NSIDRC Journal Article Alert — January 8, 2010

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

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Sudden Infant Death

1. Mage DT, Cohen M, Donner M
Sudden infant death syndrome
N Engl J Med. 2009 Dec 24;361(26):2581; author reply 2581-2

Comment on:
N Engl J Med. 2009 Aug 20;361(8):795-805

2. Klitz W, Niklasson B
Sudden infant death syndrome
N Engl J Med. 2009 Dec 24;361(26):2580-1; author reply 2581-2

3. Webb RT, Wicks S, Dalman C, Pickles AR, Appleby L, Mortensen PB, Haglund B, Abel KM
Influence of environmental factors in higher risk of sudden infant death syndrome linked with parental mental illness
Arch Gen Psychiatry. 2010 Jan;67(1):69-77

Comment on:
N Engl J Med. 2009 Aug 20;361(8):795-805

Centre for Women's Mental Health and Health Methodology Research Group, University of Manchester, Room 2.311, University Place, Oxford Road, Manchester M13 9PL, England. roger.webb@manchester.ac.uk

CONTEXT: Since national risk reduction campaigns have been conducted, sudden infant death syndrome (SIDS) has become increasingly concentrated among disadvantaged families, including those affected by mental illness. However, causal mechanisms specific to this group are poorly understood. OBJECTIVES: To estimate relative risk and compare risk factor prevalence in infants with and without parental psychiatric inpatient history, and to explore effect modification after the 1992 Swedish risk reduction campaign. DESIGN: National birth cohort. Parental psychiatric admissions, maternal prenatal smoking, obstetric and social risk factors, and cause-specific infant death were ascertained via linkage between national registers. SETTING: The Swedish population, 1978 through 2004. PARTICIPANTS: All singleton live births (N = 2.5 million). MAIN OUTCOME MEASURE: Incidence of SIDS. RESULTS: Risk of SIDS was higher with a history of parental inpatient care, especially if both parents were admitted with any mental illness (odds ratio, 6.8; 95% confidence interval, 4.7-10.0), or if the mother (6.5; 4.9-8.7) or both parents (9.5; 5.5-16.4) had an alcohol/drug disorder. A 2-fold higher risk was also seen if the mother or father was admitted with any psychiatric illness other than alcohol or other drug disorders. Elevated risk persisted even if the last maternal inpatient episode had occurred 5 or more years before the infant's birth. After the national campaign, risk factor prevalence (especially maternal antenatal smoking) remained high in this population, and relative risks therefore increased. During 1992 through 2004, smoking and individual social adversity measures jointly accounted for approximately half the excess risk linked with maternal psychiatric inpatient history, whereas the confounding effects of obstetric factors were minimal. CONCLUSIONS: Tailored approaches are needed to ensure that standard safety advice is effectively communicated to these vulnerable families. In particular, mentally ill pregnant women should be encouraged and better supported to stop smoking. Families with 2 affected parents require particularly strong support. A clearer understanding is needed as to why high risk factor prevalence persists among these parents.

4. Porzionato A, Macchi V, De Caro R
Sudden infant death syndrome
N Engl J Med. 2009 Dec 24;361(26):2580; author reply 2581-2

Comment on:
N Engl J Med. 2009 Aug 20;361(8):795-805

5. Möllborg P, Alm B
Sudden infant death syndrome during low incidence in Sweden 1997-2005
Acta Paediatr. 2010 Jan;99(1):94-8

Central Infant Welfare Unit, Primary Health Care, FyrBoDal, Uddevalla, Sweden. per.mollborg@vgregion.se

BACKGROUND: Following the change from prone to supine in preferred sleeping position, the incidence of Sudden Infant Death Syndrome (SIDS) in Sweden fell from 1.1 per 1000 live births in 1992 to 0.41 in 1995. After a further small decline, we have been experiencing a plateau at around 0.25 since 2000. AIM: To identify the changes that have occurred in the epidemiology of SIDS since the end of the Nordic Epidemiological SIDS Study in 1995. METHODS: Data from the Medical Birth Register of Sweden, covering the years 1995-2005, were used. Sleeping position is not included in the register. Results: The incidence of SIDS has remained low in Sweden. Independent risk factors were smoking during early pregnancy, parents not living together, low maternal age, high parity and short gestational age. The odds ratio for smoking has continued to increase and the median age of death has continued to decrease since the previous study. We found no signs of seasonality in the current material. CONCLUSIONS: Age at death continued to decrease. The high incidence during weekends persisted. Seasonality was not significant. There was no evidence of a changing effect from risk factors in the studied period.

6. Shapiro-Mendoza CK, Kim SY, Chu SY, Kahn E, Anderson RN
Using death certificates to characterize sudden infant death syndrome (SIDS): opportunities and limitations
J Pediatr. 2010 Jan;156(1):38-43

Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Reproductive Health, Atlanta, GA, USA. ayn9@cdc.gov

OBJECTIVE: To examine cause-of-death terminology written on death certificates for sudden infant death syndrome (SIDS) and to determine the adequacy of this text data in more fully describing circumstances potentially contributing to SIDS deaths. STUDY DESIGN: With 2003 and 2004 US mortality files, we analyzed all deaths that were assigned the underlying cause-of-death code for SIDS (R95). With the terminology written on the death certificates, we grouped cases into SIDS-related cause-of-death subcategories and then assessed the percentage of cases in each subcategory with contributory or possibly causal factors described on the certificate. RESULTS: Of the 4408 SIDS-coded deaths, we subcategorized 67.2% as "SIDS" and 11.0% as "sudden unexplained (or unexpected) infant death." The terms "probable SIDS" (2.8%) and "consistent with SIDS" (4.6%) were found less frequently. Of those death certificates that described additional factors, "bedsharing or unsafe sleep environment" was mentioned approximately 80% of the time. Most records (79.4%) did not mention any additional factors. CONCLUSION: Our death certificate analysis of the cause-of-death terminology provided a unique opportunity to more accurately characterize SIDS-coded deaths. However, the death certificate was still limited in its ability to more fully describe the circumstances leading to SIDS death, indicating the need for a more comprehensive source of SIDS data, such as a case registry.

7. Poetsch M, Nottebaum BJ, Wingenfeld L, Frede S, Vennemann M, Bajanowski T
Impact of sodium/proton exchanger 3 gene variants on sudden infant death syndrome
J Pediatr. 2010 Jan;156(1):44-48.e1

Institute of Forensic Medicine, University Hospital Essen, Essen, Germany. micaela.poetsch@uk-essen.de

OBJECTIVE: To determine the contribution of variations in the sodium/proton exchanger 3 (NHE3) gene in sudden infant death syndrome (SIDS). STUDY DESIGN: Variations in the exons and promoter of the NHE3 gene were analyzed with direct sequencing analysis and mini sequencing (SNaPshot analysis) in 251 cases of SIDS, plus 50 infant control subjects who had died of other causes, and 170 healthy adults. RESULTS: The C2405T variant (exon 16) and 2 polymorphisms in the promoter (G1131A and C1197T) were encountered significantly more frequently in cases of SIDS than in control subjects. At least 1 of these 3 variants was detected in 49% of SIDS cases, but only in 30% of control subjects. CONCLUSIONS: Our findings suggest the involvement of polymorphisms in the NHE3 gene and promoter in cases of SIDS, which may result in an overexpression of NHE3 in the medulla oblongata and which possibly leads to a disturbance in breathing control. Furthermore, our results underline the heterogeneous character of SIDS.

8. Schlaud M, Dreier M, Debertin AS, Jachau K, Heide S, Giebe B, Sperhake JP, Poets CF, Kleemann WJ
The German case-control scene investigation study on SIDS: epidemiological approach and main results
Int J Legal Med. 2010 Jan;124(1):19-26. Epub 2009 Jan 22

Department of Epidemiology, Social Medicine, and Health System Research, Hannover Medical School, Hannover, Germany. m.schlaud@rki.de

The present study, which was part of the German SIDS Study (GeSID), enrolled sudden infant death syndrome (SIDS) cases and population controls and obtained objective scene data via specifically trained observers shortly after discovery of each dead infant. Infants who had died suddenly and unexpectedly at ages between 8 and 365 days were enrolled in five regions of Germany between November 1998 and October 2001. Shortly after discovery of each dead infant, a specially trained doctor of legal medicine visited the bereaved family at home. Data were obtained by measurements and observations. Dead infants underwent a standardised autopsy, additional information being obtained by standardised parent interviews. Investigation of the sleep environment and wake-up scene in matched controls followed the same protocol. A total of 52 SIDS cases and 154 controls were enrolled, 58% were boys, and median age of cases vs. controls was 126 vs. 129 days. Risk factors in the sleeping environment were pillow use (adjusted OR 4.3; 95%CI 1.6-11.6), heavy duvets (OR 4.4; 1.5-13.3), soft underlay (OR 3.0; 1.1-8.7), face covered by bedding (OR 15.8; 2.5-102.1) and entire body covered by bedding (OR 35.5; 5.5-228.3). Using a standardised protocol, including objective measurements of the sleep environment and a case-control design, this study was able to confirm many risk factors for SIDS.

Miscarriage/Stillbirth/Prenatal Issues

1. Stortoni P, Cecati M, Giannubilo SR, Sartini D, Turi A, Emanuelli M, Tranquilli AL
Placental thrombomodulin expression in recurrent miscarriage
Reprod Biol Endocrinol. 2010 Jan 5;8(1):1. [Epub ahead of print]

ABSTRACT: BACKGROUND: Early pregnancy loss can be associated with trophoblast insufficiency and coagulation defects. Thrombomodulin is an endothelial-associated anticoagulant protein involved in the control of hemostasis and inflammation at the vascular beds and it's also a cofactor of the protein C anticoagulant pathway. DISCUSSION: We evaluate the Thrombomodulin expression in placental tissue from spontaneous recurrent miscarriage and voluntary abortion as controls. Thrombomodulin mRNA was determined using real-time quantitative polymerase chain reaction. Reduced expression levels of thrombomodulin were found in recurrent miscarriage group compared to controls (1.82-fold of reduction), that corresponds to a reduction of 45% (from control group Delta CT) of thrombomodulin expression in spontaneous miscarriage group respect the control groups. SUMMARY: We cannot state at present the exact meaning of a reduced expression of Thrombomodulin in placental tissue. Further studies are needed to elucidate the biological pathway of this important factor in the physiopathology of the trophoblast and in reproductive biology.

2. Casikar I, Bignardi T, Riemke J, Alhamdan D, Condous G
Expectant management of spontaneous first-trimester miscarriage: prospective validation of the '2-week rule'
Ultrasound Obstet Gynecol. 2010 Jan 5. [Epub ahead of print]

Acute Gynaecology, Early Pregnancy and Advanced Endosurgery Unit, Nepean Centre for Perinatal Care, Nepean Clinical School, University of Sydney, Nepean Hospital, Penrith, Sydney, Australia.

OBJECTIVES: To assess uptake and success of expectant management of first-trimester miscarriage for a finite 14-day period, in order to evaluate our '2-week rule' of management. METHODS: This was a prospective observational study evaluating our proposed 2-week rule of expectant management, which is based on the finding that women managed expectantly are most likely to miscarry in the first 14 days and that to wait longer than 2 weeks without intervention does not confer a greater chance of successful resolution. Eligible women diagnosed with first-trimester miscarriage were offered a choice of expectant management or surgical evacuation under general anesthesia. Inclusion criteria for expectant management were: diagnosis of incomplete miscarriage (heterogeneous tissue, with or without a gestational sac, seen on ultrasound in the uterine cavity and distorting the endometrial midline echo), missed miscarriage (crown-rump length (CRL) >/= 6 mm with absent fetal heart activity) or empty sac (anembryonic pregnancy) based on transvaginal ultrasonography. Women with complete miscarriage, missed miscarriage at the nuchal translucency scan, molar pregnancy or miscarriage >/= 3 weeks in duration (missed miscarriage in which the CRL was >/= 3 weeks smaller than the gestational age based on last menstrual period), or with signs of infection or hemodynamic instability were excluded. Expectant management consisted of weekly ultrasonography for 2 weeks. If after 2 weeks resolution was not complete, surgery was advised. RESULTS: 1062 consecutive pregnant women underwent transvaginal ultrasound examination. Of these, 38.6% (410/1062) were diagnosed with miscarriage, of whom 241 (59%) were symptomatic at the time of presentation and 282 were eligible for the study. These were offered expectant management and 80% (227/282) took up this option. 11% (24/227) were lost to follow-up; therefore, complete data were available on 203 women. Overall spontaneous resolution of miscarriage at 2 weeks was observed in 61% (124/203) of women. Rates of spontaneous resolution at 2 weeks according to the type of miscarriage were 71% for incomplete miscarriage, 53% for empty sac and 35% for missed miscarriage. The incidence of unplanned emergency dilatation and curettage due to gynecological infection or hemorrhage was 2.5% (5/203). CONCLUSIONS: Expectant management based on the 2-week rule is a viable and safe option for women with first-trimester miscarriage. Women with an incomplete miscarriage are apparently the most suitable for expectant management. Copyright (c) 2009 ISUOG. Published by John Wiley & Sons, Ltd.

3. 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. 2009 Dec 28. [Epub ahead of print]

Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Science, University of Sao Paulo, Brazil

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 16weeks. 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. Published by Elsevier B.V.

4. Radulovic NV, Ekerhovd E, Abrahamsson G, Norström A
Cervical tissue changes in women with miscarriage: a morphological and biochemical investigation
Acta Obstet Gynecol Scand. 2010;89(1):54-64

Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. nina.radulovic@vgregion.se

OBJECTIVE: To evaluate morphological and inflammatory events in the uterine cervix in first trimester miscarriages. DESIGN: Experimental study. SETTING: Sahlgrenska University Hospital, Gothenburg, Sweden. POPULATION: Nulliparous women with first trimester symptomatic (n = 7) or silent (n = 11) miscarriage scheduled for surgical evacuation and nulliparous women scheduled for surgical termination of first trimester pregnancies (control group n = 11). METHODS: Before evacuation, biopsies were obtained from the cervix. The specimens were either fixed in glutaraldehyde for electron microscopy or snap-frozen in liquid nitrogen and stored at -70 degrees C until analyses of interleukin-8 (IL-8) and matrix metalloproteinases (MMPs). MAIN OUTCOME MEASURES: Ultrastructure of cervical tissue, cervical tissue levels of IL-8, immunohistochemistry of MMP-1, MMP-8, MMP-9 and IL-8. RESULTS: The organization of the cervical collagen framework was deranged, the fibroblasts were reactive and the number of activated mast cells appeared to be increased in specimens from women with miscarriage compared with controls. IL-8 was significantly increased in women with miscarriage. Immunohistochemistry of MMP-1 and MMP-8 did not demonstrate any significant difference between the groups. MMP-9 was significantly lower in specimens from women with symptomatic miscarriage compared to women with silent miscarriage and women in the control group. CONCLUSIONS: An inflammatory-like response takes place in the cervix both in women with symptomatic and silent miscarriage. The intensity of the inflammatory response seems to be similar in the two groups. Therefore, inadequate cervical remodeling does not seem to be the reason why some miscarriages remain silent.

5. Zhu Y, Huo Z, Lai J, Li S, Jiao H, Dang J, Jin C
Case-control study of a HLA-G 14-bp insertion-deletion polymorphism in women with recurrent miscarriages
Scand J Immunol. 2010 Jan;71(1):52-4

Key Laboratory of Ministry of Public Health for Forensic Science, Xi'an Jiaotong University, Xi'an, China.

Human leucocyte antigen (HLA)-G is an important molecule for maintaining an immunotolerant foetal-maternal relationship. A 14-bp insertion (+14-bp)/deletion (-14-bp) polymorphism in exon 8 of the 3' untranslated region of the HLA-G gene has been proposed to be associated with HLA-G mRNA stability and the expression of HLA-G. This might play an immunomodulatory role in human pregnancy. In this study, a total of 526 Chinese women were genotyped for the +14-bp/-14-bp polymorphism, including 137 who had recurrent miscarriages (three miscarriages: 86, four or more miscarriages: 51), 138 women who had experienced two abortions and 251 women with normal fertility as controls. The +14-bp homozygote sequence was more prominent among those with recurrent miscarriages (three or more recurrent miscarriages) in contrast to fertile control women. Significant difference was observed in the distribution of +14-bp/+14-bp genotype between controls and the recurrent abortions group with four or more abortions. A 14-bp insertion/deletion polymorphism in exon 8 has a possible role in HLA-G expression in certain cases of recurrent miscarriage. However, additional studies are needed in this regard.

6. Ananth CV, Basso O
Impact of pregnancy-induced hypertension on stillbirth and neonatal mortality
Epidemiology. 2010 Jan;21(1):118-23

Division of Epidemiology and Biostatistics, Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901-1977, USA. cande.ananth@umdnj.edu

BACKGROUND: Hypertensive disorders of pregnancy are more frequent in primiparous women, but may be more severe in multiparas. We examined trends in stillbirth and neonatal mortality related to pregnancy-induced hypertension (PIH), and explored whether mortality varied by parity and maternal race. METHODS: We carried out a population-based study of 57 million singleton live births and stillbirths (24-46 weeks' gestation) in the United States between 1990 and 2004. We estimated rates and adjusted odds ratios (ORs) of stillbirth and neonatal death in relation to PIH, comparing births in 1990-1991 with 2003-2004. RESULTS: PIH increased from 3.0% in 1990-1991 to 3.8% in 2003-2004. In both periods, PIH was associated with a higher risk of stillbirth and neonatal death. We explored this in more detail in 2003-2004, and observed that the increased risk of PIH-related stillbirth was higher in women having their second or higher-order births (OR = 2.2 [95% confidence interval = 2.1-2.4]) compared with women having their first birth (1.5 [1.4-1.6]). Patterns were similar for neonatal death (1.3 [1.2-1.4] in first and 1.6 [1.5-1.8] in second or higher-order births). Among multiparas, the association between PIH and stillbirth was stronger in black women (2.9 [2.7-3.2]) than white women (2.0 [1.8-2.1]). CONCLUSIONS: A substantial burden of stillbirth and neonatal mortality is associated with PIH, especially among multiparous women, which may be due to more severe PIH, or to a higher burden of underlying disease.

7. Nielsen HS, Mortensen LH, Nygaard U, Schnor O, Christiansen OB, Andersen AM
Sex of prior children and risk of stillbirth in subsequent pregnancies
Epidemiology. 2010 Jan;21(1):114-7

The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark. henriette.svarre.nielsen@rh.regionh.dk

BACKGROUND: Delivery of a boy has been reported to increase a woman's risk of recurrent miscarriage in subsequent pregnancies. We explored whether delivery of boys similarly increases the risk of a subsequent stillbirth. METHODS: We identified all Danish women delivering their first child (singleton) between 1980 and 1998 (n = 499,731) using the Danish Birth Registry. These women had subsequent singleton births through 2004 (n = 558,314). We assessed the risk of stillbirth conditional on sex of prior children. RESULTS: The risk of stillbirth was increased by 12% after deliver of boys compared with girls (relative risk = 1.12 [95% confidence interval = 1.02-1.23]). This association did not appear to be explained by maternal confounders. CONCLUSION: Stillbirth risk appears to be slightly higher among the pregnancies of women who have previously delivered a boy. One possible mechanism is maternal immune response to male-specific minor histocompatibility antigens initiated during pregnancies with boys.

8. King K, Smith S, Chapman M, Sacks G
Detailed analysis of peripheral blood natural killer (NK) cells in women with recurrent miscarriage
Hum Reprod. 2010 Jan;25(1):52-8. Epub 2009 Oct 9

St George Hospital, UNSW and IVF Australia, Sydney, Australia

BACKGROUND: Increased peripheral blood natural killer (NK) cell activity has been associated with unexplained reproductive failure including recurrent (three or more) miscarriages (RM). Studies have reported abnormalities in both numbers (absolute and proportion) and activation. This study assessed numerous NK cell parameters to determine which (if any) are altered in women with RM compared with controls, which parameter best differentiated women with RM from controls, and what NK levels should be considered high. METHODS: Luteal-phase blood samples from women with RM (n = 104) and controls (n = 33) were analysed by four-colour flow cytometry. NK cells were analysed as a percentage of lymphocytes, total NK concentration, CD56(Dim) subtype concentration and percentage, activated CD69(+)CD56(Dim) subtype concentration and percentage and CD56(+Bright):CD56(+Dim) subtype ratio. Women with RM were analysed in two subgroups: those positive in > or =1 RM screening tests (karyotype, uterine, antiphospholipid syndrome, thrombophilia) (n = 48) and those who had negative screening tests (n = 56). RESULTS: Women with RM had significantly higher NK percentage (P < 0.001), and significantly lower CD56(+Bright):CD56(+Dim) ratio (P < 0.05) than controls. NK percentage was the only significantly higher variable in the RM screening test negative subgroup (P < 0.01). A ROC analysis (AUC = 0.71) found that an NK percentage >18% was highly specific for women with RM (97.0%), and defined 12.5% of women with RM as having high NK percentage, compared with 2.9% of controls. CONCLUSION: Women with RM have altered peripheral blood NK parameters. NK cells as a percentage of lymphocytes best discriminated RM and control populations. Women with RM and high NK levels may have an immunological disorder.

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