NSIDRC Journal Article Alert — March 5, 2010

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

These articles have been selected from PubMed, a service of the National Library of Medicine that includes over 19 million citations from MEDLINE and other life science journals for biomedical articles back to 1948. PubMed includes links to full text articles and other related resources.

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Sudden Infant Death

1. Poetsch M, Czerwinski M, Wingenfeld L, Vennemann M, Bajanowski T
A common FMO3 polymorphism may amplify the effect of nicotine exposure in sudden infant death syndrome (SIDS)
Int J Legal Med. 2010 Mar 3. [Epub ahead of print]

Institute of Legal Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany, micaela.poetsch@uk-essen.de.

Smoking during pregnancy has been identified as one of the major modifiable risk factors of sudden infant death syndrome (SIDS). It has been demonstrated that the risk of SIDS increases with increasing cigarette consumption. A variety of hypotheses have been proposed for explanation, including a genetic predisposition. The flavin-monooxygenase 3 (FMO3) is one of the enzymes metabolising nicotine, and several polymorphisms have already been described in this gene. Here, we studied variations in the exons and introns of the FMO3 gene by direct sequencing analysis and minisequencing in 159 SIDS cases and 170 controls. The three common variants G472A (E158K), G769A (V257M) and A923G (E308G) in the exons of the FMO3 gene were identified. The homozygote 472AA genotype occurred more frequently in SIDS cases than in controls (p = 0.0054) and was more frequent in those SIDS cases for which the mothers reported heavy smoking (p = 0.0084). This study is the first to demonstrate a gene-environment interaction in SIDS. The findings suggest that the common polymorphism G472A of FMO3 could act as an additional genetic SIDS risk factor in children whose mothers smoke. Parents who could pass on the 472A allele should be informed of the increased risk associated with smoking. Smoking mothers should be strongly advised to give up smoking during pregnancy and for at least the first year of the child's life.

2. Ostfeld BM, Esposito L, Perl H, Hegyi T
Concurrent risks in sudden infant death syndrome
Pediatrics. 2010 Mar;125(3):447-53. Epub 2010 Feb 15

University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Pediatrics, PO Box 19, New Brunswick, NJ 08903. hegyith@umdnj.edu.

BACKGROUND: Despite improved education on safe sleep, infants are still exposed to multiple risks for sudden infant death syndrome (SIDS). Variability among health care providers continues to exist regarding knowledge of risk factors and the provision of education to caregivers. OBJECTIVE: To enhance the content and delivery of SIDS risk-reduction initiatives by physicians and other health care providers and to provide them with a context for evaluating their discussions of risks and compensatory strategies, we sought to raise awareness of the frequency of risk factors in SIDS cases, patterns of co-occurrence, associations between modifiable and nonmodifiable risks, and the rarity of cases without risk. DESIGN AND METHODS: In a population-based retrospective review of 244 (97%) New Jersey SIDS cases (1996-2000), we assessed the frequencies and co-occurrences of modifiable (maternal and paternal smoking, nonsupine sleep or prone status at discovery, bed-sharing, or scene risks) and nonmodifiable (upper respiratory infection or <37 weeks' gestational age) risks. RESULTS: Nonsupine sleep occurred in 70.4% of cases with data on position (159 of 226). Thirteen cases were of infants who were discovered prone, with an increased positional risk to 76.1%, in which 87% contained additional risks. Maternal smoking occurred in 42.6% (92 of 216) of the cases with data on this risk, and 98% among those cases had additional risks. At least 1 risk was found in 96% of the cases, and 78% had 2 to 7 risks. Of the 9 of 244 risk-free cases (3.7%), 7 lacked data on 2 to 5 risks per case. On the basis of the complete data, only 2 (0.8%) of all 244 cases were risk free. When nonmodifiable risks were excluded, 5.3% of the cases met this definition. CONCLUSIONS: Risk-free and single-risk SIDS cases are rare, and most contain multiple risks. Parent education should be comprehensive and address compensatory strategies for nonmodifiable risks.

3. Fracasso T, Karger B, Vennemann M, Bajanowski T, Golla-Schindler UM, Pfeiffer H
Amniotic fluid aspiration in cases of SIDS
Int J Legal Med. 2010 Mar;124(2):113-7. Epub 2009 Nov 11

Institut für Rechtsmedizin, Universitätsklinikum Münster, Roentgenstrasse 23, Muenster, Germany. Tony.Fracasso@ukmuenster.de

The scope of this study was to evaluate the incidence and the eventual consequences of amniotic fluid aspiration (AFA) in cases of sudden infant death. Cases of sudden infant death syndrome (SIDS; n = 113: 39 females, 74 males; mean age 4.6 months) were compared to a control group of 39 cases of explained death (14 females, 25 males; mean age 5.6 months). In each case, sections of the lung stained with hematoxylin and eosin and with the immunohistochemical reaction 34BE12 specific for cytokeratins were available. The microscope slides were observed at x200 magnification and semi-quantitatively classified into four categories(-, +, ++, and +++). In both groups, rests of amniotic fluid could be observed up to the fourth month of life. The comparison between the two groups did not show any significant difference. In the SIDS group, immunohistochemical reactions with the antibodies CD68, MRP8, MRP14, 27E10, 25F9, CD3, CD20Cy, and CD45R0 were available for the lungs. Twelve cases with AFA were compared to a group of SIDS cases without AFA with similar age and pathological distribution to evaluate whether the presence of amniotic remnants induced inflammatory changes in the lungs. No differences emerged. This study shows that AFA is not a rare event. Even moderate to severe AFA does not necessary cause death. A correlation between AFA and SIDS could not be shown.

Miscarriage/Stillbirth/Prenatal Issues

1. Wacholder S, Chen BE, Wilcox A, Macones G, Gonzalez P, Befano B, Hildesheim A, Rodríguez AC, Solomon D, Herrero R, Schiffman M; for the CVT group
Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials
BMJ. 2010 Mar 2;340:c712. doi: 10.1136/bmj.c712

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, Rockville, MD 20852, USA.

OBJECTIVE: To assess whether vaccination against human papillomavirus (HPV) increases the risk of miscarriage. DESIGN: Pooled analysis of two multicentre, phase three masked randomised controlled trials SETTING: Multicentre trials in several continents and in Costa Rica. PARTICIPANTS: 26 130 women aged 15-25 at enrolment; 3599 pregnancies eligible for analysis. INTERVENTIONS: Participants were randomly assigned to receive three doses of bivalent HPV 16/18 VLP vaccine with AS04 adjuvant (n=13 075) or hepatitis A vaccine as control (n=13 055) over six months. MAIN OUTCOME MEASURES: Miscarriage and other pregnancy outcomes. RESULTS: The estimated rate of miscarriage was 11.5% in pregnancies in women in the HPV arm and 10.2% in the control arm. The one sided P value for the primary analysis was 0.16; thus, overall, there was no significant increase in miscarriage among women assigned to the HPV vaccine arm. In secondary descriptive analyses, miscarriage rates were 14.7% in the HPV vaccine arm and 9.1% in the control arm in pregnancies that began within three months after nearest vaccination. CONCLUSION: There is no evidence overall for an association between HPV vaccination and risk of miscarriage. Trial registration Clinical Trials NCT00128661 and NCT00122681.

2. Landres IV, Milki AA, Lathi RB
Karyotype of miscarriages in relation to maternal weight
Hum Reprod. 2010 Feb 26. [Epub ahead of print]

Department of Obstetrics and Gynecology, Stanford Hospital and Clinics, Stanford, CA, USA.

BACKGROUND Obesity has been identified as a risk factor for spontaneous miscarriage although the mechanism is unclear. The purpose of this study is to better understand the effect of obesity on early pregnancy success by examining the cytogenetic results of miscarriages in women with normal and elevated body mass index (BMI). METHODS We conducted a retrospective case-control study in an academic infertility practice. Medical records of women ages <40 years with first trimester missed abortion (n = 204), who underwent dilatation and curettage between 1999 and 2008, were reviewed for demographics, BMI, diagnosis of polycystic ovary syndrome (PCOS) and karyotype analysis. chi(2) and Student's t-test analysis were used for statistical analysis, with P < 0.05 considered significant. RESULTS A total of 204 miscarriages were included, from women with a mean age of 34.5 years. The overall rate of aneuploidy was 59%. Women with BMI >/= 25 kg/m(2) had a significant increase in euploid miscarriages compared with women with lower BMI (P = 0.04), despite a similar mean age (34.4 years for both). CONCLUSIONS We found a significant increase in normal embryonic karyotypes in the miscarriages of overweight and obese women (BMI >/= 25). These results suggest that the excess risk of miscarriages in the overweight and obese population is independent of embryonic aneuploidy. Further studies are needed to assess the impact of lifestyle modification, insulin resistance and PCOS on pregnancy outcomes in the overweight and obese population.

3. Wang WJ, Hao CF, Yi-Lin, Yin GJ, Bao SH, Qiu LH, Lin QD
Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients
J Reprod Immunol. 2010 Mar;84(2):164-70. Epub 2010 Jan 27

Department of Obstetrics and Gynecology; Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Shandong Mid Road, Shanghai 200001, China.

T helper 17 (Th17) cells and regulatory T (Treg) cells are two distinct subsets of CD4(+) T cells which have opposite effects on inflammation, autoimmunity and immunological rejection of foreign tissue. Treg cells have been shown to be important in maintaining materno-fetal tolerance, but the role of Th17 cells in human pregnancy and pathological pregnancy, especially in relation to unexplained recurrent spontaneous abortion (RSA), has not been investigated. In this study, we showed that the proportion of Th17 cells in the peripheral blood and decidua was significantly higher in unexplained RSA patients compared to normal, early pregnant women. Meanwhile, there was an inverse relationship between Th17 cells and Treg cells in the peripheral blood lymphocytes (PBL) and decidua in unexplained RSA. The expression of Th17 related factors, IL-17, IL-23 and retinoid orphan nuclear receptor (RORC), in PBL and decidua in unexplained RSA patients was significantly higher than normal, early pregnant women. This study is the first to define the occurrence of Th17 cells in unexplained RSA patients and in normal, early pregnant women. We suggest that these highly pro-inflammatory cells contribute to unexplained RSA, and the balance between Th17 cells and Treg cells may be critical to pregnancy outcomes. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

4. Finan RR, Al-Irhayim Z, Mustafa FE, Al-Zaman I, Mohammed FA, Al-Khateeb GM, Madan S, Issa AA, Almawi WY
Tumor necrosis factor-alpha polymorphisms in women with idiopathic recurrent miscarriage
J Reprod Immunol. 2010 Mar;84(2):186-92. Epub 2010 Jan 27

Faculty of Medicine, Universite St Joseph, Beirut, Lebanon.

We investigated the association of tumor necrosis factor-alpha (TNFalpha) gene polymorphisms with idiopathic recurrent miscarriage (RM). TNFalpha -1031T/C, -863C/A, -857C/T, -376G/A, -308G/A, -238G/A, and +488G/A single nucleotide polymorphisms (SNPs) were investigated in 204 RM women and 248 age-matched parous women by PCR-restriction fragment length polymorphism. Significantly higher frequencies of -1031C and -376A alleles were seen in RM patients; significant differences were also noted in the distribution of -1031T/C, -376G/A, and -238G/A genotypes between case and control subjects. Haploview analysis revealed high linkage disequilibrium between -857C/T and +488G/A SNPs, but was lower between the other polymorphisms. Of the possible 52 seven-locus haplotypes constructed, 10 were common, and were included in subsequent analysis. Increased frequency of CCCGGGG and CCCGGAA haplotypes, and reduced frequency of TCCGGGG and TCCGGGA haplotypes were seen in RM patients than in controls. When the Bonferroni correction was applied, differences were significant for the CCCGGAA haplotype, which was higher (OR=4.14; 95% CI=1.84-8.95), and the TCCGGGA haplotype, which were lower among RM cases (OR=0.09; 95% CI=0.02-0.68), thereby conferring RM susceptibility and protection to these haplotypes, respectively. Multivariate analysis confirmed the positive association of only CCCGGAA haplotype with RM (P=0.010; aOR=2.03; 95% CI=1.18-4.47), after controlling for a number of covariates. These results demonstrate that the TNFalpha polymorphisms, in particular the -1031T/C variant, are significantly associated with idiopathic RM. Additional replication studies on other racial groups are needed to confirm our findings. Copyright 2010. Published by Elsevier Ireland Ltd.

5. Saravelos SH, Cocksedge KA, Li TC
The pattern of pregnancy loss in women with congenital uterine anomalies and recurrent miscarriage
Reprod Biomed Online. 2010 Mar;20(3):416-422. Epub 2009 Dec 11

Reproductive Medicine and Surgery Unit, University of Sheffield, Sheffield Teaching Hospitals, Jessop Wing, Tree Root Walk, Sheffield S10 2SF, UK.

Congenital uterine anomalies (CUA) are a known cause of recurrent miscarriage (RM), but the pattern of pregnancy loss that different CUA produce remains unknown. This study included 665 women with RM who were screened for CUA using a combined two-dimensional ultrasound (2D-US) and hysterosalpingography (HSG) approach. All suspected CUA were definitively diagnosed and classified via a combined hysteroscopy/laparoscopy procedure. Pregnancy outcomes were evaluated and compared for each type of CUA versus a control group of women with no identifiable cause of RM (unexplained RM). Fifty-six women with CUA and 107 women with unexplained RM were identified. In total, 881 pregnancies were analysed. Analysis showed that women with a septate or bicornuate uterus suffered from significantly increased second-trimester miscarriages compared with controls (13.2% and 13.8% versus 1.0%; P<0.001 and P<0.05, respectively). Women with an arcuate, septate or bicornuate uterus showed significantly reduced rates of biochemical pregnancy losses compared with controls (9.5%, 11.1% and 11.1% versus 30.4%; P<0.01, P<0.01 and P<0.05, respectively). Pregnancies of women with RM and CUA are not associated with early implantation failure and are compromised at a more advanced gestational age. Copyright © 2009 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

6. Guerra-Shinohara EM, Pereira PM, Kubota AM, Silva TA, Reis JL, Miyashita GS, D'Almeida V, Allen RH, Stabler SP
Increased MMA concentration and body mass index are associated with spontaneous abortion in Brazilian women: a pilot study
Clin Chim Acta. 2010 Mar;411(5-6):423-7. Epub 2009 Dec 28

Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Science, University of Sao Paulo, Brazil. emguerra@usp.br

BACKGROUND: The pathophysiology of spontaneous abortion is complex and may involve the interaction of genetic and environmental factors. We evaluated the predictors of spontaneous abortion in Brazilian pregnant women. The effects of age, gestational age, body mass index (BMI), cigarette smoking, alcohol ingestion, use of multivitamins and concentrations of vitamins (folate, cobalamin and vitamin B6) and vitamin-dependent metabolites were analyzed. METHODS: Study population included 100 healthy women that attended pre-natal care in 2 health centers of Sao Paulo, Brazil, and in whom pregnancy outcome was known. Folate and cobalamin status was measured in blood specimens collected between 4 and 16 weeks. The genotypes for 8 gene polymorphisms were evaluated by PCR-RFLP. RESULTS: Eighty-eight women had normal pregnancy outcome (Group 1), while 12 experienced a miscarriage after blood collection (Group 2). Increased methylmalonic acid (MMA) concentrations were found in Group 2 (median [25th-75th percentile]=274 [149-425] nmol/l) relative to Group 1 (138 [98-185]) (P<0.01). No differences between the groups were observed for serum cobalamin, serum or red cell folate, and serum total homocysteine or allele frequencies for 8 polymorphisms. In a conditional logistic regression analysis including age, gestational age, serum creatinine, MMA, cystathionine, body mass index (BMI), cigarette smoking, alcohol ingestion and use of multivitamins the risk of abortion was significantly associated with MMA (OR [95% CI]=3.80 [1.36, 10.62] per quartile increase in MMA), BMI (OR [95% CI]=5.49 [1.29, 23.39] per quartile) and gestational age (OR [95% CI]=0.10 [0.01, 0.77] per increase of interval in gestational age). CONCLUSIONS: Increased serum MMA and BMI concentrations are associated with spontaneous abortion in Brazilian women. Copyright 2009 Elsevier B.V. All rights reserved.

7. Harris DL, Daniluk JC
The experience of spontaneous pregnancy loss for infertile women who have conceived through assisted reproduction technology
Hum Reprod. 2010 Mar;25(3):714-20. Epub 2009 Dec 19

Department of Interdisciplinary Programs, King's University College, 266 Epworth Avenue, London, ON, Canada. darcy.harris@uwo.ca

BACKGROUND: The purpose of this qualitative, phenomenological study was to explore the subjective experiences of infertile women who conceived through the use of assisted reproduction technology--ovarian stimulation, intrauterine insemination or IVF--only to lose their pregnancy at 2-16 weeks gestation. METHODS: Ten women participated in in-depth, tape-recorded interviews. After initial content analysis, a phenomenological analysis was undertaken to identify common themes in the participants' stories. RESULTS: Nine common themes were identified. These included: a sense of profound loss and grief; diminished control; a sense of shared loss with their partners; injustice or lack of fairness; ongoing reminders of the loss; social awkwardness; fear of re-investing in the treatment process or a subsequent pregnancy; the need to make sense of their experience; and feelings of personal responsibility for what had happened. CONCLUSIONS: Participants' experiences of pregnancy loss were embedded within their experiences of infertility and medical treatment, and shaped by their significant investment in having a child. A significant feature was their marked ambivalence regarding future reproductive options after their pregnancy loss, reflecting a unique overlay of prominent anxiety in their grief experience.

8. Peel E
Pregnancy loss in lesbian and bisexual women: an online survey of experiences
Hum Reprod. 2010 Mar;25(3):721-7. Epub 2009 Dec 19

School of Life & Health Sciences, Aston University, Birmingham B4 7ET, UK. e.a.peel@aston.ac.uk

BACKGROUND: Although pregnancy loss is a distressing health event for many women, research typically equates women's experiences of pregnancy loss to 'married heterosexual women's experiences of pregnancy loss'. The objective of this study was to explore lesbian and bisexual women's experiences of miscarriage, stillbirth and neonatal death. METHODS: This study analysed predominantly qualitative online survey data from 60 non-heterosexual, mostly lesbian, women from the UK, USA, Canada and Australia. All but one of the pregnancies was planned. Most respondents had physically experienced one early miscarriage during their first pregnancy, although a third had experienced multiple losses. RESULTS: The analysis highlights three themes: processes and practices for conception; amplification of loss; and health care and heterosexism. Of the respondents, 84% conceived using donor sperm; most used various resources to plan conception and engaged in preconception health care. The experience of loss was amplified due to contextual factors and the investment respondents reported making in impending motherhood. Most felt that their loss(es) had made a 'significant'/'very significant' impact on their lives. Many respondents experienced health care during their loss. Although the majority rated the overall standard of care as 'good'/'very good'/'outstanding', a minority reported experiencing heterosexism from health professionals. CONCLUSIONS: The implications for policy and practice are outlined. The main limitation was that the inflexibility of the methodology did not allow the specificities of women's experiences to be probed further. It is suggested that both coupled and single non-heterosexual women should be made more visible in reproductive health and pregnancy loss research.

9. Parveen F, Faridi RM, Das V, Tripathi G, Agrawal
Genetic association of phase I and phase II detoxification genes with recurrent miscarriages among North Indian women
Mol Hum Reprod. 2010 Mar;16(3):207-14. Epub 2009 Nov 5

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, UP 226014, India.

Allelic variants of the detoxification genes that have impaired biotransformation functions may increase susceptibility to reproductive toxicity leading to endometriosis, recurrent miscarriage (RM) or poor pregnancy outcome. In the present study, we have investigated CYP1A1, CYP2D6, GSTT1, GSTP1 and GSTM1, which are involved in the phase I and phase II detoxification systems, in relation to their role in the etiology of unexplained RMs. In a case-control study, we have investigated 200 females with RM and 300 age and ethnically matched healthy controls with successful reproductive history from North India. The frequencies of phase I wild-type genotypes of CYP1A1 and CYP2D6 in RM cases were 0.56 and 0.60, whereas in controls these were 0.68 and 0.65, respectively (both P < 0.05). The GSTM1 null-genotype frequencies were 0.66 and 0.84 among RM cases and controls, respectively, the GSTT1 null-genotype frequencies were 0.52 and 0.45 (P < 0.005) and the GSTP1 variant allele frequencies were 0.23 and 0.20, respectively. In conclusion, we observed significant protective effects of phase I wild-type genotypes and association of the GSTT1 null genotype with RM. Through combined analyses we have highlighted the importance of the balance of phase I/phase II detoxification systems, in the etiology of RM.

10. Lee HH, Hong SH, Shin SJ, Ko JJ, Oh D, Kim NK
Association study of vascular endothelial growth factor polymorphisms with the risk of recurrent spontaneous abortion
Fertil Steril. 2010 Mar 1;93(4):1244-1247. Epub 2009 Jan 7

Department of Obstetrics and Gynecology, College of Medicine, Pochon CHA University, Seongnam, South Korea; Institute for Clinical Research, College of Medicine, Pochon CHA University, Seongnam, South Korea.

OBJECTIVE: To investigate the association of vascular endothelial growth factor (VEGF) polymorphisms (-2578C>A, -1154G>A, -634G>C, 936C>T) with idiopathic recurrent spontaneous abortion (RSA) in Koreans. DESIGN: Prospective case-control study. SETTING: University-based hospital. PATIENT(S): Two hundred and fifteen patients with a history of two or more unexplained consecutive pregnancy losses and 113 healthy controls with at least one live birth and no history of pregnancy loss. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses were performed for the -2578C>A and 936C>T genotypes. Real-time PCR was also used to analyze the -1154G>A and -634G>C genotypes. RESULT(S): The GA (adjusted odds ratio [AOR] 2.774; 95% confidence interval [CI] 1.512-5.092) genotype of the VEGF -1154G>A polymorphism was significantly different between women with idiopathic RSA and controls. The difference in overall (GA + AA) frequency was also marginally significant between the controls and patients with idiopathic RSA (AOR, 2.006; 95% CI, 1.158-3.473). The differences in frequencies of the A-A-G-T and C-A-G-T haplotypes of the VEGF polymorphisms (-2578C>A, -1154G>A, -634G>C, 936C>T) were marginally significant between the patient and control groups. CONCLUSION(S): This study suggests that VEGF polymorphisms and haplotypes are a genetic determinant for the risk of idiopathic RSA in Korean women. Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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