Discussion Questions

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  What were the investigators’ overall aims?

  
  
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  What was the study design?

  
  
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  Was the statistical approach reasonable?

  
  
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  What information is contained in the tables?

  
  
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  What are the strengths and weaknesses of this study?

  
  
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  What are the clinical implications of the research?

Introduction

Women who were the product of a difficult pregnancy may find that medical history repeats itself when they become pregnant. A new study by Wikström et al examined whether the risk for disorders of placentation in pregnancy—preeclampsia, placental abruption, spontaneous preterm birth, and stillbirth—was higher when 1 parent had been born small for gestational age (SGA), another outcome related to abnormal placentation. An intergenerational linkage would suggest a genetic predisposition to these complications. If a true hereditary tendency did exist, genetic technologies could help pinpoint useful treatments. Journal Club members agreed the work was important, considering the prevalence and morbidity of these conditions.

Lorie M. Harper, MD, MSCI and George A. Macones, MD, MSCE, Associate Editor

Background

Harper: What were the overall aims of this study?

Reagan: The aims of this study were to determine the risk of placental disorders in the offspring of mothers and fathers who were born SGA and to use this information to establish maternal and paternal genetic contributions to the etiology of placental dysfunction; specifically, their contribution to the occurrence of preeclampsia, placental abruption, spontaneous preterm birth, and stillbirth. Additionally, this unique cohort allowed the investigators to examine the effect when 1 parent was born SGA and the combined effect when both parents were born SGA.

Harper: Do you think this is an important topic for clinical research?

Norman: Yes, this is an extremely important topic. This study investigated whether an association can be made between parents’ size at birth and disorders such as preeclampsia, stillbirth, spontaneous preterm delivery, and placental abruption. Because all are thought to be mediated via the placenta, investigators sought to determine if genetic components might be an etiologic factor. Both maternal and paternal genetic factors were investigated. If a strong association were to be found, it would greatly impact the direction of future research.

Study Design

Harper: What is the design of this study?

Reagan: This population-based study included 324,383 mother-offspring units and 135,632 mother-father-offspring units. The Swedish Medical Birth Register, which contains detailed demographic and pregnancy data, was used to identify mother-offspring units; researchers concentrated on the period from 1973 to 2006 to find women who were included as both infants and mothers. Linkage of the birth register to the Multi-Generation Register provided the paternal information necessary for the analysis. Outcomes were identified using International Classification of Diseases (ICD)-8 and ICD-9 codes.

Harper: Was the statistical approach reasonable? Were the researchers correct in excluding from the analysis mothers or fathers whose birth was complicated by the outcome being studied?

Stout: The authors compared pregnancy outcomes of mothers or fathers who, as neonates, were classified as being the offspring of pregnancies complicated by placental dysfunction that manifested as SGA. Birth exposures included mothers who were SGA compared to those who were not; fathers who were SGA compared to those who were not; and mother-father-offspring triads with mothers and fathers who were both of normal birthweight (reference group), mothers and fathers who were both SGA, a mother who was SGA, or a father who was SGA. Baseline demographic and risk characteristics as well as obstetric outcomes of the pregnancies were obtained from the Swedish Medical Birth Register.

Interestingly, the authors note that one outcome is likely to repeat itself exactly across a generation. For example, if a mother was born in a pregnancy complicated by placental dysfunction A, her own pregnancy may be more likely to also be complicated by placental dysfunction A. However, the authors did not want to examine the association of the same disease to repeat itself exactly a generation later but instead sought to examine whether one placental dysfunction disease predisposes to other types of placental dysfunction 1 generation later. For example, does a mother born from a pregnancy complicated by placental dysfunction A have an increased risk for placental dysfunction B, C, or D.

Thus, in the statistical analysis for early-onset preeclampsia, they excluded those mothers or fathers who were offspring of pregnancies complicated by early-onset preeclampsia. This approach attempts to evaluate whether the risk for placental dysfunction, expressed by multiple phenotypes, is itself a recurring risk across generations independent of specific phenotype. A unique tactic, it assumes that all the disorders examined by the investigators have the same underlying pathophysiology of placental dysfunction. It would have been interesting, in light of their significant results, to also include the analysis of the recurrence of the specific disorder across generations to comment on whether the association with placental dysfunction A predisposes patients even more strongly to placental dysfunction A in a subsequent generation.