Evidence-based Obstetrics and Gynecology

List of contributors

Veronica Ades

Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Jennifer Amorosa

Department of Obstetrics, Gynecology and Reproductive Sciences

Icahn School of Medicine, Mt Sinai Hospital

New York, NY, USA

Karen Archabald

Legacy Health

Portland, OR, USA

Stephanie Bakaysa

Department of Maternal‐Fetal Medicine

Tufts Medical Center

Boston, MA, USA

Oren Barak

Rehovot, affiliated with the Hadassah‐Hebrew University School of Medicine, Department of Obstetrics and Gynecology

Kaplan Medical Center

Jerusalem, Israel

Marie Beall

Obstetrics and Gynecology

Harbor UCLA Medical Center

Torrance, CA, USA

Mila de Moura Behar Pontremoli Salcedo

Department of Gynecology and Obstetrics

Federal University of Health Sciences (UFCSPA)/Santa Casa de Porto Alegre

Porto Alegre, RS, Brazil

Rana Snipe Berry

Department of Obstetrics and Gynecology

Indiana University School of Medicine

Indianapolis, IN, USA

Stephanie V. Blank

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Isaac Blickstein

Obstetrics and Gynecology, Kaplan Medical Center, Rehovot, The Hadassah‐Hebrew University School of Medicine, Jerusalem, Israel

Anne‐Sophie Boes

Leuven University Fertility Centre (LUFC)

UZ Leuven, Leuven, Belgium

Ware Branch

Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology, Medical Director of Women and Newborns Clinical Program for Intermountain Healthcare, Intermountain Medical Center

University of Utah

Murray, UT, USA

Haywood Brown

Morsani College of Medicine

University of South Florida Health Center

Tampa, FL, USA

Julie Brown

Department of Obstetrics and Gynecology

University of Auckland

New Zealand

Steve N. Caritis

Division of Maternal‐Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences

Magee Women's Hospital of UPMC

Pittsburgh, PA, USA

H. J. A. Carp

Department Obstetrics and Gynecology

Sheba Medical Center

Tel HaShomer, Israel

Steven L. Clark

Department of Obstetrics and Gynecology

Baylor College of Medicine Obstetrics and Gynecology, Service Chief MFM, Texas Children's Hospital, TCH Pavilion for Women

Houston, TX, USA

Joshua Copel

Department Obstetrics, Gynecology & Reproductive Sciences, Division of Maternal‐Fetal Medicine

Yale School of Medicine

New Haven, CT, USA

Sabrina D. Craigo

Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology

Tufts Medical Center

Boston, MA, USA

John P. Curtin

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Thomas D'Hooghe

Division of Reproductive Medicine and Biology, Department of Obstetrics and Gynecology

University of Leuven

Leuven, Belgium

Gary A. Dildy

Department of Obstetrics and Gynecology

Baylor College of Medicine Obstetrics and Gynecology, Service Chief MFM, Texas Children's Hospital, TCH Pavilion for Women

Houston, TX , USA

Margaret Dziadosz

Department of Obstetrics and Gynecology, NYU School of Medicine

New York University

New York, NY, USA

Britt K. Erickson

Division of Gynecologic Oncology

University of Alabama at Birmingham

Birmingham, AL, USA

Christine Farinelli

Obstetrix Medical Group

Tucson Medical Center

Tucson, AZ, USA

Cynthia Farquhar

Department of Obstetrics and Gynecology

University of Auckland

New Zealand

Maisa N. Feghali

Division of Maternal‐Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences

Magee Women's Hospital of UPMC

Pittsburgh, PA, USA

Kimberley Ferrante

Division of Female Pelvic Medicine and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Michael R. Foley

Banner University Medical Center Phoenix, Obstetrics and Gynecology

University of Arizona College of Medicine Phoenix

Phoenix, AZ, USA

Karin Fox

Maternal‐Fetal Medicine, Baylor College of Medicine

Texas Children's Hospital, Pavilion for Women

Houston, TX, USA

Jenna Friedenthal

Department of Obstetrics and Gynecology

New York University

New York, NY, USA

Joanna Gibson

Obstetrics and Gynecology

Yorkshire and Humber, UK

Veronica Gillispie

Ochsner Health System

New Orleans, LA, USA

Dianne Glass

Division of Female Pelvic Medicine and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Division of Female Pelvic Medicine and Reconstructive Pelvic Surgery, Department of Urology

NYU Langone Medical Center

New York, NY, USA

Katherine R. Goetzinger

Department of Obstetrics, Gynecology and Reproductive Sciences

University of Maryland School of Medicine

Baltimore, MD, USA

Jane Goldman

Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology

The Valley Hospital

Ridgewood, NJ, USA

Steven Goldstein

Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

George Graham

Department of Maternal‐Fetal Medicine

Tufts Medical Center

Boston, MA, USA

Jeanne‐Marie Guise

Division of Maternal‐Fetal Medicine, Departments of Obstetrics and Gynecology, Medical Informatics and Clinical Epidemiology, Public Health and Preventive Medicine, and Emergency Medicine

Oregon Health and Science University

Portland, OR, USA

Cynthia Gyamfi‐Bannerman

Columbia University Medical Center

New York, NY, USA

Cara Heuser

Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology

University of Utah and Intermountain Medical Center

Murray, UT, USA

Alexandria J. Hill

High Risk Pregnancy Center

Las Vegas, NV, USA

Texas A&M College of Medicine

College Station, TX, USA

University of Arizona

Phoenix, AZ, USA

Kathy Huang

Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Warner K. Huh

Division of Gynecologic Oncology

University of Alabama at Birmingham

Birmingham, AL, USA

Joses A. Jain

Columbia University Medical Center

New York, NY, USA

Arun Jeyabalan

Division of Maternal‐Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences

University of Pittsburgh School of Medicine, Magee‐Women's Hospital

Pittsburgh, PA, USA

Carrie Lynn Johnson

Department of Obstetrics and Gynecology

University of Miami, Miller School of Medicine

Miami, FL, USA

Emily L. Johnson

Johns Hopkins Bayview Medical Center, Department of Neurology

Johns Hopkins University School of Medicine

Baltimore, MD, USA

Megan L. Jones

The University of Ohio Wexner Medical Center

Columbus, OH, USA

Peter W. Kaplan

Johns Hopkins Bayview Medical Center, Department of Neurology

Johns Hopkins University School of Medicine

Baltimore, MD, USA

David L. Keefe

Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Rasha S. Khoury

Division of Family Planning and Global Women's Health

Department of Obstetrics, Gynecology & Reproductive Biology

Brigham and Women's Hospital, Harvard Medical School

Boston, MA, USA

Sarah J. Kilpatrick

Department of Obstetrics and Gynecology

Cedars‐Sinai Medical Center

Los Angeles, CA, USA

David L. Kulak

Department of Obstetrics and Gynecology

Johns Hopkins Medical Center

Baltimore, MD, USA

Jessica Lee

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Richard H. Lee

Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine

Los Angeles, CA, USA

Patricia A. Lohr

bpas (British Pregnancy Advisory Service)

Stratford Upon Avon, UK

Sherri Longo

Ochsner Health System

New Orleans, LA, USA

Richard Lyus

bpas (British Pregnancy Advisory Service) Richmond

East Twickenham, UK

Dominique Malacarne

Division of Female Pelvic Medicine and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Division of Female Pelvic Medicine and Reconstructive Pelvic Surgery, Department of Urology

NYU Langone Medical Center

New York, NY, USA

Peter W. Marks

Center for Biologics Evaluation and Research, U.S. Food and Drug Administration

Silver Spring, MD, USA

Jovana Y. Martin

Department of Obstetrics and Gynecology

University of Alabama at Birmingham

Birmingham, AL, USA

Stephanie R. Martin

Clinical Concepts in Obstetrics

Scottsdale, AZ, USA

Christel Meuleman

Leuven University Fertility Centre (LUFC)

UZ Leuven, Leuven, Belgium

David A. Miller

Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology, Keck School of Medicine

University of Southern California

Los Angeles, CA, USA

Payam Mohassel

Johns Hopkins Bayview Medical Center, Department of Neurology

Johns Hopkins University School of Medicine

Baltimore, MD, USA

Jane Moore

Nuffield Department of Obstetrics and Gynecology

University of Oxford

Oxford, UK

Lila Nachtigall

Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Frederick Naftolin

Department of Obstetrics and Gynecology

New York University

New York, NY, USA

Jennifer A. Namazy

Scripps Clinic

San Diego, CA, USA

James Neilson

Obstetrics and Gynecology

University of Liverpool

Liverpool, UK

Diane De Neubourg

Leuven University Fertility Centre (LUFC)

UZ Leuven, Leuven, Belgium

Errol R. Norwitz

Louis E. Phaneuf Professor of Obstetrics & Gynecology

Tufts University School of Medicine

Chief Scientific Officer Chair, Department of Obstetrics & Gynecology Tufts Medical Center

Boston, USA

Anthony O. Odibo

Department of Obstetrics and Gynecology

University of South Florida

Tampa, FL, USA

Joseph G. Ouzounian

Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology

University of Southern California, Keck School of Medicine

Los Angeles, CA, USA

Michael J. Paidas

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine

Section of Maternal‐Fetal Medicine

New Haven, CN, USA

Lubna Pal

Department of Obstetrics, Gynecology and Reproductive Sciences

Yale University School of Medicine

New Haven, CT, USA

Joong Shin Park

Department of Obstetrics and Gynecology

Seoul National University College of Medicine

Seoul National University Hospital

Seoul, Korea

Anita Patel

University of Central Florida

Center for Reproductive Medicine

Orlando, FL, USA

Shivani R. Patel

Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology

University of Southern California, Keck School of Medicine

Los Angeles, CA, USA

Shefali Pathy

Department of Obstetrics, Gynecology and Reproductive Sciences

Yale University School of Medicine

New Haven, CT, USA

Karen Peeraer

Leuven University Fertility Centre (LUFC)

UZ Leuven, Leuven, Belgium

Ashley T. Peterson

Division of Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology

Tufts Medical Center

Boston, MA, USA

Joanne Quinones

Department of Obstetrics and Gynecology, Maternal Fetal Medicine, Lehigh Valley Health Network

The Center for Advanced Perinatal Care, Allentown, PA, USA

University of South Florida‐Morsani College of Medicine

Tampa, FL, USA

Diana A. Racusin

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine

Baylor College of Medicine, Texas Children's Hospital Pavilion for Women

Houston, TX, USA

A. Reza Radjabi

Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Andrei Rebarber

Mount Sinai St. Luke's and Mount Sinai West, Mount Sinai Beth Israel, The Mount Sinai Hospital

Obstetrics, Gynecology and Reproductive Sciences

New York, NY, USA

Danielle M. Roncari

Division of Family Planning, Department of Obstetrics and Gynecology

Tufts University School of Medicine

Boston, MA, USA

Ashley S. Roman

Department of Obstetrics and Gynecology, NYU School of Medicine

New York University

New York, NY, USA

Michael Ross

Obstetrics and Gynecology

Harbor UCLA Medical Center

Torrance, CA, USA

B. Ryan Ball

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine

Section of Maternal‐Fetal Medicine

New Haven, CN, USA

Nada Sabir

Obstetrics and Gynecology/Maternal Medicine, Bradford Teaching Hospitals NHS Foundation Trust

Bradford, UK

Michael Schatz

Kaiser Permanente

San Diego, CA, USA

Kathleen M. Schmeler

Department of Gynecologic Oncology and Reproductive Medicine

The University of Texas, MD Anderson Cancer Center

Houston, TX, USA

Zachary P. Schwartz

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

James H. Segars

National Institute of Child Health and Human Development

National Institutes of Health

Bethesda, MD, USA

Lili Sheibani

Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology

University of California

Irvine, Orange, CA, USA

Celso Silva

University of Central Florida, Center for Reproductive Medicine

Orlando, FL, USA

Michael K. Simoni

Department of Psychiatry

Yale School of Medicine

Yale, New Haven, CN, USA

Scott W. Smilen

Division of Female Pelvic Medicine and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology

NYU Langone Medical Center

New York, NY, USA

Division of Female Pelvic Medicine and Reconstructive Pelvic Surgery, Department of Urology

NYU Langone Medical Center

New York, NY, USA

John Smulian

Department of Obstetrics and Gynecology, Maternal Fetal Medicine, Lehigh Valley Health Network

The Center for Advanced Perinatal Care, Allentown, PA, USA

University of South Florida‐Morsani College of Medicine

Tampa, FL, USA

Rhoda Sperling

Department of Obstetrics, Gynecology and Reproductive Sciences

Icahn School of Medicine, Mt Sinai Hospital

New York, NY, USA

Medicine, Infectious Diseases

Icahn School of Medicine, Mt Sinai Hospital

New York, NY, USA

Carla Tomassetti

Leuven University Fertility Centre (LUFC)

UZ Leuven, Leuven, Belgium

Maria Victoria Vargas

Department of Obstetrics and Gynecology

George Washington University Medical Center

USA

Alex C. Vidaeff

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine

Baylor College of Medicine, Texas Children's Hospital Pavilion for Women

Houston, TX, USA

Deborah Wing

Maternal‐Fetal Medicine, Department of Obstetrics and Gynecology

University of California

Irvine, Orange, CA, USA

Kimberly Yonkers

Department of Psychiatry

Yale School of Medicine

Yale, New Haven, CN, USA

Carolyn M. Zelop

Ultrasound and Perinatal Research, Division of MFM and Department of Obstetrics and Gynecology, The Valley Hospital, Ridgewood, NJ, USA

Department of Obstetrics and Gynecology NYU School of Medicine, New York, NY, USA

Lisa C. Zuckerwise

Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Maternal‐Fetal Medicine

Yale School of Medicine

New Haven, CT, USA

CHAPTER 1

Evidence‐based medicine in obstetrics and gynecology

Jeanne‐Marie Guise

Division of Maternal‐Fetal Medicine, Departments of Obstetrics and Gynecology, Medical Informatics and Clinical Epidemiology, Public Health and Preventive Medicine, and Emergency Medicine, Oregon Health and Science University, Portland, OR, USA

…decisions about the care of individual patients should be based on the conscientious, explicit, and judicious use of the current best evidence on the effectiveness of clinical services.

IOM Knowing What Works in Health Care 2008 [1]

While all clinicians want to use the best evidence to make health care decisions, with 37 reviews, 47 randomized control trials (RCTs), and two guidelines published every day, it is impossible for practicing clinicians to keep up with all the new evidence and decide whether it is sufficient to suggest that they should change their practice. This book provides a summary of evidence for the major clinical areas of practice within the specialty of Obstetrics and Gynecology (OB/GYN), and this chapter (i) provides an overview and context, discussing the history of evidence based medicine (EBM) in OB/GYN; (ii) describes the importance and conduct of a systematic evidence review, a hallmark of EBM and contemporary evidence‐based decision‐making; and (iii) provides additional EBM resources and references for interested readers.

History of obstetrics and evidence‐based medicine

OB/GYN has played a long and important role in shaping what is known today as EBM, although it did not always embrace evidence. The beginnings of OB/GYNs relationship with EBM may have started in the 1800s when women went to Lying‐in Hospitals to stay for days or months in preparation for and recovery from childbirth. Lying‐in hospitals were often crowded, and rates of maternal and child death from childbed fever (puerperal sepsis) were high. Some women were said to prefer giving birth in the streets, pretending to have given birth en route to the hospital. Ignac Semmelweiss, perplexed by the lower rates of maternal mortality for women delivering outside the hospital said: To me, it appeared logical that patients who experienced street births would become ill at least as frequently as those who delivered in the clinic…What protected those who delivered outside the clinic from these destructive unknown endemic influences? [2]. He also observed that there were higher rates of maternal mortality from childbed fever in the First Division Hospital, which was staffed by physicians, compared with the Second which was staffed by midwives. Both units had trainees, performed examinations, and saw roughly similar populations. He realized that unlike the midwives, physicians all performed autopsies on women who died the night before prior to beginning their clinical duties on the maternity ward. In 1847, Semmelweiss figured out what might be occurring when a forensic medical professor, Jakob Kolletschka, died of sepsis after sustaining an accidental finger stick during an autopsy. He concluded that, In Kolletschka, the specific causal factor was the cadaverous particles that were introduced into his vascular system. I was compelled to ask whether cadaverous particles had been introduced into the vascular systems of those patients whom I had seen die of this identical disease. I was forced to answer affirmatively [2]. He required physicians wash their hands with chlorinated lime before examining patients. The mortality rate in District 1 fell from 11.4% prior to handwashing to 1.27% (rates were 2.7% and 1.33% in District 2). The medical community did not embrace this new evidence. Semmelweiss was ridiculed by physicians who were offended by the suggestion they were unclean, and his theory was rejected because it was contrary to the accepted belief that childbed fever was caused by miasmas or bad air. In response, Semmelweiss could only figuratively shake his head: One would believe that the clarity of things would have made the truth apparent to everyone and that they would have behaved accordingly. Experience teaches otherwise. Most medical lecture halls continue to resound with lectures on epidemic childbed fever and with discourses against my theories [2].

Fast forward to the 1950s and 1960s and two stories demonstrate how difficult it is for new evidence to change clinical practice even when that evidence is strong – and how profound the consequences for this failure.

In the 1950s, diethylstilboestrol (DES) therapy was used to prevent miscarriage. Its use was established through uncontrolled studies. Even though randomized controlled trials were published in the mid‐1950s that found no significant prevention offered by DES, its use had become so commonplace that it continued despite the evidence. It was not until 1971 that the food and drug administration (FDA) brought national attention to the harms of DES exposure (associated with vaginal clear cell carcinoma) and banned its use in pregnancy. Total exposure to DES for mothers and daughters has been estimated to exceed 10 million worldwide.

The story of antenatal corticosteroids is not only a major discovery in obstetrics but is also emblematic of the importance of EBM. In the 1960s, Graham Mont Liggins, an Australian obstetrician, had a sheep farmer neighbor and wondered why ewes delivered prematurely when worried by dogs [3]. Liggins suspected it may have something to do with the stress‐response in the mother and the release of cortisol. He conducted an experiment where he administered corticosteroids to pregnant ewes and found they delivered prematurely. Unexpectedly, he also found that the lambs delivered by ewes that received corticosteroids survived in far greater numbers than he would have expected given the severe degree of their prematurity [4]. In the 1970s, Liggins and a pediatrician colleague, Ross Howie, conducted the first randomized trial in humans to test their theory that corticosteroids reduced the occurrence of respiratory distress syndrome (RDS). RDS and mortality rates were significantly reduced in the treated group (6.4%) as opposed to 18% in placebo treated mothers. Within a decade of this first RCT additional studies supported the conclusion that corticosteroids significantly reduced infant mortality for prematurely born children. However it was not until the mid‐1990s that antenatal steroids became part of routine practice for women at risk of premature delivery (after a meta‐analysis was published in 1989). The forest plot from a meta‐analysis of antenatal corticosteroids represents this delay, demonstrates the potential power of systematic reviews and meta‐analyses of a body of evidence, and has become the symbol for the Cochrane Collaboration, the most recognized source for evidence‐based systematic reviews in medicine. It has been estimated that tens of thousands of babies would have been saved by earlier implementation of steroids.

It is perhaps not a surprise that Archie Cochrane, for whom the Cochrane Collaboration is named awarded the field of OB/GYN the first wooden spoon award for failing to evaluate the care they provide with RCTs and failing to apply results of RCTs in practice [5]. He went further stating that GO in Gynecology and Obstetrics should stand for go ahead without evidence [6].

What is evidence‐based medicine?

EBM, refers to a process of turning clinical problems into questions and systematically locating, appraising, and synthesizing research findings as a basis for clinical decision‐making. Gordon Guyatt [7] first used the term EBM in the 1980s to describe an approach to residency training at McMaster University School of Medicine where residents were taught how to identify, interpret, and use the literature in their clinical decision‐making. At first he wanted to call it Scientific Medicine but reconsidered when others argued that the title would imply all other medicine was non‐scientific [8]. Further refined by David Sackett, EBM requires a bottom‐up approach that integrates the best external evidence with individual clinical expertise and patient choice [9].

The systematic review is a hallmark of EBM. Systematic reviews apply a scientific review strategy that limits bias by the systematic assembly, critical appraisal, and synthesis of all relevant studies on a specific topic. As shown in Figure 1.1, systematic reviews are at the top of the evidence hierarchy pyramid. Clinicians in pursuit of the best evidence, should first search for high‐quality systematic reviews. Since systematic reviews are such an important part of EBM and are instrumental to clinical decision‐making, this chapter provides a brief description of the systematic review process.

Figure 1.1 Systematic review processes.

Systematic review processes

If, as is sometimes supposed, science consisted in nothing but the laborious accumulation of facts, it would soon come to a standstill, crushed, as it were, under its own weight... Two processes are thus at work side by side, the reception of new material and the digestion and assimilation of the old [10]

A systematic review is a scientific review strategy that limits bias by the systematic assembly, critical appraisal, and synthesis of all relevant studies on a specific topic. Table 1.1 presents the six steps for Evidence‐based Obstetrics. The first four of these are covered by, and critical to, systematic review. Therefore, busy clinicians can shortcut these steps if they are able to find a high‐quality systematic review that answers their clinical question.

Table 1.1 Steps for evidence‐based obstetrics

Each of these steps is covered briefly below.

Formulating the question

A prudent question is one‐half of wisdom [11]

Sir Francis Bacon

Questions arise every day a clinician cares for patients: some they can answer easily, others they know where to find the answers quickly, and many require investigation. The ability to take an everyday dilemma and turn it into an answerable and searchable question is important not only for systematic reviews, but also for good clinical care. Questions often fall into specific categories: incidence/prevalence, causation/etiology, screening, diagnostic, therapeutic/treatment, prevention, outcomes (benefits and/or harms), prognostic, and they can be expressed as, In patients with…how effective is…compared with…for the outcome[s] of…. Formulating an answerable and relevant question is a critical foundational step to determining the relevant scope of a review; too big and the review may not be feasible, too narrow and the results may not be relevant. Systematic review questions are often formulated according to a PICOTS format, that is, Population, Intervention, Comparator, Outcome, Timing, and Setting (Table 1.2).

Population – Understanding the population of reviews and research studies is often one of the clearest ways clinicians can determine whether the scope of a review or study is pertinent to their clinical population. Factors often considered include age (e.g. child, teen, young adult, elderly), sex, medical conditions, pregnancy status, and social factors (education required, skill‐level, access to care). A description of such factors helps clinicians understand whether the review will be applicable to their patient population.

Intervention – The intervention is often the main subject of reviews. Interventions can involve medical, surgical, health systems, social, or behavioral interventions and can have one or many components.

Comparator – The comparator group is often overlooked, yet is critical to understanding the relative effectiveness of an intervention. Comparators include no treatment, placebo, standard of care, active alternative treatment. It is important to describe the underlying condition considered standard of care as what is considered standard might be an intervention in other settings.

Outcomes – Outcomes include health outcomes, intermediate outcomes, and harms.

Timing – Timing is increasingly recognized as an important consideration. Timing refers to the timing of the intervention or parts of the intervention and also may describe the time of patient eligibility, intervention, and follow‐up for a target trial.

Setting – Setting or context factors such as organizational characteristics, financial setting (fee‐for‐ service, capitated, uninsured; geographic and clinical settings (solo or group practice, public or private, for profit or non‐profit, etc.) are often critical to interventional effectiveness and should be described in systematic reviews.

Table 1.2 PICOTS

Often the S in PICOTS is used to refer to study design. While that use is not usually an element in the question, it can be helpful to consider the types of studies that are most likely to inform particular types of questions. Table 1.3 aligns common types of questions with study designs.

Table 1.3 Studies applicable to particular review questions

Descriptions of these PICOTS elements enables the reader of a systematic review to understand whether the question is relevant to their clinical dilemma and setting. The questions also specify search terms and the inclusion and exclusion criteria for studies.

Searching the literature and identifying relevant studies

A comprehensive search and a systematic, unbiased approach to finding, selecting, and interpreting evidence are distinguishing features of systematic reviews. Searches of systematic reviews are meant to include all of the evidence and not just published articles. In general, bibliographic searches for systematic reviews in health care should always include MEDLINE® and the Cochrane Central Register of Controlled Trials. Additional databases that are often useful include Embase, CINAHL, Scopus, and PsychINFO. In addition to searching bibliographic databases, systematic reviews search reference lists of relevant reviews and articles and conduct searches for unpublished literature from registries, government or industry documents, Websites, and other sources. Once you have conducted a comprehensive search, the next critical ingredient of a systematic review is applying an unbiased approach to including and excluding articles. This process involves a priori decision‐making about issues such as date range, study design, language, key subject matter issues etc. A PRISMA [12] or QUORUM [13] figure is often used to detail finding and selecting pertinent literature for a review.

Critically appraising studies and assessing the strength of a body of literature

Critically appraising the literature involves two major stages: (i) evaluating the risk of bias for individual studies based upon study design; and (ii) grading the overall strength of evidence for a body of literature. Problems with an individual study's design or conduct have the potential to introduce bias or inferential error, and raise questions about the validity of their findings. Numerous tools exist to evaluate the risk of bias for controlled trials [14–16] and observational studies [16–18]. In general risk of bias tools evaluate participant selection; outcome, exposure, and process measures; study processes such as blinding; and appropriate analytic methods including intent to treat and considerations for confounding. This stage of individual study evaluation is critically important. One element in assessing the strength of the body of literature, it can inform quantitative syntheses such as meta‐analyses, and provide insights on how to strengthen future research studies in design and conduct. Because raters may vary in their interpretation, reviewers will usually pilot test the application of the tool prior to wide‐scale use across studies.

Understanding the reliability of the overall body of evidence is critical for guideline groups, policymakers, and clinicians. Methods for evaluating the overall strength of evidence have evolved over the past several decades. Organizations such as the US Preventive Services Task Force (USPSTF) [19] the US Evidence‐based Practice Centers (EPCs) Program [20], and the Oxford Center for Evidence‐based Medicine [21] have all developed criteria. The USPSTF risk of bias/quality rating scale has been adapted for easy use by relative novices and is available at www.storc.org) In 2000, a collaboration of international experts formed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group to establish common and transparent criteria to grade the literature. The group has grown tremendously over the years and experts in the field continue to refine the application of GRADE criteria by examining and debating their experiences and exemplars (www.gradeworkinggroup.org). According to GRADE, evidence from randomized controlled trials starts as high quality and that from observational studies starts as low quality based on the assumption that randomization controls for systematic bias in effect estimates. The body of evidence is evaluated using five main criteria: (i) risk of bias; (ii) inconsistency of results across studies; (iii) indirectness; (iv) imprecision; and (v) publication bias [22]. Risk of bias was discussed above. Consistency involves determining the degree to which studies were similar in direction and range of effect sizes. Directness involves assessing whether the evidence reflects a single direct link to the outcome or whether it involves several indirect links in a chain of evidence or surrogate outcomes. Precision has to do with the certainty of the effect which is often judged by the narrowness of the confidence interval. Publication bias is the last major GRADE criterion. It has long been recognized that studies with positive findings are more likely to be published. (Several factors can contribute to this, including journal bias toward positive results and author awareness of those journal preferences.) This alone can bias the overall body of literature. Published studies can show an intervention's effect while there could be a large body of unpublished evidence suggesting no effect. Because of this, GRADE recommends conducting an evaluation for publication bias. After considering GRADE elements, the entire body of literature for a given outcome is rated as high, moderate, low, or very low. Table 1.4 presents the summary grades and their meaning.

Table 1.4 GRADING the quality of a body of literature [22]

Knowing that guideline groups, policymakers, and clinicians have limited time, the GRADE working group also recommends use of a summary of evidence table to summarize: (i) key outcomes; (ii) effect sizes (magnitude and confidence interval); (iii) numbers of studies and participants; (iv) overall GRADE of evidence by outcome; and (v) important notes or comments. Ultimately, the GRADE approach provides a system for evaluating the strength of the literature as a whole and determining the strength of recommendation that can be made. For example a strong recommendation could be made when the effect size is large and overall evidence quality is high, meaning that it is unlikely to have occurred in the absence of a true effect of the intervention. However, a weak recommendation would be made for low or very low evidence where any effect could have occurred solely as a result of bias from confounding factors. The GRADE system or adaptations of the GRADE system are used by numerous guideline groups including since 2015 the International Consensus on cerebroplacental ratio (CPR) and endocervical curettage (ECC), Science with Treatment Recommendations provided by the International Liaison Committee for Resuscitation (ILCOR) which are used in this book [23]. Ultimately these processes and products are tools to promote transparency, understanding, and dialogue around the totality of evidence, our certainty in that evidence, and a rationale for practice.

Evidence‐based resources

Table 1.5 provides the interested reader with additional resources to find evidence‐based reviews and guidance and/or to learn more about evidence‐based practices. Some of the major resources are discussed in some detail.

Table 1.5 List of evidence‐based organizations and resources

The Cochrane Collaboration

Realizing that it is a daunting if not impossible challenge for the individual practicing clinician to keep abreast and synthesize the medical literature, Sir Ian Chalmers, motivated by Archie Cochrane's wooden spoon challenge to obstetrics, developed a database of all existing and relevant randomized controlled clinical trials for interventions in OB/GYN and a repository of systematic reviews the Cochrane library. The Cochrane Collaboration (http://www.cochrane.org) is now one of the largest networks of global scientists, with more than 37 000 volunteers who synthesize the world's evidence and produce high‐quality systematic reviews. The Collaboration is organized into review groups that are responsible for conducting and updating systematic reviews for specific topic areas. Several review groups are pertinent to OB/GYN including:

Pregnancy and Childbirth

The Cochrane Menstrual Disorders and Subfertility Group

The Cochrane Fertility Regulation Group

The Cochrane Gynecological Cancer Group

The Cochrane Library (http://www.cochranelibrary.com) has become one of the world's most recognized sources of high‐quality systematic reviews in medicine. The origins and symbol of the Cochrane are connected to obstetrics, and as mentioned earlier, the very symbol for the Cochrane reflects the story of antenatal corticosteroid therapy.

The US preventive services task force and the US evidence‐based practice centers program

The USPSTF (www.uspreventiveservicestaskforce.org) is an excellent resource for evidence and recommendations in primary care and prevention. The USPSTF was established in 1984 as an independent, volunteer panel of national experts in prevention and EBM who issue recommendations on clinical preventive services such as screenings, counseling services, and preventive medications. Topics relating to OB/GYN and women's health include cervical cancer screening; screening for bacterial vaginosis in pregnancy to prevent preterm birth; mammography; breastfeeding; screening for BRCA‐related cancer, chlamydia, and gonorrhea, depression, genital herpes; counseling for gynecologic cancers; immunizations, and many more. It is an excellent resource for primary care issues and is considered by the US government when making coverage decisions. All USPSTF recommendations are paired with systematic evidence reviews conducted by EPCs. In 1997, Agency for Healthcare Research and Quality (AHRQ) (then known as the Agency for Health Care Policy and Research) established the EPC program to develop evidence reports to inform health policy, guidelines, coverage decisions, patient decision‐making, and clinical practice for clinical professional societies, insurers, employers, healthcare organizations, and policymakers. Examples of reports that are relevant to OB/GYN include comparative effectiveness of therapies to treat menopausal symptoms, antidepressant treatment of depression during pregnancy and postpartum, smoking cessation interventions in pregnancy and postpartum care, oral contraception use for the prevention of ovarian cancer, progestogens for the prevention of preterm birth, and nitrous oxide for the management of labor pain (a full list can be found at http://www.ahrq.gov/research/findings/evidence‐based‐reports/search.html?f[0]=field_evidence_based_reports%3A13971).

Rationale for this book

Clinicians have more access to evidence than ever before; this is both a cure and a curse. While the process of finding, appraising, and synthesizing evidence is possible for practitioners, studies suggest that the process is too time consuming for most [24, 25]. Inadequate time (74%), limited searching skills (41%), and limited access to evidence (43%) have been cited by physicians as barriers to implementing evidence‐based care [25]. This book is written to provide a central resource for evidence in OB/GYN for the busy clinician. The chapters that follow provide an overview of the evidence across major clinical topics faced on a daily bases by Obstetricians and Gynecologists.

References

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3. Norwitz, E. and Greeberg, J. (2010). Beyond antenatal corticosteroids: what did mont liggins teach us? Reviews in Obstetrics and Gynecology 3 (3): 79.

4. Gluckman, P. and Buklijas, T. (2013). Sir Graham Collingwood (Mont) Liggins. Biographical Memoirs of Fellows of the Royal Society 59: 193–214.

5. Ohlsson, A. and Clark, K. (2002). Evidence‐based perinatal and paediatric health care: the contribution of the Cochrane collaboration and tte Canadian Cochrane network and Centre. Paediatrics & Child Health 7: 319–322.

6. The Cochrane Pregnancy and Childbirth Database. (1989). Effective Care in Pregnancy and Childbirth. http://journals.sagepub.com/doi/abs/10.1177/016327879501800406.

7. Guyatt, G. and Voelker, R. (2012). Everything you ever wanted to know about evidence‐based medicine. JAMA 313 (18): 1783–1785.

8. Smith, R. and Rennie, D. (2014). Evidence‐based medicine—an oral history. JAMA 311 (4): 365–367.

9. Sackett, D., Rosenberg, W., and Gray, J. (1996). Evidence based medicine: what it is and what it isn't. BMJ 312: 71–72.

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11. Bacon S.F. http://www.azquotes.com/quotes/topics/prudent.html

12. Moher, D., Liberati, A., Tetzlaff, J., and Altman, D. (2009). Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. Annals of Internal Medicine 151 (4): 264–269.

13. Clarke, M. (2000). The QUORUM statement. Lancet 355: 756–757.

14. Collaboration TC (2011; 5.1.0). Cochrane Handbook for Systematic Reviews of Interventions (ed. H. JPT and S. Green). Wiley.

15. Higgins, J. and Altman, D. (2011). The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 343: d5928.

16. Viswanathan M., Ansari M., Berkman N., et al. (2012) Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions Agency for Healthcare Research and Quality; Methods Guide for Comparative Effectiveness Reviews (AHRQ Publication No. 12‐EHC047‐EF).

17. Harris, R., Helfand, M., Woolf, S. et al. (2001). Methods work group, third US preventative services task force. Current methods of the US preventative services task force: a review of the process. American Journal of Preventative Medicine 20 (3): 21–35.

18. Wells G., Shea B., O'Connell D., et al. The Newcastle‐Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta‐Analyses https://www.ncbi.nlm.nih.gov/books/NBK99082/bin/appb‐fm4.pdf.

19. Force USPST. Grade Definitions. 2015. https://www.uspreventiveservicestaskforce.org/Page/Name/grade‐definitions.

20. Berkman, N.D.L.K., Ansari, M., McDonagh, M. et al. (2013). Grading the strength of a body of evidence when assessing health care interventions for the effective health care program of the Agency for Healthcare Research and Quality: an update. Methods Guide for Comparative Effectiveness Reviews AHRQ Publication No. 13(14)‐EHC130‐EF.

21. Howick, J., Chalmers, I., Glasziou, P. et al. (2011). The 2011 Oxford CEBM levels of evidence (introductory document). Oxford Centre for Evidence‐Based Medicine.

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23. Morrison, L., Chair, L., Gent, E. et al. (2015). Part 2: evidence evaluation and Management of Conflicts of interest 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 132: S368–S382.

24. Cumbers, B. (1999). Evidence‐based practice data day. Health Services Journal 109 (5650): 30–31.

25. Craig, J., Irwig, L., and Stockler, M. (2001). Evidence‐based tools: useful tools for decision making. The Medical Journal of Australia 174: 248–253.

SECTION 1

Gynecology

David L. Keefe

General Gynecology

CHAPTER 2

Abnormal menstrual bleeding

Cynthia Farquhar and Julie Brown

Department of Obstetrics and Gynecology, University of Auckland, Auckland, New Zealand

Clinical scenario

A 42‐year‐old mother of four children presents to her general practitioner on the eighth day of her menstrual period. She fainted at home when she got up that morning and her husband has brought her to the clinic. She recovered completely from the faint and walks into the clinic. She usually has regular periods and the typical duration is six days. The first four days are heavy and she changes pads and tampons hourly during the day and twice during the night. They are not painful. She has no other health problems except that she is 90 kg and 159 cm tall. The body mass index (BMI) is 35.6 kg m−2.

On examination she looked very pale. She has a pulse rate of 88b m−1 and her blood pressure is 125/80. The rest of the findings are normal. A vaginal examination is not done but there are no abdominal masses.

The general practitioner arranges an urgent hemoglobin test and later that day the result is reported as 60 g l−1.

Background

The International Federation of Gynecology and Obstetrics (FIGO) defines chronic abnormal uterine bleeding (AUB) as bleeding from the uterine corpus that is abnormal in duration, volume, and/or frequency and has been present for the majority of the last 6 months [1, 2]. The prevalence of AUB in the general population is predicted to range between 11% and 13% rising to 24% for those women aged 36–45 years [3]. The extent of the menstrual bleeding has been linked to the likelihood of anemia [4, 5].

Heavy menstrual bleeding (HMB) without underlying pathology (also known as menorrhagia or dysfunctional uterine bleeding) can be a major health problem for many women, frequently resulting in referral for hysterectomy (National Health Committee, 1998) [6]. The National Institute for Health and Clinical Excellence defines HMB as as excessive menstrual blood loss which interferes with the woman's physical, emotional, social, and material quality of life, and which can occur alone or in combination with other symptoms. (p8) [7]. Table 2.1 indicates that menstrual blood loss per month in excess of 80 ml is considered to be heavy [8]. Unfortunately, measurement of the volume of monthly menstrual blood loss is not possible outside the research setting, and clinicians are dependent on self‐report by women about the heaviness of their menstrual loss.

Table 2.1 Suggested normal limits for menstrual parameters in the mid‐reproductive years

Source: Fraser et al. 2007 [8].

HMB may occur at any time between puberty and the menopause and is typically described as either ovulatory or anovulatory. A history of HMB with regular menstrual cycles is usually associated with ovulation whereas an anovulatory pattern of bleeding with erratic intervals between menstrual periods, is common in puberty and as women near the menopause. Anovulatory menorrhagia may also be present in women with polycystic ovaries who often have irregular and heavy menses. This dysfunctional uterine bleeding is defined in the NICE guidelines as Abnormal vaginal bleeding that occurs during a menstrual cycle that produced no egg (ovulation did not take place). The occurrence of irregular or excessive uterine bleeding in the absence of pregnancy, infection, trauma, new growth or hormone treatment (p. xiii) [7].

Vannella et al. (2008) reported iron deficiency anemia (serum ferritin <30 μg dl−1) in two‐thirds (67%) of women (aged 20–56 years) who had a diagnosis of menorrhagia [9]. As HMB is the most common presentation of abnormal menstrual bleeding this chapter will focus on HMB.

Differential diagnoses of HMB that should be considered include uterine pathology such as fibroids and hyperplastic endometrium, complications of early pregnancy such as miscarriage, carcinoma of the cervix and endometrium (rarely), and exogenous hormones taken for menopausal symptoms. Fibroids are present in about 40% of women with menorrhagia [7] although they are probably only responsible for menorrhagia when they result in an enlargement of the endometrial cavity or when they are submucous fibroids. Rarely, disorders of coagulation may be present. Approximately 5% of women with menorrhagia have endometrial hyperplasia, a premalignant condition of the endometrium, which is more likely to occur in women who weigh 90 kg or more and women who are 45 years old. In the majority of women no obvious cause is found for their HMB [6, 7].

Scope: This chapter is limited to women with HMB without pathology and does not cover the management of women with known pathology such as endometrial hyperplasia and uterine fibroids.

Clinical questions

Are there tests to establish the severity of HMB?

In women with HMB, what initial investigations should be undertaken?

Which women with HMB should have investigations to exclude serious pathology?

In a woman with HMB, what is the management of acute anemia?

In women with HMB, what is the effectiveness and safety of oral progestogens?

What is the effectiveness and safety of antifibrinolytics for women with HMB?

What is the effectiveness and safety of non‐steroidal anti‐inflammatory drugs for women with HMB?

What is the effectiveness and safety of combined oral contraceptives for women with HMB?

What is the effectiveness and safety of progesterone containing intrauterine devices for women with HMB?

What is the effectiveness and safety of injected/depot progestogens for women with HMB?

What is the effectiveness and safety of surgery, e.g. endometrial ablation/resection or hysterectomy for women with HMB?

Search strategy

The following search strategy was used to identify potential studies to answer the clinical questions. The databases that were searched included MEDLINE, Embase, and the Cochrane Database of Systematic Reviews from inception until January 2012. The following search terms were used: uterine hemorrhage/or menorrhagia/or metrorrhagia, dysfunctional uterine bleeding, AUB, metrorrhagia, menometrorrhagia, HMB, hypermenorrhagia, and systematic review and meta‐analysis.

Critical appraisal of literature for each clinical question

Are there tests to establish the extent of HMB?

The clinical symptoms that women with HMB experience is variable with some women only presenting after severe anemia has been diagnosed and others presenting with no derangement in their hematology results. The NICE guidelines for HMB recommend that history taking should cover the nature of the bleeding (frequency, heaviness, and length) and seek to identify any potential pathology (pain or pressure symptoms) and also to identify the woman's concerns and expectations [7]. Although it is possible to objectively measure menstrual blood, the tests involve the collection of menstrual pads and tampons and are rarely undertaken except in the research setting. Subjective measures such as pictorial bleeding charts are reported to have highly variable sensitivity and sensitivity and are not recommended. [7] (p35). There is no simple and reliable way of identifying women who have severe HMB and the question of whether menstrual blood loss is a problem can only truly be determined by the woman herself [7] (p35).

Women with anemia have been found to be more likely to have excessive menstrual blood loss and therefore anemia can be used as an indicator of the severity of HMB providing other factors such as diet are taken into account. Ferritin levels have been reported to be the most sensitive test for diagnosing Fe deficiency anemia [10].

2.In women with HMB, what initial investigations should be undertaken?

A full history should be obtained including the nature of bleeding and symptomology that may indicate structural or histological abnormalities. A physical examination (observation, abdominal palpation, visualization of the cervix, and bi‐manual examination) is recommended prior to investigations for structural or histological abnormalities, and prior to levonorgestrel intrauterine system (LNG‐IUS) fitting [7].

The preceding paragraph has described that anemia is common and testing is recommended.

There are other conditions that may be present such as hormonal, thyroid, and coagulation disorders. Studies have reported on the association between hormonal conditions and HMB and no link has been reported [11, 12]. There is only one case‐control study that considered thyroid disorders and there was no evidence of a link between thyroid disorders and menstrual disorders [13]. With regard to coagulation disorders such as von Willebrand disease, two systematic reviews suggested a prevalence between 5% and 20% [14, 15]. No case‐control studies were available to establish the prevalence in the general population.

The NICE guidelines 2007 made the following recommendations for laboratory testing for women with HMB:

A full blood count test should be carried out on all women with HMB. This should be done in parallel with any HMB treatment offered. [C]

Testing for coagulation disorders (for example, von Willebrand disease) should be considered in women who have had HMB since menarche and have personal or family history suggesting a coagulation disorder. [C]

A serum ferritin test should not routinely be carried out on women with HMB. [B]

Female hormone testing should not be carried out on women with HMB. [C]

Thyroid testing should only be carried out when other signs and symptoms of thyroid disease are present. [C] National Institute for Health and Clinical Excellence, 2007 [7].

3.Which women with HMB should have investigations to exclude serious pathology?

The question of which women should be further investigated for pathology such as fibroids and endometrial pathology is an important one as some serious underlying conditions may be present (for example, endometrial hyperplasia) and some conditions are not amenable to medical treatments (e.g. use of tranexamic acid in women with HMB in association with uterine bleeding has been shown not be effective).

Therefore, women at risk of endometrial hyperplasia and carcinoma should have an assessment of their endometrium by either ultrasound or by endometrial biopsy. For women in the premenopausal age group the threshold for endometrial biopsy is ≥12 mm [6, 16]. Risk factors for endometrial pathology include high body mass indices (≥90 kg), age > 45 years, persistent intermenstrual bleeding and treatment failure [3, 6, 16–18].

Women with a clinical examination that suggests a structural or histological abnormality further investigations such as pelvic ultrasound is recommended [3, 7]. If there is uncertainty about the location of a centrally located fibroid, then saline infusion sonography is a useful second line investigation. There is no role for magnetic resonance imaging in the investigation of AUB as a first line test [6, 16].

4.In a woman with HMB, what is the management of acute anemia?

The NICE guideline 2007 notes the common association between anemia and women with HMB with iron deficiency anemia emerging as a clinical problem with a menstrual blood loss of 60–80 ml [7]. Serum ferritin is the most accurate test for iron deficiency anemia (likelihood ratio (LR) 51.85 at a level of <15 ng ml−1) [7]. Marret et al. (2010) recommended that iron must be administered to women with iron deficiency anemia [3]. There are a number of options for administration including daily and intermittent doses via oral or intravenous routes.

The evidence for the management of women with iron deficiency anemia in women with HMB is limited. A meta‐analysis of daily versus intermittent treatment with iron supplements in menstruating women found that intermittent iron supplementation resulted in more frequent presentations with anemia compared with daily supplementation (Risk Ratio (RR) 1.26, 95%CI 1.04–1.51). Intermittent iron supplementation did reduce the risk of anemia (RR 0.73, 95%CI 0.56–0.95) and improve hemoglobin concentration (MD 4.58 g l−1, 95%CI 2.56–6.59) and ferritin (MD 8.32, 95%CI 4.97–11.66) compared with no treatment or placebo [19].

In a randomized trial, intravenous administration of ferric carboxymaltose (≤1 g over 15 minutes, administered weekly to achieve a total calculated replacement dose) has also been shown to be safe and more effective than oral ferrous sulfate (325 mg, three times daily for six weeks) in women with iron deficiency anemia associated with heavy uterine bleeding [20].

5.In women with HMB, what is the effectiveness and safety of oral progestogens?

Progestogen therapy given in the luteal phase has been widely used in the treatment of dysfunctional uterine bleeding for many years. However, randomized controlled trials have shown it to be repeatedly ineffective in ovulatory menorrhagia. It can be used to manage irregular anovulatory cycles as it will induce a regular withdrawal bleed when given for seven days of each calendar month. Once menstruation commences other therapies may be given such as non‐steroidal anti‐inflammatory drugs (NSAIDs) or tranexamic acid.

Although progesterone therapy no longer has a place in the maintenance therapy of regular heavy periods it still has an important role in emergency suppression of a heavy extended menstrual bleeding episode. This is achieved by giving Norethisterone (15 mg per day) or medroxyprogesterone acetate (30 mg per day) for three to four weeks. The dosage can be decreased once bleeding has ceased. Bleeding should stop in the first week, but if it does not the dosage can be increased. Once the patient has been free of bleeding for three to four weeks progestogen can be stopped and a withdrawal bleed should occur. Maintenance therapy can then be instituted. Another regime is to give medroxyprogesterone acetate 10 mg per day initially and increase the dosage each day until the bleeding has stopped.

6.What is the effectiveness and safety of antifibrinolytics for women with HMB?

The mode of action of tranexamic acid is to depress the fibrinolytic activity of peripheral blood through the inhibition of plasminogen activation [18]. The dosage is 1 g three or four times a day on the days of heavy bleeding.

A Cochrane systematic review reported that antifibrinolytic therapy (tranexamic acid) resulted in a significant reduction in menstrual blood loss (weighted mean difference (WMD) −94, 95%CI (CI) −151.4 to −36.5) and significant change in mean reduction of blood loss (WMD −110.2, 95%CI −146.5 to −73.8) compared with placebo [21]. This was supported in another systematic review that found that tranexamic acid resulted in a reduction of menstrual blood loss of 34–54% in women with idiopathic menorrhagia [22].

Antifibrinolytics have also been reported to result in a significant reduction in mean blood loss when compared with other medical therapies, including mefenamic acid, norethisterone (administered in the luteal phase) and ethamsylate [21].

Non‐specific side effects are reported in approximately one‐third of women and include nausea and leg cramps [18]. There is no overall benefit in reduction in dysmenorrhea with antifibrinolytic agents [23] and no effect on duration of menses compared with control [22]. There is also thought to be an increased risk of thromboembolism. No differences in adverse effects between tranexamic acid and placebo were reported by Naoulou (2012) [22]. Longitudinal Swedish studies have also shown no difference in the occurrence of thrombosis in women treated with tranexamic acid compared with spontaneous thrombosis in women [21, 22].

The available evidence suggests that tranexamic acid is safe and effective at reducing menstrual blood loss and may also improve quality of life, including reduced flooding/leakage and improved sex life [22].

7.What is the effectiveness and safety of non‐steroidal anti‐inflammatories for women with HMB?

Endometrial prostaglandins are elevated when menstruation is excessive. NSAIDs reduce prostaglandin levels by inhibiting the enzyme cyclo‐oxygenase [7, 18]. Randomized controlled trials have consistently shown that NSAIDs decrease menstrual blood loss by between 20 and 50% [7]. Mefenamic acid, Ibuprofen, Naproxen, and Diclofenac have all been shown to be effective. NSAIDs are also helpful for women who have dysmenorrhea and up to 70% of women experience significant relief of pain [6]. NSAIDS were not as effective as danazol or tranexamic acid but had fewer side effects than danazol. The common side effects associated with NSAIDs are headaches and gastrointestinal disturbances, including dyspepsia, nausea, vomiting, and diarrhea. These disturbances can be avoided by taking the medication with food and are unlikely to occur if taken for a short time or intermittently. Women with a previous history of gastrointestinal ulceration or a history of bronchospasm with aspirin, should not be given NSAIDS. Non‐steroidal anti‐inflammatories should be taken regularly from the onset of menses, or just before, until heavy bleeding has subsided [7].

8.What is the effectiveness and safety of the combined oral contraceptive pill for women with HMB?

The combined oral contraceptive pill is useful in reducing menstrual blood loss and establishing regular cycles but the reduction in menstrual blood loss is less certain. Use of the combined oral contraceptive pill has the additional advantage of reducing dysmenorrhea and providing contraception [18].

A Cochrane systematic review identified only one randomized trial. There was no evidence of a significant difference in menstrual blood loss between those women treated with the oral contraceptive pill and those treated with danazol, or mefenemic acid, or naproxen [24]. A 2011 placebo controlled randomized trial comparing estradiol (E2) valerate and dienogest with placebo found that the oral contraceptive pill was effective in the treatment of women with idiopathic heavy and/or prolonged menstrual bleeding when compared with placebo with a mean reduction of −64.2% in the oral contraceptive group compared with −7.8% in the placebo group [25].

9.What is the effectiveness and safety of progesterone containing intrauterine devices for women with HMB?

Medicated intrauterine devices which release levonorgestrel (LNG‐IUS; Mirena™) in a controlled manner have been shown to reduce menstrual blood loss by up to 90% in women with menorrhagia [7, 26] with increasing effectiveness after approximately six months of use [26]. Patient satisfaction has also been shown to be high over 3–24 months of use, ranging from 63% to 87% [26]. The side effects reported are minor and include irregular bleeding, breast tenderness, and expulsion of the device [26].

The evidence currently suggests that LNG‐IUS is more effective at reducing menstrual blood loss that other medical interventions (combined oral contraceptive, oral progestogens, tranexamic acid, mefenamic acid, and fluriprofen). Reductions in mean blood loss volume ranging from 62% to 96% have been reported for LNG‐IUS compared with 11–44% for other pharmacological interventions [26] (Table 2.2).

Table 2.2 Pharmacological treatment options for heavy menstrual bleeding

Source: Adapted from National Institute for Health and Clinical Excellence (2007)