Resource Center Journal Article Alert — September 5, 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.

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Sudden Infant Death

1. Hanzer M, Zotter H, Sauseng W, Pfurtscheller K, Müller W, Kerbl R Pacifier use does not alter the frequency or duration of spontaneous arousals in sleeping infants Sleep Med. 2008 Aug 4. [Epub ahead of print]

Division of Neonatology, Department of Pediatrics, Medical University of Graz, Auenbruggerplatz 30, 8036 Graz, Styria, Austria.

OBJECTIVE: It has been reported that pacifiers might reduce the risk of SIDS by favouring infants' arousability from sleep. We evaluated the influence of a pacifier on the frequency and duration of spontaneous arousals in healthy infants. METHODS: Polygraphic recordings were performed in 14 infants with an age of 51.7+/-19.9 days (means+/-SD) who regularly used a pacifier during sleep. Cortical and subcortical arousals were scored according to the recommendations of the "International Paediatric Work Group on Arousals." The number of arousals per 10-min-period and the duration of arousals were determined for periods of pacifier use as well as for periods after pacifier dislodgement and were compared with the data of 10 control infants (age 49.8+/-16.5 days) who never used a pacifier. RESULTS: Altogether, 211 arousals in pacifier users and 225 arousals in non-users were scored. In pacifier users, 2.0+/-1.6 arousals per 10-min-period with a duration of 12.2+/-3.0s occurred during pacifier use, and 1.7+/-1.6 arousals per 10-min-period with a duration of 12.2+/-3.1s occurred during periods without pacifier. In pacifier non-users, 2.3+/-1.2 arousals per 10-min-period (duration 13.9+/-2.9s) were scored. The results did not show a significant difference concerning frequency and duration of spontaneous arousals between pacifier users and non-users. CONCLUSIONS: Our findings suggest that factors other than arousal mechanisms might be responsible for the efficacy of pacifiers in SIDS prophylaxis.

2. Berner J, Ringstedt T, Brodin E, Hökfelt T, Lagercrantz H, Wickström R Prenatal exposure to nicotine affects substance P and preprotachykinin-A mRNA levels in newborn rat Pediatr Res. 2008 Jul 23. [Epub ahead of print]

Department of Woman and Child Health [J.B., T.R., H.L., R.W.], Department of Neuroscience [T.R., T.H.], Department of Physiology and Pharmacology [E.B.], Karolinska Institutet, 171 77 Stockholm, Sweden.

Prenatal nicotine exposure influences neuronal development including effects on several neurotransmitter systems. It also attenuates the ventilatory response to hypoxia, known to require a functional substance P-ergic system. Previous studies have shown that nicotine increases the risk for sudden infant death syndrome (SIDS) by four-fold and that SIDS-victims have elevated brainstem levels of substance P. We therefore studied the effect of prenatal nicotine exposure on the levels of substance P-like immunoreactivity by radioimmunoassay in the brain in newborn rat pups. The expression of the substance P precursor preprotachykinin A mRNA was also determined by real-time RT-PCR in carotid body, in petrosal/jugular and trigeminal ganglia, in cervical and lumbar dorsal root ganglia as well as in the brainstem. We found that prenatal nicotine exposure increased levels of substance P- like immunoreactivity in the brainstem without changing levels in other parts of the brain or in the adrenals. Furthermore, mRNA levels were increased in the carotid bodies and in the petrosal ganglia, in contrast to the decreased levels in the cervical dorsal root ganglia. We conclude that nicotine causes alterations in the substance P-ergic system in the brainstem, possibly linked to the increased risk for SIDS after prenatal nicotine exposure.

3. Tang S, Machaalani R, Waters KA Brain Res. 2008 Jul 19. [Epub ahead of print] Brain-derived neurotrophic factor (BDNF) and TrkB in the piglet brainstem after post-natal nicotine and intermittent hypercapnic hypoxia

Department of Paediatrics and Child Health, The University of Sydney, NSW 2006, Australia.

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a significant role in the regulation of cell growth, survival and death during central nervous system development. The expression of BDNF and TrkB is affected by noxious insults. Two insults during the early post-natal period that are of interest to our laboratory are exposure to nicotine and to intermittent hypercapnic hypoxia (IHH). Piglet models were used to mimic the conditions associated with the risk factors for the sudden infant death syndrome (SIDS) including post-natal cigarette smoke exposure (nicotine model) and prone sleeping where the infant is subjected to re-breathing of expired gases (IHH model). We aimed to determine the effects of nicotine and IHH, alone or in combination, on pro- and rhBDNF and TrkB expression in the developing piglet brainstem. Four piglet groups were studied, with equal gender ratios in each: control (n=14), nicotine (n=14), IHH (n=10) and nic+IHH (n=14). Applying immunohistochemistry, and studying six nuclei of the caudal medulla, we found that compared to controls, TrkB was the only protein significantly decreased after nicotine and nic+IHH exposure regardless of gender. For pro-BDNF and rhBDNF however, observed changes were more evident in males than females exposed to nicotine and nic+IHH. The implications of these findings are that a prior nicotine exposure makes the developing brainstem susceptible to greater changes in the neurotrophic effects of BDNF and its receptor TrkB in the face of a hypoxic insult, and that the effects are greater in males than females.

Other Infant Death

1. Wong A, Elder D, Zuccollo J N Z Med J. 2008 Jul 4;121(1277):39-46 Changes in cause of neonatal death over a decade

University of Otago, Wellington, New Zealand.

AIMS: To classify neonatal deaths at Wellington Hospital (Wellington, New Zealand) over a 10-year period and assess changes in cause of death over time. METHODS: Retrospective audit from 1995-2004 of live-born infants > or = 20 weeks gestation dying before 28 days of age. Deaths were classified according to the PSANZ-NDC Classification guideline. The years 1995-1999 and 2000-2004 were compared to analyse for changes in cause of death. RESULTS: There were 219 neonatal deaths: 67(31%) of these were term infants and 154 preterm; 109 infants from 1995-1999 and 110 from 2000-2004. The autopsy rate was 62% and highest in term infants (76%). Deaths due to congenital anomaly and extreme prematurity decreased over time and deaths due to infection increased. CONCLUSIONS: Use of the PSANZ-NDC death classification system enables an accurate cause of death to be established for most neonatal deaths and allows monitoring of mortality rates over time.

2. Malloy MH Impact of cesarean section on neonatal mortality rates among very preterm infants in the United States, 2000-2003 Pediatrics. 2008 Aug;122(2):285-92

Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0526, USA. mmalloy@utmb.edu

OBJECTIVE: The objective of this analysis was to compare the neonatal mortality rates for infants delivered through primary cesarean section versus vaginal delivery, taking into consideration a number of potentially risk-modifying conditions. METHODS: US linked birth and infant death certificate files for 2000-2003 were used. Demographic, medical, and labor and delivery complications were abstracted from the files with infant information. The primary outcome examined was neonatal death (death at 0-27 days of age). Because of concern regarding misclassification of gestational age, a procedure was used to trim away births for which the birth weight for a specific gestational age was incongruous. Adjusted odds ratios were calculated for the risk of neonatal death relative to the mode of delivery (primary cesarean section versus vaginal delivery), using logistic regression analysis. RESULTS: There were data for 13,733 neonatal deaths and 106,809 survivors available from the trimmed data set for analysis for the 4-year period. More than 80% of pregnancies with delivery between 22 and 31 weeks of gestation experienced >or=1 risk factor. Adjusted odds ratios demonstrated significantly reduced risk of neonatal death for infants delivered through cesarean section at 22 to 25 weeks of gestation (adjusted odds ratios of 0.58, 0.52, 0.72, and 0.81 for 22, 23, 24, and 25 weeks, respectively). CONCLUSION: Cesarean section does seem to provide survival advantages for the most immature infants delivered at 22 to 25 weeks of gestation, independent of maternal risk factors for cesarean section.

3. Rimsza ME, Newberry S Unexpected infant deaths associated with use of cough and cold medications Pediatrics. 2008 Aug;122(2):e318-22

Department of Pediatrics, University of Arizona College of Medicine, Tucson, Arizona, USA. mrimsza@aap.net

OBJECTIVE: The objective of this study was to determine whether caregivers had given infants who died unexpectedly over-the-counter cough and cold medications before the infant deaths to identify sociodemographic risk factors for their use. METHODS: The Arizona Child Fatality Review Program reviews the circumstances surrounding every child death that occurs in the state each year. By statute, the multidisciplinary review teams have access to all medical charts, autopsy reports, law enforcement reports, and other records for their review and use these data to determine the cause of death and its preventability. The data on all infants who died unexpectedly in 2006 and had an autopsy and postmortem toxicologic studies were reviewed for this analysis. RESULTS: Ten unexpected infant deaths that were associated with cold-medication use were identified. The infants ranged in age from 17 days to 10 months. Postmortem toxicology testing found evidence of recent administration of pseudoephedrine, antihistamine, dextromethorphan, and/or other cold-medication ingredients in these infants. The families who used these medications were poor and publicly insured, and 50% of them had limited English proficiency. Only 4 of these infants had received medical care for their current illness before their death. The over-the-counter cough and cold medication had been prescribed by a clinician for only 1 of these infants. CONCLUSIONS: Review of these infants' deaths raises concern about the role of the over-the-counter cough and cold medications in these deaths. These findings support the recommendation that such medications not be given to infants. In addition, these findings suggest that warnings on these medications "to consult a clinician" before use are not being followed by parents. Educational campaigns to decrease the use of over-the-counter cough and cold medications in infants need to be increased.

4. Boccoli J, Loidl CF, Lopez-Costa JJ, Creydt VP, Ibarra C, Goldstein J Intracerebroventricular administration of Shiga toxin type 2 altered the expression levels of neuronal nitric oxide synthase and glial fibrillary acidic protein in rat brains Brain Res. 2008 Sep 16;1230:320-33. Epub 2008 Jul 22

Laboratorio de Fisiopatogenia, Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155 piso 7, Ciudad Autónoma de Buenos Aires, 1121, Argentina.

Shiga toxin (Stx) from enterohemorrhagic Escherichia coli (STEC) is the main cause of hemorrhagic colitis which may derive into Hemolytic Uremic Syndrome (HUS) and acute encephalopathy, one of the major risk factors for infant death caused by the toxin. We have previously demonstrated that intracerebroventricular administration of Stx2 causes neuronal death and glial cell damage in rat brains. In the present work, we observed that the intracerebroventricular administration of Stx2 increased the expression of glial fibrillary acidic protein (GFAP) leading to astrogliosis. Confocal microscopy showed reactive astrocytes in contact with Stx2-containing neurons. Immunocolocalization of increased GFAP and Stx2 in astrocytes was also observed. This insult in the brain was correlated with changes in the expression and activity of neuronal nitric oxide synthase (nNOS) by using the NADPH-diaphorase histochemical technique (NADPH-d HT). A significant decrease in NOS/NADPH-d-positive neurons and NOS/NADPH-d activity was observed in cerebral cortex and striatum, whereas an opposite effect was found in the hypothalamic paraventricular nucleus. We concluded that the i.c.v. administration of Stx2 promotes a typical pattern of brain injury showing reactive astrocytes and an alteration in the number and activity of nNOS/NADPH-d. According to the functional state of nNOS/NADPH-d and to brain cell morphology data, it could be inferred that the i.c.v. administration of Stx2 leads to either a neurodegenerative or a neuroprotective mechanism in the affected brain areas. The present animal model resembles the encephalopathy developed in Hemolytic Uremic Syndrome (HUS) patients by STEC intoxication.

Miscarriage/Stillbirth/Prenatal Issues

1. Nakashima A, Shiozaki A, Myojo S, Ito M, Tatematsu M, Sakai M, Takamori Y, Ogawa K, Nagata K, Saito S Granulysin produced by uterine natural killer cells induces apoptosis of extravillous trophoblasts in spontaneous abortion. Am J Pathol. 2008 Sep;173(3):653-64. Epub 2008 Aug 7.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.

Immune changes are known to occur in recurrent spontaneous abortion, but it is unclear whether either maternal natural killer (NK) cells or T cells attack fetus-derived trophoblasts. To clarify the immunological causes of spontaneous abortion, we examined the relationship between cytotoxic granule proteins in decidual lymphocytes, such as granulysin, granzyme B, and perforin, and the induction of apoptosis in extravillous trophoblasts (EVTs). The number of granulysin-positive CD56(bright) NK cells increased significantly in the decidua basalis during spontaneous abortion compared with normal pregnancy; however, granzyme B- and perforin-positive cells did not change. Interestingly, the expression of granulysin was also detected in the nuclei of EVTs in spontaneous abortion samples. When IL-2-stimulated CD56(bright) NK cells were cocultured with EVT cells (HTR-8/SV40neo), granulysin was found initially in the cytoplasm and then accumulated in the nuclei of the HTR-8/SV40neo cells. Furthermore, transfected cells expressing a GFP-granulysin fusion protein induced apoptosis in HTR-8/SV40neo cells independently of caspases. Our results suggest that granulysin-positive uterine NK cells attack EVTs; subsequently, the uNK-derived granulysin actively accumulates in the nuclei of EVTs, causing the death of EVTs due to apoptosis. These data support a new apoptosis pathway for trophoblasts via uNK-derived granulysin, suggesting that granulysin is involved in spontaneous abortion.

2. Odendaal HJ, Steyn DW, Elliott A, Burd L Combined Effects of Cigarette Smoking and Alcohol Consumption on Perinatal Outcome Gynecol Obstet Invest. 2008 Aug 6;67(1):1-8. [Epub ahead of print]

Department of Obstetrics and Gynaecology, Stellenbosch University, Tygerberg, South Africa.

Background: An increase in various congenital abnormalities associated with cigarette smoking and the use of alcohol during pregnancy has been reported in many studies. These exposures also increase the risk of pregnancy complications such as abruptio placentae, unexplained stillbirth, preterm labor and intrauterine growth restriction. However, very few studies have addressed the combined effect of smoking and drinking on pregnancy outcomes. Methods: In this review, the adverse effects of smoking or drinking on pregnancy were obtained from publications in which both substances were addressed in the same study population. A special effort was made to find studies in which the combined effect of these substances was investigated. Results: Preterm labor occurred more frequently in women who drank and smoked during pregnancy. This increased odds ratio was more than the sum of the effects of either smoking or drinking, indicating that the use of both substances by the same woman has a synergistic effect that increases the risk of preterm labor. This synergistic effect was also found for low birth weight and growth restriction. Conclusions: As most of the women who drink during pregnancy also smoke cigarettes, attention should be given to the prevention or reduced use of both substances during pregnancy. Copyright © 2008 S. Karger AG, Basel.

3. Christiansen OB, Steffensen R, Nielsen HS, Varming K Multifactorial Etiology of Recurrent Miscarriage and Its Scientific and Clinical Implications Gynecol Obstet Invest. 2008 Aug 1;66(4):257-267. [Epub ahead of print]

Fertility Clinic 4071, Rigshospitalet, Copenhagen, Denmark.

A considerable proportion of recurrent miscarriage (RM) cases are caused by recurrent chromosomally abnormal conceptions. However, in younger patients and patients with multiple miscarriages, maternal causes seem to dominate. No single biomarker with a high predictive value of maternally caused RM has been identified. Non-genetic biomarkers in RM may not reflect conditions in the pregnant uterus and we rarely know whether they are causes or consequences of miscarriage. Studies of genetic biomarkers are probably the best way to reveal the pathophysiological mechanisms behind RM. Epidemiological and genetic studies suggest that RM due to maternal causes has a multifactorial background. The risk of RM in each patient is probably determined by the interaction of many genetic variants and environmental factors but only few of these have so far been identified. The genetic biomarkers for RM can probably be classified into three groups: (1) variants associated with excessive inflammatory responses and autoimmunity; (2) variants of importance for insulin and androgen sensitivity and turn-over, and (3) variants associated with thrombophilia. Identification of these markers will require whole genome association studies comprising thousands of individuals. Acknowledgement of the multifactorial background for RM has important implications for the management of patients in clinical practice. Copyright © 2008 S. Karger AG, Basel.

4. Pittschieler S, Brezinka C, Jahn B, Trinka E, Unterberger I, Dobesberger J, Walser G, Auckenthaler A, Embacher N, Bauer G, Luef G Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy J Neurol. 2008 Jul 25. [Epub ahead of print]

Dept. of Neurology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.

BACKGROUND : Antiepileptic drugs (AEDs) like phenytoin (PHE), carbamazepine (CBZ), barbiturates and valproic acid (VPA) interfere with folic acid absorption and metabolism, which in turn can be the cause of adverse pregnancy outcome. OBJECTIVE : To study the prophylactic effect of folic acid supplementation with regard to spontaneous abortion and preterm delivery (fetal demise after week 20 of gestational age) in pregnant women receiving AED therapy, as well as benefits of most common dosage and preconceptional commencement. METHODS : Prospective examination of 104 patients, registered in EURAP from 1999-2004 at a single center and a retrospective analysis of data from our epilepsy databank completed with medical records and patients interviews of the Department of Neurology of Innsbruck University Hospital from 1971 to 1999. RESULTS : 388 pregnancies in 244 patients were analyzed. Pregnancies with folic acid supplementation showed significant reduction of spontaneous abortion. With regard to monotherapies, in the group of women taking VPA, supplementation of folic acid had significant benefit. Other examined monotherapies (CBZ, PHE, and PB) known to interfere with folic acid showed no significant results. CONCLUSIONS : This study confirms the prophylactic effect of folic acid supplementation on spontaneous abortion. For AED therapy, folic acid supplementation should be part of the therapy of every pregnant epileptic woman, especially for those treated with VPA.

5. Latini C, Frontini A, Morroni M, Marzioni D, Castellucci M, Smith PG Remodeling of uterine innervation Cell Tissue Res. 2008 Aug 2. [Epub ahead of print]

Institute of Normal Human Morphology - Anatomy, Faculty of Medicine, Polytechnic University of Marche, Via Tronto 10/A, 60020, Ancona, Italy.

This minireview reports current hypotheses concerning the remodeling of sympathetic innervation in rodent and human uterus during the estrous cycle and gestation. Neural modulation in this organ is related to sexual hormone concentrations, and a reduction in nerve density is observed when estrogen levels are high during the estrous cycle. Estrogen receptor alpha is considered to be the major receptor mediating the action of estrogen. In the uterus, the expression of neurotrophins, such as nerve growth factor, which are involved in the survival and growth of nerve fibers, changes in response to steroid levels. Despite much research, further studies are necessary to clarify various aspects of nerve growth control under diverse physiological conditions. These studies could be of importance, since alterations of the biological mechanisms of uterus innervation may play significant roles in various pathologies, such as infertility and spontaneous abortion.

6. Plunkett BA, Fitchev P, Doll JA, Gerber SE, Cornwell M, Greenstein EP, Crawford SE Decreased expression of pigment epithelium derived factor (PEDF), an inhibitor of angiogenesis, in placentas of unexplained stillbirths Reprod Biol. 2008 Jul;8(2):107-20

Northwestern University Feinberg School of Medicine, 250 E. Superior St., Suite 05-2175, Chicago, IL 60611, USA. p-beth@northwestern.edu.

Normal placental vascular development depends upon the complex interactions between angiogenic inducers and inhibitors within the placenta. Alterations within the placental microenvironment can promote an imbalance in angiogenic mediators which may be associated with adverse perinatal outcomes. The purpose of this study was to investigate the placentas of infants with unexplained stillbirth as compared to live-born infants and to determine whether alterations in angiogenic inducer vascular endothelial growth factor (VEGF) or inhibitor pigment epithelium-derived factor (PEDF) are associated with altered angiogenesis, vascular remodeling and stillbirth. Placentas of 22 unexplained stillbirths and 44 age-matched live-born controls were scored for microvascular density (MVD), vasculopathy and microvascular permeability. A subset was scored for expression of angiogenic inducer VEGF and inhibitor pigment epithelium-derived factor. Stillborn placentas demonstrated higher MVD than controls (mean+SD: 116.6+/-46.3 v. 60.8+/-13.5, respectively, p<0.001). Vasculopathy was present in 10/22 (45%) stillbirths compared to 0/44 (0%) controls (p<0.001); increased vascular permeability was present in 15/22 (68%) cases and 5/44 (11%) controls (p<0.001). PEDF expression was significantly lower in stillborn placentas (1.7+/-0.3) than live-born controls (3.6+/-0.8, p<0.01) while VEGF expression was similar (3.3+/-0.7 v. 3.7+/-0.4, respectively, p>0.05). In conclusion, we found that unexplained stillbirth is associated with loss of angiogenic inhibitor PEDF, vasculopathy and heightened angiogenesis in the placenta.

7. Yang H, Qiu L, Di W, Zhao A, Chen G, Hu K, Lin Q Fertil Steril. 2008 Aug 1. [Epub ahead of print] Proportional change of CD4(+)CD25(+) regulatory T cells after lymphocyte therapy in unexplained recurrent spontaneous abortion patients

Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

OBJECTIVE: To investigate the proportional changes of CD4(+)CD25(+) regulatory T cells in peripheral blood after lymphocyte therapy in unexplained recurrent spontaneous abortion (URSA) patients. DESIGN: Prospective cohort study. SETTING: University Hospital. PATIENT(S): Twenty-five URSA patients. INTERVENTION(S): Measurements of CD4(+)CD25(+) regulatory T cells in peripheral blood before and after paternal or third-party lymphocyte immunization. MAIN OUTCOME MEASURE(S): The proportion of CD4(+)CD25(bright) regulatory T cells and the percentage of CD25(bright) cells in the CD4(+) T-cell population. RESULT(S): The proportion of CD4(+)CD25(bright) T cells in peripheral blood from URSA patients was increased significantly after paternal or third-party lymphocyte immunization therapy, whereas the percentage of CD4(+)CD25(dim) cells were decreased significantly. The percentage of CD4(+)CD25(bright) cells in the CD4(+) T-cell population was significantly increased, and the proportion of CD4(+)CD25(bright) T cells was significantly higher in successfully pregnant women than in those with pregnancy loss after lymphocyte therapy. CONCLUSION(S): Allogeneic lymphocyte therapy can enhance the percentage of CD4(+)CD25(bright) regulatory T cells in peripheral blood, therefore CD4(+)CD25(+) regulatory T cells may serve as a novel biomarker for monitoring allogeneic lymphocyte therapy in URSA patients.

8. Joó JG, Beke A, Papp Z, Rigó J, Papp C Pathol Res Pract. 2008 Jul 30. [Epub ahead of print] Single umbilical artery in fetopathological investigations

1st Department of Obstetrics and Gynecology, Faculty of General Medicine, Semmelweis University, 1088 Budapest, Hungary

Single umbilical artery (SUA) is a relatively common malformation that may call attention to the possibility of associated malformations (often chromosome aberrations). The current study aimed at surveying malformations associated with SUA on the basis of fetopathological investigations, analyzing the role of history, summarizing the clinically important factors emerging together with this malformation. In this study, we processed the details of 204 cases in which SUA was confirmed fetopathologically after miscarriage or induced abortion between 1990 and 2007. In our sample, SUA occurred in 7.38% of the cases. The history was positive in almost 30% of the cases. The majority of the cases had a positive obstetric and the minority of them a positive genetic history. The highest association of SUA with other malformations was found for craniospinal ones, but an association with cardiovascular malformations should also be mentioned. Regarding the individual types of malformation, SUA was most commonly associated with hydrocephalus, but Potter's sequence, trisomy 21, and atrioventricular septal defect also reached a higher rate in associated SUA. Previously published articles dealing with associated malformations found that urogenital malformations were most commonly associated with SUA. 'Itemizing' the different non-chromosomal malformations in association with SUA, we found that hydrocephalus, Potter's sequence, and atrioventricular septal defect were the most frequent malformations, while in earlier studies, the association with non-chromosomal malformations such as vertebral malformations, imperforated anus, cheilognathopalatoschisis, and renal agenesis occurred more frequently than usual.

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