Epidemiologic and Research Methods in Fetal Medicine

Key Points

The randomised controlled trial (RCT) is the least biased method of assessing the effectiveness of clinical interventions. It has been little used in fetal medicine, but reports are increasing.
The details of good clinical trial methodology are now well established. It is critically important to avoid selection bias by ensuring allocation concealment at randomisation.
Research synthesis allows the reader to review the totality of relevant evidence on a particular topic. Systematic reviews can be performed of RCTs (‘reviews of effectiveness’), screening and diagnostic tests, or other types of scientific literature. Meta-analysis may or may not be a component of a systematic review.
The Cochrane Database of Systematic Reviews is the largest source of high-quality systematic reviews of health care interventions.
The likelihood ratio describes the usefulness of a screening or diagnostic test.
Routinely collected perinatal datasets can generate useful information and important hypotheses (e.g., the ‘Barker hypothesis’) as long as the quality of data is sound.

Introduction

Epidemiology–the science of the study of the distribution and causes of diseases in populations–has produced a rich set of tools that are being increasingly applied in clinical research. This growing specialty has led to birth of a subspecialty that is termed ‘clinical epidemiology’. This chapter explores these tools and the concepts that underpin them and illustrates their application with reference to diagnostic and screening tests and therapeutic interventions in fetal and perinatal medicine. Fetal medicine is itself a young speciality, and its short history and rapid progress have inevitably resulted in some errors and blind alleys. The methodological concepts presented here hopefully will help obstetricians caring for fetuses–‘maternal-fetal medicine’ specialists in North America and ‘fetal medicine’ specialists in Europe–learn from past mistakes and provide introduction to scientific research foundations crucial to ensure that the application of fetal medicine contributes more good than harm.

Care during pregnancy and childbirth has been among the vanguard areas of clinical activity in moving towards ‘evidence-based’ clinical practice. The basis of this process–the production of systematic reviews of scientifically rigorous studies–has been likened in scale and importance to the Human Genome Project. This chapter is organised under two themes. We begin with a description of epidemiologic methods necessary to understand and make meaningful interpretations of research findings in fetal medicine, and part two is devoted to principles and concepts in general research methods. Empirical applications of methods relating to fetal medicine are infused throughout to facilitate an easier grasp of the concepts.

Epidemiologic Study Designs

Epidemiologic study designs fall under two broad categories: experimental design and observational designs. Randomised controlled trials (RCTs) are experimental designs (discussed later). Observational designs can be classified as analytical or descriptive. The most common analytical study designs include prospective (including the longitudinal design), retrospective (including the case-control design) and cross-sectional study designs. Descriptive studies include meta-analysis (both aggregate and individual patient-level meta-analysis) and case series. Interested readers are referred to the large body of literature on the topic of epidemiological study designs.

Randomised Controlled Trials

Not all interventions can be evaluated by randomised trials; one cannot foresee, for example, randomised trials of fetal transfusion for severe fetal anaemia or of immediate versus delayed delivery for prolonged fetal bradycardia in labour. However, different methods of fetal transfusion or of techniques of caesarean delivery would be obvious candidates for further evaluation.

Randomisation

The RCT is a simple but powerful method of avoiding systematic errors, or bias, by ensuring that experimental (study) and control groups are comparable in all important respects other than in their exposure to the intervention being tested. By random allocation, the investigator accounts not only for known confounding variables but also for factors that are unknown but are also potentially important determinants of final outcome. Random allocation depends on allocation solely on the basis of chance–metaphorically, on the basis of the flip of a coin.

The essence of secure randomisation requires that those involved in the study cannot know in advance to which group a particular woman will be allocated (i.e., concealment of allocation). Thus the use of hospital case numbers, alternate days or date of birth will not adequately conceal the direction of allocation. This prevents clinicians having preconceptions about the effectiveness of the two treatment options from selectively enrolling patients based on the next treatment assignment. These methods of participant allocation to the study groups are sometimes called ‘quasi-random’ and with current concepts of good trial methodology should not be used.

Even apparently robust methods of random allocation, such as the commonly used sealed opaque envelope to be opened only after the woman has consented to entering the trial, have been known to be abused on occasion. The gold-standard methods, used now in large trials, include computerised online or web and telephone randomisation in which someone based at a remote site gives randomisation instructions only after basic descriptive data about the woman and confirmation of eligibility have been recorded. Electronic communication may be particularly difficult in parts of the developing world, and randomised trials may be particularly important in such settings because rates of both maternal and fetal mortality are high. The Collaborative Eclampsia Trial, which for the first time demonstrated the indisputable preeminence of magnesium sulphate as the anticonvulsant of choice for eclampsia, took place mainly in developing countries. This trial used identical boxes containing magnesium sulphate, diazepam or phenytoin, which were opened only when a woman had an eclamptic seizure. Increasingly, web-based randomisation procedures are used.

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