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    Do genetic factors explain recurrent pregnancy loss?

    We are at the dawn of a new age in the identification of etiologies for both isolated and recurrent pregnancy loss


    Lethal fetal arrhythmias caused by ion channel mutations

    Recently Crotti and associates tested the hypothesis that mutations leading to long QT syndrome (LQTS)—a cause of unexpected death in infants, children, and young adults—might also cause fetal death after 13 weeks.6 They conducted postmortem anatomic studies and karyotype, toxicological, microbiologic, and biochemical analyses on a series of fetuses that died in utero, followed by an analysis for genes causing (or strongly associated with) LQTS. A total of 91 cases were evaluated (51 females, 40 males) with an average gestational age of 26.3 weeks (range, 14-41 weeks) at demise. The investigators identified 8 cases (8.8% [95% CI, 3.9%-16.6%]) where there were mutations associated with dysfunctional LQTS-associated ion channels (2 in losses at <20 weeks and 6 in losses at ≥20 weeks). This high frequency stands in stark contrast to the reported frequency of LQTS in adults (1/5,500 to 1/10,000)7 suggesting that lethality might be greatly enhanced during fetal life.

    The authors theorize that high levels of circulating progesterone, a hormone that prolongs the QT interval, may contribute to higher lethality of these mutations in affected fetuses.6 Other factors that may contribute to lethality in an affected fetus include immaturity of the cardiac conduction system, volatility of the fetal autonomic nervous system with large physiological swings in sympathetic tone, and cord compression leading to sequential parasympathetic and sympathetic stimulation. Perhaps some losses associated with nuchal cords may have this underlying disorder. Of note, the prevalence of LQTS mutations is also greatly increased in infants who die of SIDS (10%) compared with adults.8

    Clearly, additional studies are needed to confirm these observations. Moreover, because more than 300 mutations contribute to LQTS,9 expanded genetic surveys are needed. It will also be important to learn what percent of such mutations occur de novo and what percent reflect cryptic parental disease. Confirmation of inheritance also presents the opportunity for prevention in future pregnancies through maternal beta-adrenergic blockade therapy and detection of adults at risk for sudden death.9


    Charles J Lockwood, MD, MHCM
    Dr Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South ...

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    • Dr. Robert Knuppel
      Dr. Lockwood makes very important points to help constructively assist patients who generally are grasping at straws for an answer. They are generally offered the expensive testing for answers from non-proven causes. The increase in these very,very low yielding tests has been increasing largely because many offer "answers" and do not say " we simply do not know "and do not reveal the poor positive predictive value of the tests. This plethora of tests are of non-value to the customer and perhaps Lockwood's commentary should be shared with the patient with explanation of the more abstruse terminology.


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