slightly increased risk incidence of preeclampsia, but with a better
pregnancy outcome than pregnancy complicated by chronic hypertension.18, 51 If the optimal management of white coat hypertension is uncertain, especially in the post-partum period, its identification may prevent unnecessary use of anti-hypertensive medication. Among the 28 patients under treatment, ABPM allowed the interruption of 5 (17.9%) unnecessary treatments and to maximize the therapy in 5 masked uncontrolled hypertension.
We also found that 11.6 % of our patients displayed a masked hypertension or phenomena in the post partum. Masked hypertension was equally found in both normotensive groups after a preeclampsia, regardless of the presence of albuminuria. Masked hypertension has been
11 associated with a higher long-term cardiovascular risk and an increased rate of target organ damage similar to sustained hypertension.20-23 To the best of our knowledge, masked
hypertension has never been described in the post-partum period. The occurrence of a masked hypertension could shed light on another link between cardiovascular disease and
preeclampsia.
Here again, evidence on the timing for the screening of masked hypertension after
preeclampsia and its management, is lacking.20, 22, 52 However, considering the potential long- term consequences for the mother, masked hypertension in pregnancy and in the post-partum period needs closer attention. As it is impossible to screen all normotensive women in their reproductive age for masked hypertension, specific factors such as a history of preeclampsia, gestational hypertension, persisting proteinuria and co-existing cardiovascular risk factors could be used to guide clinical decision.
Non-dipping profile is associated with an increased cardiovascular risk. Early studies on the circadian variation of blood pressure during preeclampsia showed the loss of the normal nocturnal fall and its correlation with the severity of the disease.25 In a previous paper, we observed the persistence of the non-dipper status for up to 10 years after a preeclampsia.31 In the present study, we found that 59.3% of women with preeclampsia had lost their normal nocturnal dipping and among them 9.7% had a reversed circadian rhythm. The control group also displayed a non-dipper pattern, however with very low nocturnal blood pressure
(94.3±7.6/61.7±4.6 mmHg in the control group versus 111.2 ± 17.6/74.8 ± 11.0 mmHg in preeclamptic women). Sleep disruption of the breastfeeding mother may explain the absence of nocturnal BP drop in both groups. In normotensive subjects, however, nocturnal BP remains in a low normal range whereas preeclamptic women reach a level of diastolic nocturnal BP that is abnormal.
Salt-sensitivity of the BP is defined as an increase of 5-10% of office BP or of ≥ 4mmHg of
12 the mean ambulatory BP after a high salt intake.28 A salt sensitive profile is a known
cardiovascular and renal risk factor independent of hypertension and is associated with lack of nocturnal BP fall.29, 30 We previously showed that women with a history of severe
preeclampsia had an increased salt-sensitivity of the ambulatory BP and a lack of nocturnal dipping compared with uncomplicated pregnancies, 10 years after the event.31 In this previous study we validated the method of Castiglioni et al. in a group of preeclamptic women by assessing the salt-sensitivity with a gold standard protocol that allowed us to validate the formula derived from ABPM parameters to estimate the risk of salt sensitivity.34 In the present study, 58.6% of women with a preeclampsia were classified as having a high-risk of salt sensitivity in the post-partum period versus 17.7% in the control group. Elevated
nocturnal BP may result from a defect in diurnal salt excretory capacity of the kidneys, with enhanced pressure natriuresis curve at nighttime.53 The kidney is the first organ, after the placenta, to be damaged in preeclampsia and consequently sodium balance may be altered in the post-partum period and later in life. This emphasizes the need to implement low salt diet counseling together with lifestyle modifications.
The increased short-term blood pressure variability on 24-hour ambulatory BP monitoring is known to be an independent risk factor for cardiovascular eventsand has been associated with arterial stiffness, stroke, and heart damage and salt sensitivity of the BP.54 In salt sensitive rat models and in humans, the variability of the BP was correlated with salt intake.55 Salt
restriction has been shown to decrease ambulatory BP variability in hypertensive patients with type 2 diabetes.56
Preeclamptic women in our work display a significantly higher standard deviation of the ambulatory daytime systolic and diastolic BP (13.8±4.7/ 11.4±6.1 vs 10.8±4.5/8.7±2.4 in controls, p<0.01). The same pattern was observed at night time (table 2). Together with a high ambulatory BP, a lack of nocturnal dipping and an increased salt sensitivity index, all these
13 BP phenotypes may help us to understand the mechanisms associated to the morbidity of preeclampsia later in life. Altogether, PE women seem to share mechanisms usually evoked for BP variability and salt sensitivity with people with increased CV risk, including increased sympathetic nervous system activity during the night,decreased renal sodium excretory ability andsalt sensitivity.
We have to acknowledge some limitations in our study. First is the lack of homogeneity in the ethnic origin of the patients included the control group. As women of Afro-Caribbean and Hispanic origin are more at risk for preeclampsia, and therefore more represented in the preeclampsia groups, we performed a secondary analysis excluding black ethnic group and found similar results (supplemental material). Secondly, we did not systematically perform ABPM in normotensive subject or purely albuminuric patients after a preeclampsia and the prevalence of masked hypertension may be underestimated.
Our strength is that we present to the best of our knowledge, the first study on the use of 24- ABPM in the early follow-up of hypertensive disease of pregnancy in the post-partum. We are able to show that 24h-ABPM in the post-partum is very useful to discriminate between fixed ambulatory hypertension that requires a close follow-up and treatment from the white coat hypertension. Moreover, it allows detection of masked hypertension in patients with persistent albuminuria and offers analysis of non-dipper status after a preeclampsia, pointing on possible salt sensitivity and renal damage. We also provide normal values of ambulatory BP after an uncomplicated pregnancy, which resulted to be very low. Use of 24h-ABPM in the post-partum is a valuable tool for pregnancy related hypertensive disorders follow-up.
Whether these early persistent hypertensive profiles have consequences on future cardiovascular events remains to be determined. This would strongly advise for early
detection as it allow early identification of high risk patients, improve adherence and provides an opportunity to discuss and apply preventives measures.
14 Perspectives
In this study, we show that 24h-ABPM is a valuable tool in the follow-up of preeclampsia. It discriminates between fixed ambulatory hypertension and white-coat hypertension, and identifies masked hypertension as well as non-dipper status. The use of 24h-ABPM helps identifying patients at risk for cardiovascular disease later in life and allows early implementation of life-style modifications. Further studies are required to guide clinical management of cardiovascular prevention in this population.
Acknowledgments: Sylvie Tremblay and Philippe Montillier for their help in data collection, and Nicolas Fernandez for his linguistic revision.
Source(s) of Funding: AD received a grant from the Swiss National Science Foundation and the Swiss Research on Hypertension Foundation; APB received a grant from the Clinical Research Centre of the University Hospital of Geneva.
Conflict(s) of Interest/Disclosure(s): none
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19 Novelty and significance
1) What is new?
• 24h-ABPM in the post-partum period and its use in the follow-up of preeclampsia have never been studied.
2) What is relevant?
• 24h-ABPM allows to discriminate the different patterns of high blood pressure after a preeclampsia
• Masked hypertension is more frequent in women with a recent history of preeclampsia than in controls and should be searched in case of persistent isolated albuminuria.
• 24h-ABPM is a valuable tool for pregnancy related hypertensive disorders follow-up. It enables to identify high-risk women for cardiovascular disease later in life and to target sub-groups of women for whom prevention has to be intensively implemented.
Summary
Hypertensive phenotypes have a high prevalence in the early post-partum period after a preeclampsia. Post-partum 24h-ABPM helps discriminate between fixed and white coat hypertension, detects masked hypertension and identify non-dipper status pointing on possible salt sensitivity. The use of 24h-ABPM in the post-partum is a valuable tool for pregnancy related hypertensive disorders follow-up. It allows early identification of risk factors and helps the management of high-risk women.
20 Figure legends
Figure 1. Flow-chart
Figure 2. Hypertension patterns among groups: daytime systolic blood pressure Figure 3. Hypertension patterns among groups: daytime diastolic blood pressure Figure 4. Classes of salt-sensitivity risk among groups
Tables
Table 1. Baseline characteristics of patients
Characteristics Preeclampsia (n=115) Controls (n=41) p
Age, y 33.7 ± 5.7 33.2 ± 6.7 0.6
Ethnic group Caucasian Afro-Caribbean Hispanic
Asian
58.3 (67) 27.0 (31) 9.6 (11)
5.2 (6)
97.6 (40) 0.0 (0) 0.0 (0) 2.4 (1)
< 0.01
Pregestational BMI, kg/m2 25.4 ± 5.2 22.3 ± 3.3 < 0.01
Smokers 16.5 (19) 0.0 (0) < 0.01
Chronic hypertension 13.9 (16) 0.0 (0) 0.01
Pregestational diabetes 4.34 (5) 0.0 (0) 0.14
Primiparity 60.0 (69) 53.7 (22) 0.5
Twin pregnancy 7.0 (8) 0.0 (0) 0.2
Cesarean 49.6 (57) 0.0 (0) < 0.01
Birth gestational age,wk 36.0 ± 3.9 39.4 ± 1.6 < 0.01 Birth weight, grams (n=125)
Birth weight < 10th centile*
2525.6 ± 898.1 24.0 (30)
3230 ± 449.9 17.1 (7)
< 0.01 0.03 Plasma creatinine, μmol/L
eGFR, mL/min/1.73m2
61.6 ± 13.6 113.2 ± 18.5
71.5 ± 9.8 96.6 ± 13.8
< 0.01
< 0.01 Urine Albuminuria, mg/L 96.2 ± 453.4 18.6 ± 35.7 < 0.01
ACR, mg/mmol 11.3 ± 64.8 < detection limit < 0.01
Abbreviations are: BMI, body mass index, eGFR, estimated glomerular filtration rate by CKD-EPI equation, ACR, urinary albumin on creatinine ratio.
Data are expressed in mean ± standard deviation or percentage (absolute) and analyzed using Student’s t-test, Kruskal-Wallis test, Fisher test or the Chi2 test as appropriate.
* Birth weight percentiles are determined according to the Swiss Society of Pediatrics standards.
21 Table 2. Office and 24h ambulatory blood pressures
Parameters Preeclampsia (n=112) Controls (n=36) p Office measurements
Office BP systolic Office BP diastolic Heart rate, bpm Diurnal ABP
130.4 ± 14.1 89.7 ± 11.5
77.8 ± 9.9
107.7 ± 10.3 69.2 ± 9.0 74.4 ± 8.8
< 0.01
< 0.01 0.1
ABP, systolic ABP, diastolic Pulse pressure Heart rate, bpm SD, systolic SD, diastolic Nocturnal ABP
118.9 ± 15.0 83.2 ± 10.4
36.5 ± 9.6 83.6 ± 9.2 13.8 ± 4.7 11.4 ± 6.1
104.8 ± 7.9 71.6 ± 5.3 33.1 ± 4.8 79.4 ± 7.2 10.8 ± 4.5 8.7 ± 2.4
< 0.01
< 0.01 0.1 0.01
< 0.01 0.01
ABP, systolic ABP, diastolic Pulse pressure Heart rate, bpm SD, systolic SD, diastolic
111.2 ± 17.6 74.8 ± 11.0 36.6 ± 11.1 72.0 ± 10.6 11.0 ± 4.5
9.8 ± 3.3
94.3 ± 7.6 61.7 ± 4.6 32.5 ± 6.0 60.0 ± 6.7 9.1 ± 2.1 8.0 ± 2.0
< 0.01
< 0.01 0.03
< 0.01 0.01
< 0.01 Abbreviations are: BP, blood pressure, ABP, ambulatory blood pressure, SD, standard deviation.
Values are in mm Hg unless specified otherwise.
Data are expressed in mean ± standard deviation or percentage (absolute) and analyzed using the Student’s t-test or Kruskall-Wallis as appropriate.
22 Table 3. Patterns of high blood pressure and salt-sensitivity risk
Patterns of blood pressure Preeclampsia (n=112)
Controls (n=36)
p
Ambulatory BP without treatment (n=84) Normal ABP
HTN (ABP ≥135/85 mmHg) White coat HTN
Masked HTN
48.8 (41) 23.8 (20) 17.9 (15) 9.5 (8)
97.2 (35) 0.0(0) 2.8 (1) 0.0 (0)
< 0.01
Ambulatory BP with treatment (n=28) Controlled HTN
Uncontrolled HTN White-coat effect Masked phenomena
14.3 (4) 50 (14) 17.9 (5) 17.9 (5)
N/A N/A
Categories of hypertension on 24h-ABP Systolic
Diastolic
Systolo-diastolic Nocturnal HTN
2.7 (3) 28.6 (32) 15.2 (17) 42.0 (47)
0 2.8 (1)
0 0
< 0.01
Mean circadian rhythm:
Dippers, % Non dippers, % Extreme dippers, % Reverse dippers, %
40.7 (42) 46.6 (48) 2.9 (3) 9.7 (10)
47.1 (16) 41.2 (14) 11.8 (4)
0.0 (0)
0.054
Salt-Sensitivity Risk:
Low-risk, % High-risk, %
Intermediate risk, %
3.9 (4) 58.6 (50) 47.6 (49)
14.7 (5) 17.7 (6) 67.7 (23)
< 0.01
Abbreviations are: HTN, hypertension; ABP, ambulatory blood pressure.
Definitions are: dippers: 10-20% nocturnal fall of mean ABP; non-dippers: 0-9% nocturnal fall of mean ABP; extreme dippers: > 20% nocturnal fall of mean ABP; reverse dippers:
nocturnal increase of mean ABP.
Data are expressed in percentage (absolute) and analyzed using the Chi2 test.
23 Figure 1
24 Figure 2
25 Figure 3
26 Figure 4
27 Supplemental material
Table S1. Baseline characteristics of patients, Afro-Caribbean and Hispanic ethnic groups excluded
Preeclampsia (n=73) Controls (n=41) p
Age, y 33.5 ± 5.8 33.2 ± 6.7 0.8
Ethnic groups : Asian, % Caucasian, %
6.8 (5) 93.2 ()
2.4 (1) 97.6 (40)
0.7
Pregestational BMI, kg/m2 25.6 ± 5.3 22.3 ± 3.3 < 0.01
Smokers, % 20.6 (15) 0.0(0) < 0.01
Chronic hypertension, % 15.1 (11) 0.0(0) < 0.01
Pregestational diabetes, % 4.1 (3) 0.0(0) 0.2
Primiparity, % 65.8 (48) 53.7 (22) 0.2
Twin pregnancy, % 9.6 (7) 0.0(0) 0.1
Caesarean, % 49.3 (36) 0.0(0) < 0.01
Birth gestational age,wk 36.0 ± 4.0 39.4 ± 1. < 0.01
Birth weight, grams 2533.1 ± 898.3 3230 ± 449.9 < 0.01
Neonatal death, % 4.1 (3) 0(0) 0.2
Abbreviations are: BMI, body mass index, eGFR, estimated glomerular filtration rate by CKD-EPI equation, ACR, urinary albumin on creatinine ratio.
Data are expressed in mean ± standard deviation or percentage (absolute) and analyzed using Student t-test, Fisher test or the Chi2 test as appropriate.
28 Table S2. Office and 24h ambulatory blood pressures, Afro-Caribbean and Hispanic ethnic groups excluded
Preeclampsia (n=72) Controls (n=36) p Office blood pressure
Systolic, mm Hg Diastolic, mm Hg Heart rate, bpm
127.8 ± 11.1 87.7 ± 10.2
76.7 ± 9.5
107.7 ± 10.3 69.2 ± 8.9 74.4 ± 8.8
< 0.01
< 0.01 0.2 24h-Ambulatory BP
Systolic, mmHg Diastolic, mmHg Pulse pressure, mm Hg Heart rate, bpm
115.4 ± 13.7 79.2 ± 8.2 36.2 ± 7.6 81.5 ± 11.9
100.8 ± 7.0 68.0 ± 4.3 32.8 ± 5.1 72.1 ± 6.5
< 0.01
< 0.01
<0.01
< 0.01 BP profiles
Normal BP
HTN (24h ABP ≥135/85 mm Hg) White coat HTN, %
Masked HTN, %
44.4 (32) 20.8 (15) 20.8 (15) 13.9 (10)
97.2 (35) 0.0(0) 2.78 (1)
0.0(0)
< 0.01
Mean circadian rhythm Dipper, %
Non-dipper, % Extreme dipper, % Reverse dipper, %
43.9 (29) 42.4 (28) 4.6 (3) 9.1 (6)
47.1 (16) 41.2 (14) 11.8 (4)
0.0(0)
0.2
Salt-Sensitivity Risk Low-risk, % High-risk, %
Intermediate risk, %
3.0 (2) 40.9 (27) 56.1 (37)
14.7 (5) 17.7 (6) 67.7 (23)
0.014
Abbreviations are: HTN, hypertension; ABP, ambulatory blood pressure.
Definitions are: dippers: 10-20% nocturnal fall of mean ABP; non-dippers: 0-10% nocturnal fall of mean ABP; extreme dippers: > 20% nocturnal fall of mean ABP; reverse dippers:
nocturnal increase of mean ABP. Data are analyzed using the Student’s t-test and Chi2 test.
