University of Groningen Hypertensive disorders of pregnancy Pereira Bernardes, Thomas Patrick Custodio Heinrich

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University of Groningen

Hypertensive disorders of pregnancy

Pereira Bernardes, Thomas Patrick Custodio Heinrich

DOI:

10.33612/diss.99788387

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Publication date: 2019

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Pereira Bernardes, T. P. C. H. (2019). Hypertensive disorders of pregnancy: occurrence, recurrence, and management. University of Groningen. https://doi.org/10.33612/diss.99788387

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Nederlandse samenvatting

Sumário em Português do Brasil

Co-author affiliations

Acknowledgements

About the author

Research Institute SHARE

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NEDERLANDSE SAMENVATTING

Homo sum, humani nihil a me alienum puto Publius Terentius Afer

Hypertensieve zwangerschapsaandoeningen komen voor in tot 10% van de meer dan 200 miljoen zwangerschappen per jaar wereldwijd. Aangezien ongeveer 14% van de moedersterfte en 10% van de doodgeboorten hypertensieve aandoeningen als oorzaak hebben, is de studie van hun preventie en management van duidelijk belang. Vrouwen met een hoog risico op het ontwikkelen van hypertensieve zwangerschapsaandoeningen zijn waarschijnlijk het meest gebaat bij effectieve preventiemaatregelen. Het eerste deel van dit proefschrift beschrijft twee studies die zich concentreerden op de identificatie van deze vrouwen. Ondanks voorzorgsmaatregelen en gepaste zorg komen deze aandoeningen nog steeds evenveel voor en moeten ze optimaal worden gemanaged. Het tweede deel van dit proefschrift was gewijd aan de vergelijking van twee opties voor ziekte management, inductie van baring en afwachten, en hun gevolgen voor de moeder en het kind.

Hoofdstukken 2 en 3 beschrijven studies van een Nederlands populatie-breed cohort waarin verschillende risicofactoren voor pre-eclampsie en de bevalling van een klein-voor-zwangerschapsduur-kind (SGA) zijn onderzocht. Het gekoppelde ontwerp van de cohortdataset in deze studies maakte het mogelijk om zowel klinische risicofactoren die aanwezig waren in de eerste zwangerschap als hun effect op de risico’s bij een tweede zwangerschap te onderzoeken.

Hoofdstuk 2 beschrijft waarom de maximale diastolische arteriële bloeddrukwaarde in de eerste zwangerschap als een nieuwe risicofactor voor het risico op pre-eclampsie in een volgende zwangerschap moet worden beschouwd. Tevens bewijst het dat een voorgeschiedenis van pre-eclampsie de belangrijkste risicofactor is voor herhaling. Bij vrouwen zonder pre-eclampsie tijdens de eerste zwangerschap was er een direct verband tussen een verhoogde maximale diastolische bloeddruk en een verhoogd risico op pre-eclampsie.

Hoofdstuk 3 laat zien dat de bevalling van een SGA-kind het risico op pre-eclampsie verhoogt in de volgende zwangerschap en vice versa, maar dit is beperkt tot specifieke situaties. Bij afwezigheid van hypertensieve aandoeningen in de eerste zwangerschap verhoogde het bevallen van een SGA-kind het risico op pre-eclampsie in de daaropvolgende zwangerschap enigszins, maar bleef het absolute risico lager dan één procent. In aanwezigheid van hypertensieve aandoeningen, verhoogde het bevallen van een SGA-kind het risico op pre-eclampsie niet. Op gelijke wijze verhoogde pre-pre-eclampsie in een laat stadium het risico op

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Nederlandse samenvatting

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een SGA-kind in kleine mate, maar waren de risico’s geassocieerd met pre-eclampsie in een vroeg stadium even groot als die geassocieerd met een premature bevalling.

Hoofdstuk 4 beschrijft de uitdagingen van gerandomiseerd gecontroleerd onderzoek (RCT’s) die gericht zijn op het evalueren van zeldzame uitkomsten in een heterogene populatie, gezien vanuit het obstetrische dilemma ‘inleiden van de baring versus afwachten’ bij vrouwen waarin hypertensieve zwangerschapsaandoeningen worden ontdekt nabij de uitgerekende termijn. Om deze uitdagingen te overwinnen, werd voorgesteld een individuele meta-analyse van gegevens van deelnemers (IPDMA) te realiseren. Deze IPD meta-analyse kwam tot stand in de studie beschreven in Hoofdstuk 5, waarin data van vrouwen uit vijf RCT’s werden samengevoegd om de bewijsgrond te versterken voor de behandeling van hypertensieve zwangerschapsaandoeningen. Hoewel is aangetoond dat inleiden van de baring het risico op een samengestelde uitkomst van het HELLP-syndroom en eclampsie vermindert, zijn de nadelige gevolgen van een vroeggeboorte zoals weergegeven door een toename in de kans op respiratory distress syndrome (RDS) duidelijk. Een beleid van bevalling na 37 weken zwangerschap voor vrouwen met pre-eclampsie zonder ernstige kenmerken lijkt een redelijk evenwicht te bieden tussen de risico’s voor moeder en kind. Het is echter nog steeds onduidelijk of dat ook het geval is bij zwangerschapshypertensie en bij vrouwen met chronische hypertensie.

Waar Hoofdstuk 5 een bredere strekking had, concentreerde Hoofdstuk 6 zich op de specifieke populatie van vrouwen met onrijpe baarmoedermond tijdens zwangerschappen die gecompliceerd werden door hypertensieve aandoeningen of vermoede intra-uteriene groeiachterstand. Voor deze groep vrouwen was het nog onduidelijk of inleiden van de bevalling vanaf de 37e_{week de frequentie van keizersnedes en nadelige neonatale}

uitkomsten verhoogde in vergelijking met afwachten. Deze frequenties bleken vergelijkbaar te zijn en het inleiden van de bevalling resulteerde in een lager aantal zuigelingen met navelstreng-arteriële pH < 7,05.

De traagheid die inherent is aan de gezondheidszorg, biedt een enorme uitdaging voor de spannende en om-de-hoek liggende toekomst, b.v. was betreft machine learning die toegepast wordt op Big Data. Waar de aanvankelijke gemengde resultaten lieten blijken dat er nog veel werk te doen is, bieden elektronische gezondheidsdossiers, gevoed door real-time gegevens verzameld door persoonlijke elektronische apparaten, onvoorziene mogelijkheden voor geïndividualiseerde, tijdige en effectieve zorg. Het is vrijwel zeker dat benaderingen zoals genoemd in hoofdstukken 2 en 3 in de nabije toekomst worden vervangen door nationale of zelfs internationale registers die automatisch worden bijgewerkt, direct toegankelijk zijn en klaar zijn om modellen gebaseerd op kunstmatige intelligentie meteen up-to-date te maken wat tot een grote verbetering kan leiden in de klinische praktijk. Op een

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vergelijkbare manier, en een beperktere schaal, geven de hoofdstukken 5 en 6 voorbeelden van het voordeel van het verzamelen van gegevens uit verschillende bronnen, om zo tot een klinisch relevante bevinding te komen. Aanvullende gegevens uit lopende en toekomstige onderzoeken bieden kansen voor nieuwe inzichten en om gerichte antwoorden te vinden. Of de algemene boodschappen in dit proefschrift grotendeels ongewijzigd zullen blijven of aanzienlijk zullen worden veranderd is onduidelijk, hoewel mijn vooringenomenheid natuurlijk neigt naar het eerste. “Vertrouw op je ervaring, maar blijf je zicht verfijnen”.

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Nederlandse samenvatting

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SUMÁRIO EM PORTUGUÊS DO BRASIL

Ô! Esse Brasil lindo e trigueiro, É o meu Brasil Brasileiro, Terra de samba e pandeiro. Excerpt from “Aquarela do Brasil”, Ary Barroso

As doenças hipertensivas na gestação ocorrem em até 10% das mais de 200 milhões de gestações que ocorrem anualmente no mundo. Como aproximadamente 14% das mortes maternas e 10% das natimortes tem como causa as doenças hipertensivas na gestação, o estudo de sua prevenção e manejo tem clara importância. Mulheres que apresentam alto risco de desenvolverem doenças hipertensivas na gestação tem o benefício mais provável associado a medidas de prevenção efetivas. A primeira parte desta tesa descreve dois estudos que focaram no esforço para identificar estas mulheres. A despeito de intervenções preventivas e cuidado apropriado, esses transtornos invariavelmente ainda ocorrem e precisam ser manejados de forma otimizada. A segunda parte desta tese foi dedicada à comparação de duas alternativas de manejo, o parto imediato e monitoramento expectante, e seus desfechos para a mãe e para a criança.

Os Capítulos 2 e 3 descrevem estudos de coorte populacionais holandeses que avaliaram diferentes fatores de risco para pré-eclâmpsia e nascimento de bebês pequenos para idade gestacional (PIG). O desenho acoplado do banco de dados da coorte nesses estudos permitiu a avaliação de fatores de risco clínicos na primeira gestação e seus efeitos sobre riscos na segunda gestação.

O Capítulo 2 descreve valores da pressão arterial diastólica máxima durante a primeira gestação devem ser considerados um novo fator de risco para pré-eclâmpsia na gestação subsequente e oferece mais evidência para história prévia de pré-eclâmpsia como o principal fator de risco para recorrência. Em mulheres que não apresentaram pré-eclâmpsia na primeira gestação, valores crescentes de pressão arterial diastólica máxima são diretamente proporcionais ao risco de pré-eclâmpsia na gestação subsequente.

O Capítulo 3 mostra que o nascimento de um bebê PIG aumenta o risco de pré-eclâmpsia na gestação seguinte e vice-versa, porém isto é limitado a situações específicas. Na ausência de doenças hipertensivas na primeira gestação, nascimento PIG aumentou discretamente o risco de pré-eclâmpsia na gestação seguinte, mas o risco absoluto permaneceu menor que 1%. Na presença de doenças hipertensivas, nascimento PIG não impôs risco adicional de pré-eclâmpsia. De forma similar, enquanto pré-eclâmpsia de início tardio (a partir de 34 semanas completas de gestação) aumentou discretamente o risco de nascimento PIG, o

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Sumário em Português do Brasil

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maior risco associado a pré-eclâmpsia de início precoce (anterior a 34 semanas de gestação) foi da mesma ordem de magnitude que o associado ao parto prematuro anterior a 34 semanas completas de gestação.

O Capítulo 4 explora os desafios associados a estudos clínicos randomizados controlados (ECR) direcionados ao estudo de desfechos raros em uma população heterogêneaatravés da lente obstétrica que avalia o dilema entre parto imediato e monitoramento expectante para mulheres que tenham atingido ou estejam próximas do termo e apresentam doenças hipertensivas da gravidez. Para superar os desafios, a realização de uma meta-análise com dados individuais de participantes (MA-DIP) foi proposta. O Capítulo 5 descreve a realização desta MA-DIP, com a inclusão de mulheres participantes de cinco ECRs e que teve o objetivo de fortalecer a base de evidências no manejo de doenças hipertensivas na gravidez. Apesar do parto imediato demonstrar uma redução no risco de um desfecho composto de síndrome HELLP e eclâmpsia, o impacto de um parto antes do termo sobre as taxas de síndrome do desconforto respiratório também são evidentes. Uma política de parto imediato assim que 37 semanas de gestação sejam completadas para mulheres que apresentam pré-eclâmpsia sem sinais de gravidade aparenta equilibrar riscos maternos e neonatais. Ainda não está claro, no entanto, se este é também o caso para hipertensão gestacional e em mulheres que apresentam hipertensão arterial crônica.

Enquanto o estudo do Capítulo 5 apresenta amplo escopo, o Capítulo 6 foi dedicado ao estudo a população específica de mulheres que apresentam condições cervicais desfavoráveis (índice de Bishop menor ou igual a 6) em gestações complicadas por doenças hipertensivas ou suspeita de restrição de crescimento intrauterino. Para este grupo de mulheres, ainda não estava claro se a indução de parto a termo aumentava as taxas de cesarianas e de desfechos neonatais adversos quando comparada ao monitoramento expectante. Neste estudo as taxas foram similares, com a exceção do desfecho relacionado ao pH do sangue arterial umbilical < 7.05, que favoreceu a indução do parto imediata.

A inércia inerente aos cuidados de saúde representa um grande desafio para as promessas de futuro associadas a machine learning aplicados a Big Data. Apesar de os resultados iniciais controversos demonstrarem que ainda há muito trabalho à frente, prontuários eletrônicos alimentados com dados em tempo real coletados por dispositivos eletrônicos pessoais oferecem perspectivas antes inimagináveis em termos de cuidado individualizado, oportuno e efetivo. É quase certo que abordagens de análise como as encontradas nos Capítulos 2 e 3 serão em um futuro não tão distante substituídas por bases de dados nacionais e até mesmo internacionais, atualizadas automaticamente, abertas a acesso em tempo real e prontas para alimentarem modelos de inteligência artificial que irão imensamente aprimorar a prática clínica. Da mesma forma, mas em menor escala, os Capítulos 5 e 6

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são exemplos do benefício em agregar dados de diferentes fontes para que evidências clínicas relevantes sejam encontradas. Dados de ensaions em andamento e futuros vão oferecer novas oportunidades para o surgimento de insights e respostas específicas sejam encontradas. Se as conclusões encontradas nesta tese vão permanecer em grande parte inalteradas ou completamente descartas a luz de novas evidências é incerto, apesar de meu viés tender naturalmente para a primeira hipótese. “Confie em sua experiência, mas continue aprimorando sua visão”.

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Sumário em Português do Brasil

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CO-AUTHOR AFFILIATIONS

Andrew H. Shennan Division of Women’s Health

King’s College London Women’s Health Academic Centre Kings Health Partners United Kingdom

Anitta Ravelli

Department of Medical Informatics Academic Medical Center

University of Amsterdam The Netherlands Ben Willem Mol

Department of Obstetrics and Gynaecology Monash University

Australia

Corine M. Koopmans

Department of Obstetrics and Gynaecology University of Groningen

University Medical Center Groningen The Netherlands

Eva F. Zwerbroek

Gert-Jan van Baaren

Department of Obstetrics and Gynaecology Academic Medical Center

University of Amsterdam The Netherlands

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C0-author affiliations

8

H. Marike Boezen

Department of Epidemiology University of Groningen

Henk Groen

Department of Epidemiology University of Groningen

Jim Thornton

Department of Obstetrics and Gynaecology University of Nottingham

United Kingdom Josje Langenveld

Department of Obstetrics and Gynaecology Zuyderland Medical Centre

The Netherlands Kedra Wallace

Department of Obstetrics and Gynecology University of Mississippi Medical Center United States of America

Kim Boers

Department of Obstetrics and Gynaecology Bronovo Hospital

The Netherlands Kim Broekhuijsen

Department of Obstetrics and Gynaecology Haaglanden Medisch Centrum

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Linda van Wyk

Department of Obstetrics and Gynaecology Leiden University Medical Centre

The Netherlands Mariëlle G. van Pampus

Department of Obstetrics & Gynaecology Onze Lieve Vrouwe Gasthuis

The Netherlands Maureen T.M. Franssen

Michelle Owens

Department of Obstetrics and Gynecology University of Mississippi Medical Center United States of America

Natalia Novikova

Department of Obstetrics and Gynaecology Frere Hospital

South Africa Parvin Tajik

Department of Clinical Epidemiology and Biostatistics Academic Medical Center

University of Amsterdam The Netherlands Paul van den Berg

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C0-author affiliations

8

Shakila Thangaratinam Women’s Health Research Unit

Centre for Primary Care and Public Health Queen Mary University of London United Kingdom

Sicco Scherjon

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ACKNOWLEDGEMENTS

No man is an island, entire of itself; every man is a piece of the continent, a part of the main. If a clod be washed away by the sea, Europe is the less, as well as if a promontory were, as well as if a manor of thy friend’s or of thine own were: any man’s death diminishes me, because I am involved in mankind, and therefore never send to know for whom the bells tolls; it tolls for thee.

Excerpt from “Devotions upon Emergent Occasions”, John Donne

However carefully stitched together, it is doubtful that any number of words can adequately honor the work and dedication of the many generous hands involved in this thesis. Nonetheless, they were put forth and got to work. The effortless recognition that this is and will continue to be the case for any example of genuinely human endeavor not only warms my heart, but strengthens the bonds that tie it to all others. Because of this, in reading the following notes, I ask you to please trust that they cannot possibly represent the entirety of the gratitude that is felt and that is due.

To the ones who extended their hands, offered this opportunity and supported me through its completion, Dr. Henk Groen, my co-promotor, as well as Prof. H. Marike Boezen, Prof. Paul van den Berg, and Prof. Ben Willem Mol, my promotors, I express my deeply held gratitude and

respect.

The gentle enthusiasm I was met with in my first time at your office was an early sign of the good things to come, Henk. Your enormous patience, tireless dedication and deeply knowledgeable

guidance are hard to find treasures. I feel tremendously fortunate and happy to have met you and for being your student these past years. Thank you.

I don’t recall the first time we’ve met, Paul, but it did not take long for me to develop a liking for

your quick humor and start to count on your broad perspective and keen insight. Having you as a promotor meant keeping both the clinical and human aspects of care in balance with the at times cold conclusions drawn from the data. For that, for the much-needed support and so much more, I thank you.

Ben, despite the distance, having you as a promotor was a privilege. Your creative and pragmatic

vision was the key that unlocked every article of this thesis. For everything and especially for being there when you were dearly needed, I thank you.

For opening the doors of the UMCG Epidemiology Department, for laying the foundation for all of these research efforts, and for the valuable feedback on them, I’m very thankful to Prof. H. Marike Boezen and Prof. Ronald Stolk, current and former heads of our department.

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Acknowledgements

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I’m confident, perhaps hopeful, that you don’t remember this episode, Marike, but the first time

we’ve met was in a statistics course. The course’s 1st_{day schedule showed that it would start with}

a video presentation and it was just too tempting to skip it and sneak in another hour of sleep. I’m unsure if the deserved and prompt scolding was worth it, but I’m glad that first impression did not last.

Standing along the many other teachers and professors I’ve learned from and admire, I’m especially thankful to Prof. José Medina Pestana and Prof. Rodrigo Bressan. Without your

support none of this would have been possible. You are both inspiring examples of what hard work driven by sharp minds and open hearts can achieve. Thank you.

I’m very thankful to all of my many co-authors, and in particular to Kim Broekhuijsen and Eva Zwertbroek. It was a pleasure to directly work with and learn from you both. I wish you all the

best, thank you.

I’m also thankful to Prof. Yvonne van der Schouw, Prof. Marc Spaanderman, and Prof. Jan Jaap Erwich for accepting the invitation to take part in the assessment committee of this thesis. I

thank you very much for taking the time to read and evaluate it.

To the anonymous nurses, technicians, neonatologists, obstetricians, data analysts, managers, and all manner of people that heavily or lightly touched or were touched by the projects involved in this thesis, and especially to the studied women and children, I express my profound gratitude. To friends, old and new, thank you! Thaís and Rubens, comrades-in-arms in so many adventures,

not the least or last of them our first trip to the Netherlands. An ocean of distance doesn’t make a difference. And to my “Dutch” and Dutch friends, Emma, Gerian, Octavio, Susana, Isabel: here’s

to joy, laughter and game nights with full bellies. Thank you!

Finally, the very thought of family brings up an easy smile and imensa saudade. Fully conscious of being tiresomely repetitive: words aren’t nearly enough.

Mãe, pai, Ni, Ké e Ste. Eu amo vocês. Obrigado!

And then… Emilia happens! Without you we would never see the end of this project. Thank you

for being my partner throughout this journey and beyond. Measuring up to your love is a tall order that I’m happy to strive towards. I love you!

Thank you,

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ABOUT THE AUTHOR

Nunca conheci quem tivesse levado porrada. Todos os meus conhecidos têm sido campeões em tudo. Excerpt from “Poema em Linha Reta”, Álvaro Campos (Fernando Pessoa)

Son of Monika and Custodio Bernardes, Thomas was born in São Paulo on April 9 1982, growing up there for the first ten years of his life. Those years were followed by the family moving to Florianópolis, an island in the south of Brazil. By 2001 he was back in São Paulo to pursue a bachelor’s degree in Management at Fundação Getulio Vargas in São Paulo. Having obtained that degree and with little desire to join the corporate world, in 2006 he moved to Rio de Janeiro to pursue a master’s degree in Economics at Pontifícia Universidade Católica. Coming to a sense that a life dedicated to more service would be more fulfilling he abandoned that program and decided to apply to medical school.

In 2008 he was able to join Escola Paulista de Medicina. His first research project was in the Nephrology department, supervised by Prof. Dr. Elisa Higa. The study of adverse effects of gadolinium in a chronic kidney disease rodent model showed him that animal lab work was likely not in his future. The Psychiatry department provided his second research opportunity: early identification of children at risk of psychiatric disorders, under the supervision of Prof. Dr. Rodrigo Bressan. Alongside this research, Thomas participated in a student interest group in Transplantation Medicine, mentored by Prof. Dr. José Medina Pestana. In 2011, with the support of both, Thomas was able to visit the Netherlands for the first time and present research results in the student-organized conference ISCOMS at the University Medical Center Groningen.

This conference was followed by a short 4-week research fellowship in the Epidemiology Department, supervised by Dr. Henk Groen. Charmed by the Netherlands and encouraged by Dr. Groen, Thomas was able to return in the following year, this time supported by a one-year scholarship from the “Ciências Sem Fronteiras” (“Sciences without Borders”) program. The fruitful research in that year led to the offer of an Abel Tasman Talent Program scholarship. This allowed the pursuit of a doctorate degree in the University of Groningen.

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About the author

8

After a second year of research in the Netherlands, Thomas returned to Brazil to finish his medical training. He obtained that degree by the end of 2015 and started to work in primary Pediatric care in low socioeconomic status neighborhoods in São Paulo. By the end of 2017 he was back in the Netherlands to finish his PhD research, the results of which you now have in hands.

Thomas and his partner Emilia live in Groningen and thoroughly enjoy their small apartment near the Noorderplantsoen.

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RESEARCH INSTITUTE SHARE

This thesis is published within the Research Institute SHARE (Science in Healthy Ageing and healthcaRE) of the University Medical Center Groningen / University of Groningen.

Further information regarding the institute and its research can be obtained from our internet site: http://www.share.umcg.nl/

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