NSIDRC Journal Article Alert — September 26, 2008

Prepared by the National Sudden and Unexpected Infant/Child Death and Pregnancy Loss Resource Center at Georgetown University.

This journal article alert provides selected items added to the National Library of Medicine's PubMed database in the last week.

Past issues of Resource Center journal alerts are available at http://www.sidscenter.org.
Availability of full-text journal articles is often limited to subscribers or through inter-library loan. Please see your local library for copies of these articles, or view PubMed's How to Get the Journal Article for more details.

Sudden Infant Death

1. Filonzi L, Magnani C, Lavezzi AM, Rindi G, Parmigiani S, Bevilacqua G, Matturri L, Nonnis Marzano F
Association of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis
Neurogenetics. 2008 Sep 23. [Epub ahead of print]

Department of Evolutionary and Functional Biology, University of Parma, Viale G.P. Usberti 11, 43100, Parma, Italy.

Recent findings demonstrated the role of neurotransmitters in the aetiopathogenesis of sudden unexpected deaths in infancy. Although genes involved in serotonin metabolism have been proposed as risk factors for sudden infant death syndrome (SIDS), the contribution of additional neurotransmitters and genes different from the serotonin transporter (SLC6A4, 5-HTT) has not been investigated. Considering the common metabolic pathway and synergism between dopamine and serotonin, the role of dopamine transporter (SLC6A3, DAT) and monoamine oxidase A (MAOA) genes in SIDS and stillbirth (sudden intrauterine unexplained death, SIUD) was investigated. Genotypes and allelic frequencies of DAT and MAOA were determined in 20 SIDS and five stillbirth cases and compared with 150 controls. No association was found between DAT polymorphisms and SIDS either at genotype (P = 0.64) or allelic (P = 0.86) level; however, a highly significant association was found between MAOA genotypes (P = 0.047) and alleles (P = 0.002) regulating different expression patterns (3R/3R vs 3.5R/3.5R + 4R/4R) in SIDS + SIUD and controls. Analysis of combined 5-HTTLPR (serotonin transporter linked polymorphic region)/MAOA genotypes revealed that frequency of L/L-4R/4R genotype combination was eightfold higher in SIDS + SIUD than in controls (P < 0.001). Findings are discussed considering the metabolic association among DAT, 5-HTT and MAOA with special emphasis on the linked action of 5-HTT/MAOA in regulating serotonin metabolism of SIDS and SIUD infants.

Miscarriage/Stillbirth/Prenatal Issues

1. Ananth CV, Liu S, Joseph KS, Kramer MS; for the Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System
A comparison of foetal and infant mortality in the United States and Canada
Int J Epidemiol. 2008 Sep 20 [Epub ahead of print]

Division of Epidemiology and Biostatistics, Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, New Jersey, USA.

BACKGROUND: Infant mortality rates are higher in the United States than in Canada. We explored this difference by comparing gestational age distributions and gestational age-specific mortality rates in the two countries. METHODS: Stillbirth and infant mortality rates were compared for singleton births at >/=22 weeks and newborns weighing >/=500 g in the United States and Canada (1996-2000). Since menstrual-based gestational age appears to misclassify gestational duration and overestimate both preterm and postterm birth rates, and because a clinical estimate of gestation is the only available measure of gestational age in Canada, all comparisons were based on the clinical estimate. Data for California were excluded because they lacked a clinical estimate. Gestational age-specific comparisons were based on the foetuses-at-risk approach. RESULTS: The overall stillbirth rate in the United States (37.9 per 10 000 births) was similar to that in Canada (38.2 per 10 000 births), while the overall infant mortality rate was 23% (95% CI 19-26%) higher (50.8 vs 41.4 per 10 000 births, respectively). The gestational age distribution was left-shifted in the United States relative to Canada; consequently, preterm birth rates were 8.0 and 6.0%, respectively. Stillbirth and early neonatal mortality rates in the United States were lower at term gestation only. However, gestational age-specific late neonatal, post-neonatal and infant mortality rates were higher in the United States at virtually every gestation. The overall stillbirth rates (per 10 000 foetuses at risk) among Blacks and Whites in the United States, and in Canada were 59.6, 35.0 and 38.3, respectively, whereas the corresponding infant mortality rates were 85.6, 49.7 and 42.2, respectively. CONCLUSIONS: Differences in gestational age distributions and in gestational age-specific stillbirth and infant mortality in the United States and Canada underscore substantial differences in healthcare services, population health status and health policy between the two neighbouring countries.

2. Wong EY, Ray RM, Gao DL, Wernli KJ, Li W, Fitzgibbons ED, Camp JE, Astrakianakis G, Heagerty PJ, Thomas DB, Checkoway H
Dust and chemical exposures, and spontaneous abortion risk among women textile workers in Shanghai, China
Occup Environ Med. 2008 Sep 19. [Epub ahead of print]

University of Washington, United States.

OBJECTIVE: To investigate possible associations between spontaneous abortion and occupational exposures in the Shanghai Textile Industry. METHODS: We conducted a retrospective cohort study of spontaneous abortions among 1,752 women in the Shanghai textile industry. Reproductive history was self-reported by women and occupational work histories were collected from factory personnel records. Occupational exposures were assigned by linking work history information to an industry-specific job-exposure matrix informed by factory-specific textile process information and industrial hygiene assessments. Estimates of cotton dust and endotoxin exposure were also assigned. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multivariate logistic regression, with adjustment for age at pregnancy, education level, smoking status of woman and spouse, use of alcohol, and woman's year of birth. RESULTS: An elevation in risk of a spontaneously aborted first pregnancy was associated with exposure to synthetic fibers (1.89, 95% CI: 1.20-3.00) and mixed synthetic and natural fibers (3.31, 95% CI: 1.30-8.42). No increased risks were observed for women working with solvents, nor were significant associations observed with quantitative cotton dust or endotoxin exposures. Associations were robust and similar when all pregnancies in a woman's reproductive history were considered. Conclusions. Occupational exposure to synthetic fibers may cause spontaneous abortions, and this possibility should be the subject of further investigation.

3. Draper ES, Zeitlin J, Fenton AC, Weber T, Gerrits J, Martens G, Misselwitz B, Breart G
Investigating the variations in survival rates for very preterm infants in ten European regions: the MOSAIC birth cohort
Arch Dis Child Fetal Neonatal Ed. 2008 Sep 19. [Epub ahead of print]

University of Leicester, United Kingdom.

OBJECTIVE: To investigate the variation in the survival rate and the mortality rates for very preterm infants across Europe. DESIGN: A prospective birth cohort of very preterm infants for ten geographically defined European regions during 2003 followed to discharge home from hospital. PARTICIPANTS: All deliveries from 22+0 to 31+6 weeks gestation. MAIN OUTCOME MEASURE: All outcomes of pregnancy by gestational age group, including termination of pregnancy for congenital anomalies and other reasons, ante-partum stillbirth, intra-partum stillbirth, labour ward death, death after admission to a neonatal intensive care unit (NICU) and survival to discharge. RESULTS: Overall the proportion of this very preterm cohort who survived to discharge from neonatal care was 89.5%, varying from 93.2% to 74.8% across the regions. Less than 2% of infants <24 weeks gestation and approximately half of the infants from 24 to 27 weeks gestation survived to discharge home from NIC. However large variations were seen in the timing of the deaths by region. Among all fetuses alive at onset of labour of 24-27 weeks gestation, between 84.0% and 98.9% were born alive and between 64.6% and 97.8% were admitted for NIC. For babies <24 weeks, between 0% and 79.6% of babies alive at onset of labour were admitted to neonatal intensive care. CONCLUSIONS: There are wide variations in the survival rates to discharge from NIC for very preterm deliveries and in the timing of death across the MOSAIC regions. In order to directly compare international statistics for mortality in very preterm infants, data collection needs to be standardised. We believe that the standard point of comparison should be using all those infants alive at the onset of labour as the denominator for comparisons of mortality rates for very preterm infants analysing the cohort by gestational age band.

4. Chamley LW, Bhalla A, Stone PR, Liddell H, O'Carroll S, Kearn C, Glass M
Nuclear Localisation of the Endocannabinoid Metabolizing Enzyme Fatty Acid Amide Hydrolase (FAAH) in Invasive Trophoblasts and an Association with Recurrent Miscarriage
Placenta. 2008 Sep 19. [Epub ahead of print]

Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand; Fertility Plus, Auckland District Health Board, Auckland, New Zealand.

Endocannabiniods are lipid signalling molecules that are related to the major psychoactive component in marijuana, delta-9-tetrahydrocannabinol and are increasingly recognized as being important in implantation and development of early embryos. The endocannabinoid anandamide, is metabolized by the enzyme fatty acid amide hydrolase (FAAH), and insufficient levels of this enzyme have been implicated in spontaneous miscarriage in women and implantation failure in mice. We screened placental bed biopsies and placental tissue from 45 women with recurrent miscarriage and 17 gestation-matched women with normal pregnancies for the expression of FAAH by immunohistochemistry. Unexpectedly, the enzyme appeared to be localised to the nucleus of trophoblasts and this was confirmed by western blotting of sub-cellular fractions and confocal microscopy. FAAH was expressed in the cytoplasm of large decidual stromal cells and significantly more women with recurrent miscarriage (73%) expressed FAAH in these cells than women with normal pregnancy (31%). FAAH was also expressed in the nucleus of extravillous trophoblasts that had invaded the decidua from 67% of women with recurrent miscarriage but was not expressed by these cells in any women with normal pregnancies. In contrast, FAAH was expressed in extravillous trophoblasts that had migrated out of the villi but that had not yet invaded the decidua in both normal pregnancies and in cases of recurrent miscarriage. FAAH was also present in the nucleus of a small number of villous trophoblasts in some specimens. FAAH appears to be over expressed in trophoblasts that have invaded the decidua, as well as in large decidual stromal cells in many cases of recurrent miscarriage. This may reflect inadequate control of the cannabinoid system in the uterus of women who experience recurrent miscarriages. The functional significance of the unexpected nuclear localisation of FAAH in trophoblasts is not yet clear.

5. Coulam CB, Wallis D, Weinstein J, Dasgupta DS, Jeyendran RS
Comparison of Thrombophilic Gene Mutations Among Patients Experiencing Recurrent Miscarriage and Deep Vein Thrombosis
Am J Reprod Immunol. 2008 Sep 18. [Epub ahead of print]

Rinehart Center for Reproductive Medicine, Evanston, IL, USA.

Problem Inherited thrombophilia has been shown to be a risk factor for cardiovascular disease including deep venous thrombosis as well as reproductive disorders including recurrent pregnancy loss. We have previously reported three out of the 10 thrombophilic mutations studied, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, factor XIII V34L, and homozygous MTHFR C667T, correlated significantly with recurrent pregnancy loss compared with controls. This study was undertaken to compare the frequencies of nine inherited thrombophilias among women with a history of recurrent pregnancy loss with individuals experiencing deep venous thrombosis and fertile controls. Method of study Six hundred thirty-four participants including 550 women with a history of recurrent pregnancy loss, 43 individuals with deep vein thrombosis and 41 fertile women without a history of recurrent miscarriage. All participants had buccal swabs taken for DNA analyses of nine gene polymorphisms including factor V G1691A, factor V H1299R (R2), factor II Prothrombin G20210A, factor XIII V34L, beta-fibrinogen -455G>A, PAI-1 4G/5G, human platelet antigen 1 a/b (L33P), MTHFR C677T, MTHFR A1298C. Frequencies of thrombophilic gene polymorphisms were compared among the three populations studied. Results Individuals with a history of DVT had a significantly higher frequency of all of the polymorphisms studied compared with women experiencing a history of recurrent pregnancy loss and the fertile controls. The frequencies of mutations for V34L and PAI-1 4G/5G were significantly increased among women experiencing recurrent pregnancy loss compared with controls. The most prevalent polymorphisms were factor XIII V34L and PAI-1 4G/4G for both individuals with a history of deep vein thrombosis and recurrent pregnancy loss compared with controls. Conclusion Screening for risk factors for inherited thrombophilia with only polymorphisms for factor V von Leiden, factor II prothrombin and MTHFR may be missing the more prevalent identifiers of jeopardy.

6. Mania-Pramanik J, Kerkar SC, Mehta PB, Potdar S, Salvi VS
Use of vaginal pH in diagnosis of infections and its association with reproductive manifestations
J Clin Lab Anal. 2008 Sep 19;22(5):375-379. [Epub ahead of print]

National Institute for Research in Reproductive Health, Indian Council of Medical Research, Mumbai, India.

Increase in vaginal secretion pH is an indicator of bacterial vaginosis (BV), but is yet to be in use as a diagnostic tool by clinicians. Similarly, no reports are available on the effect of cervical chlamydia infection and different reproductive manifestations on vaginal secretion pH. This study evaluated the use of vaginal pH for screening of BV, the effect of Chlamydia trachomatis (C. trachomatis) infection, and different reproductive manifestations on vaginal pH of women attending the gynecology outpatient department of a general hospital. Vaginal pH was recorded while diagnosing infections in 358 women, among which 45 were with repeated spontaneous abortion, 79 with infertility, 185 had sign and symptoms of lower genital tract infection, and 49 had no history or symptom of any complications or infections. Normal vaginal pH, BV, and C. trachomatis infection were observed in 72.6, 21.5, and 10.1% of women, respectively. BV and C. trachomatis were observed in 78.6 and 4.1% of women, respectively, with high vaginal pH; 12.3% of women with normal vaginal pH had C. trachomatis infection. C. trachomatis infection or different reproductive manifestations do not lead to change in vaginal pH but high vaginal pH correlated with BV and should be used as a simple tool for its diagnosis. J. Clin. Lab. Anal. 22:375-379, 2008. (c) 2008 Wiley-Liss, Inc.

7. Kurzawa R, Ciepiela P, Baczkowski T, Safranow K, Brelik P
Comparison of embryological and clinical outcome in GnRH antagonist vs. GnRH agonist protocols for in vitro fertilization in PCOS non-obese patients. A prospective randomized study
J Assist Reprod Genet. 2008 Sep 19. [Epub ahead of print]

Department of Reproductive Medicine and Gynecology, Pomeranian Medical University, 2 Siedlecka Street, Szczecin-Police, 72-010, Poland.

PURPOSE: Embryological and clinical efficacy of gonadotropin-releasing hormone (GnRH) antagonist and agonist stimulation protocols in non-obese women with polycystic ovarian syndrome (PCOS) were compared. METHODS: A prospective randomized study. Setting: Medical University Hospital. Patients: 70 infertile PCOS patients; 33 in GnRH antagonist and 37 in GnRH agonist group. RESULTS: Similar mature metaphase II oocyte rate (76% vs. 76%) was observed in both protocols. Optimal pronuclear morphology zygotes dominated in both groups (64% vs. 66%). Transferred embryo quality did not differ in both protocols. No significant differences between both protocols were found in delivery rate (p = 0.481), pregnancy rate (p = 0.810), multiple pregnancy rate (p = 0.501), miscarriage rate (p = 0.154), fertilization rate (p = 0.388) and implantation rate (p = 1.000). Duration of stimulation and total follicle-stimulating hormone (FSH) dose were significantly lower in GnRH antagonist protocol (p = 0.0005). CONCLUSIONS: GnRH antagonist and agonist protocols in non-obese PCOS patients yield similar embryological and clinical outcomes. Shorter duration of treatment and lower FSH requirement in GnRH antagonist group may be financially beneficial and therefore attractive for patients.

8. Redecha P, Franzke CW, Ruf W, Mackman N, Girardi G
Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome
J Clin Invest. 2008 Sep 18. [Epub ahead of print]

Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York, USA. The Scripps Research Institute, La Jolla, California, USA. University of North Carolina, Chapel Hill, North Carolina, USA.

Women with antiphospholipid syndrome (APS), a condition characterized by the presence of antiphospholipid antibodies (aPL), often suffer pregnancy-related complications, including miscarriage. We have previously shown that C5a induction of tissue factor (TF) expression in neutrophils contributes to respiratory burst, trophoblast injury, and pregnancy loss in mice treated with aPL. Here we analyzed how TF contributes to neutrophil activation and trophoblast injury in this model. Neutrophils from aPL-treated mice expressed protease-activated receptor 2 (PAR2), and stimulation of this receptor led to neutrophil activation, trophoblast injury, and fetal death. An antibody specific for human TF that has little impact on coagulation, but potently inhibits TF/Factor VIIa (FVIIa) signaling through PAR2, inhibited aPL-induced neutrophil activation in mice that expressed human TF. Genetic deletion of the TF cytoplasmic domain, which allows interaction between TF and PAR2, reduced aPL-induced neutrophil activation in aPL-treated mice. Par2(-/-) mice treated with aPL exhibited reduced neutrophil activation and normal pregnancies, which indicates that PAR2 plays an important role in the pathogenesis of aPL-induced fetal injury. We also demonstrated that simvastatin and pravastatin decreased TF and PAR2 expression on neutrophils and prevented pregnancy loss. Our results suggest that TF/FVIIa/PAR2 signaling mediates neutrophil activation and fetal death in APS and that statins may be a good treatment for women with aPL-induced pregnancy complications.

9. Petrou S, McIntosh E
Women's Preferences for Attributes of First-Trimester Miscarriage Management: A Stated Preference Discrete-Choice Experiment
Value Health. 2008 Sep 16. [Epub ahead of print]

Health Economics Research Centre, Department of Public Health, University of Oxford, Oxford, UK.

Objective: To elicit women's preferences for attributes of alternative management options for first-trimester miscarriage. Methods: A stated preference discrete-choice experiment was conducted among 1198 women with a confirmed pregnancy of less than 13 weeks gestation, who had been diagnosed with either an incomplete miscarriage or missed miscarriage/early fetal demise and who had been recruited as part of a randomized controlled trial (miscarriage treatment [MIST] trial) comparing expectant, medical, and surgical miscarriage. Six attributes, each with three or four levels, were used in the statistical design. An orthogonal main effects design was generated (i.e., a design where the attributes are independent of each other) and the choice sets devised according to the principles of minimum overlap and level balance. A cost attribute was included to allow estimation of willingness to pay (WTP) values. Three different questionnaires were designed such that women were asked their preferences for attributes of the two management options they had not been allocated to in the trial. Results: A total of 630 women completed the stated preference discrete-choice survey questionnaires: 189 out of 398 women (47.5%) allocated to expectant management, 223 out of 398 women (56.0%) allocated to medical management, and 218 out of 402 women (54.2%) allocated to surgical management. For each of the three discrete-choice survey questionnaires, women expressed a clear preference for decreased levels of all six attributes (time spent at the hospital receiving treatment, level of pain experienced, number of days of bleeding after treatment, time taken to return to normal activities after treatment, cost of treatment to women, and chance of complications requiring more time or readmission to hospital). For each of the three discrete-choice survey questionnaires, the highest valued attribute in terms of WTP was for a reduction in pain levels followed by time taken to return to normal activities after treatment. On aggregate, surgical management was valued more highly than expectant and medical management by women allocated to medical and expectant management, respectively, and medical management was valued more highly than expectant management by women allocated to surgical management. This held true regardless of the application of either hypothetical data for each attribute generated by the pretrial-designed discrete-choice experiment questionnaires or actual data for each attribute observed in the MIST trial. Conclusions: The preference results generated by this study suggest that many women undergoing management of first-trimester miscarriage would value being offered alternatives to expectant management. The data from this study should be considered by decision-makers in conjunction with the clinical and cost-effectiveness evidence base in this area as well as consideration of the budgets available to them for such services.

10. Engels H, Eggermann T, Caliebe A, Jelska A, Schubert R, Schüler HM, Panasiuk B, Zaremba J, Latos-Biele?ska A, Jakubowski L, Zerres KP, Schwanitz G, Midro AT
Genetic counseling in Robertsonian translocations der(13;14): Frequencies of reproductive outcomes and infertility in 101 pedigrees
Am J Med Genet A. 2008 Sep 16. [Epub ahead of print]

Institute of Human Genetics, Bonn, Germany.

Robertsonian translocations 13/14 are the most common chromosome rearrangements in humans. However, most studies aimed at determining risk figures are more than 20 years old. Their results are often contradictory regarding important topics in genetic counseling such as infertility and unfavorable pregnancy outcomes. Here, we present a study on a sample of 101 previously unreported pedigrees of der(13;14)(q10;q10). In order to minimize problems of partial ascertainment, we included families with a wide range of reasons of ascertainment such as birth of a child with congenital anomalies, prenatal diagnosis due to maternal age, fertility problems and recurrent pregnancy loss. No evidence of increased infertility rates of female and male carriers was found. The detected miscarriage frequency of female carriers was higher than previously reported (27.6 +/- 4.0% of all spontaneous pregnancies). This may be explained by an over-correction of earlier studies, which excluded all unkaryotyped miscarriages. In three out of 42 amniocenteses, translocation trisomies 13 were diagnosed (7.1 +/- 4.0% of all amniocenteses). The frequency of stillbirths was 3.3 +/- 1.6% for female carriers and 1.4 +/- 1.4% for male carriers. A low risk for the live birth of translocation trisomy 13 children was confirmed since no live born children with trisomy 13 or Pätau syndrome were detected in the ascertainment-corrected sample. (c) 2008 Wiley-Liss, Inc.

11. Leong H, Stachnik J, Bonk ME, Matuszewski KA
Unlabeled uses of intravenous immune globulin
Am J Health Syst Pharm. 2008 Oct 1;65(19):1815-24

Drug Information and Technology Assessment Groups, University HealthSystem Consortium, Oak Brook, IL 60523, USA.

PURPOSE: The unlabeled uses of intravenous immune globulin (IVIG) were reviewed. SUMMARY: A literature review was conducted to identify studies examining the unlabeled uses of IVIG. A review of 138 clinical trial abstracts identified 10 trials examining 2 labeled uses (635 patients) and 128 trials examining 61 different off-label uses (6781 patients). The most common off-label indications included multiple sclerosis, graft-versus-host disease in transplant patients, prevention of antiphospholipid syndrome in miscarriage, Guillain-Barré syndrome, and progression of human immunodeficiency virus after delivery. The studies appeared to support many of the acceptable off-label uses cited by various guideline groups. A total of 276 case reports were identified, with 268 reports representing 156 different off-label uses (362 patients). Seven meta-analyses were identified, evaluating recurrent miscarriage, in vitro fertilization failure, infection in preterm infants, multiple sclerosis, immune thrombocytopenic purpura, and pemphigoid. With the exception of recurrent miscarriage and infection in preterm infants, the off-label use of IVIG for these indications was associated with positive outcomes. An examination of IVIG guidelines by specialty society, payer, and other review organizations revealed that the biomedical evidence supporting off-label uses is being interpreted in different ways. Health care institutions are strongly urged to approve and closely monitor specific uses of IVIG to reserve dwindling supplies for the "best-evidence" uses. Clinicians should be aware of the limits of knowledge in many off-label uses and exercise restraint in prescribing for unproven indications. CONCLUSION: A literature review identified more than 150 unlabeled uses of IVIG. The evidence for these uses is being interpreted in different ways by various reviewing organizations.

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