Demographic, reproductive, medical, and environmental factors in relation to gastroschisis.

To identify risk factors for gastroschisis other than drug use in pregnancy, an analysis of data collected in a case-control surveillance program of birth defects (1976-1990) was conducted. Drug use is considered in Werler et al., Teratology, 45:361-367, 1992. Maternal demographic, reproductive, and medical factors, and first trimester environmental exposures, were compared between 76 gastroschisis cases and 2,581 malformed controls. A strong inverse association was found for maternal age: relative to women 30 years or older, relative risks for 25-29, 20-24, and less than 20-year-old women were 1.7, 5.4, and 16, respectively. Multivariate relative risks (and 95% confidence intervals) for alcohol use were as follows: for 1-5 drinks per week, 1.6 (0.7-3.4); for greater than or equal to 6 drinks per week, 2.5 (0.9-6.8); for a maximum of 1-4 drinks at any one time, 0.8 (0.4-1.6); and for a maximum of greater than or equal to 5 drinks, 2.8 (1.2-6.5). With the effect of age taken into account, no associations were identified for cigarette smoking, consumption of caffeinated or decaffeinated coffee, unplanned pregnancy, 12 or less years of education, or a parity of two or more. Other medical and reproductive factors, including weight gain, vaginal bleeding, nausea or vomiting, influenza, "other" infection, and history of spontaneous abortion or elective abortion did not increase the risk.     

Selected gene polymorphisms and their interaction with maternal smoking, as risk factors for gastroschisis

BACKGROUND: Gastroschisis is a severe birth defect in which the infant is born with a portion of the intestines extruding through a small tear in the abdominal wall, usually to the right of the umbilical cord. Its etiology is unknown, but the prevailing hypothesis is that it results from a vascular accident at the time of involution of the right umbilical vein or of the development of the superior mesenteric artery. METHODS: In a case-control study of 57 cases of gastroschisis and 506 controls, we tested DNA for polymorphisms of 32 genes representing enzymes involved in angiogenesis, blood vessel integrity, inflammation, wound repair, and dermal or epidermal strength. RESULTS: In logistic regression, controlling for maternal ethnicity, and using the homozygote wild-type as referent, the following gene polymorphisms were associated with an increased risk for a gastroschisis for heterozygotes: ICAM1 gly241arg (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1 -3.4); NOS3 glu298asp (OR, 1.9; 95% CI, 1.1-3.4); NPPA 2238T > C (OR, 1.9; 95% CI, 1.0-3.4); and ADD1 gly460trp (OR, 1.5; 95% CI, 0.8-2.8). Additionally, for the NPPA and ADD1 single-nucleotide polymorphisms (SNPs), the homozygote variants had a significantly higher risk than the heterozygotes (OR, 7.5; 95% CI, 1.7-33.5 and OR, 4.9; 95% CI, 1.9-12.9, respectively). Three SNPs showed a strong interaction with maternal smoking. The risk for smokers with 1 or 2 variant alleles compared to nonsmokers with the wild-type allele were: NOS3 (OR, 5.2; 95% CI, 2.4-11.4); ICAM1 (OR, 5.2; 95% CI, 2.1-12.7); and NPPA (OR, 6.4; 95% CI, 2.8-14.6). CONCLUSIONS: These results support the hypothesis of a vascular compromise as part of a multifactorial etiology of gastroschisis involving both genes and environmental factors.     

Epidemiologic analysis of maternal factors and amniotic band defects

BACKGROUND

The group of defects identified as amniotic bands includes amnion rupture sequence (ARS) and body wall complex (BWC). Little is known about risk factors for either ARS or BWC, except that maternal age has been shown to affect risk inversely.

METHODS

The present analysis used data collected from 1976 to 1998 as part of an ongoing case control study of birth defects in the metropolitan areas of Boston, Philadelphia, and Toronto. There were 73 cases with ARS and 11 cases with BWC. ARS cases were further subdivided according to affected structures: there were 53 with only limbs affected (ARS‐L) and 20 with nonlimb defects with or without limb defects (ARS‐NL). The control group comprised 12,227 subjects with other major malformations. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors.

RESULTS

Multivariate adjusted odds ratios for BWC were increased more than threefold for maternal age < 25 years and maternal education < 12 years, but neither estimate was statistically significant. Corresponding estimates for ARS‐L and ARS‐NL ranged from 1.3 to 1.5 and also were not statistically significant. Cases were less likely to be white non‐Hispanic than controls and the odds ratio for ARS‐NL excluded the null. The multivariate adjusted odds ratio (MVOR) for unplanned pregnancy and BWC was 1.9 (95% confidence interval, 0.5–6.7) compared to 1.2 and 1.0 for ARS‐L and ARS‐NL, respectively. Neither parity nor maternal smoking was associated with any case group. The MVORs for first trimester acetaminophen use in relation to ARS‐L and ARS‐NL risks were 2.1 (1.1–3.9) and 3.4 (1.1–10.3), respectively. Such use was less common among BWC cases (MVOR was 0.4; 0.1–1.4).

CONCLUSIONS

Risk estimates tended to be similar for ARS‐L and ARS‐NL cases but different for BWC cases, suggesting different etiologies. These data suggest that young maternal age, low maternal education, unplanned pregnancy, and non‐white/non‐Hispanic race/ethnicity might increase the risk of BWC in offspring. Increased risks for acetaminophen use should be interpreted with caution because they may be confounded by indication for use. Birth Defects Research (Part A) 67:68–72, 2003. © 2003 Wiley‐Liss, Inc.

     

Fat intake and the risk of gastroschisis

BACKGROUND: Young age has been associated with an increased risk of gastroschisis. It has been suggested that the pathogenesis of gastroschisis may be related to vascular disruption. Nutrients that may be associated with vasoconstriction include dietary fat and its subtypes. The objective of this study was to examine the association between dietary fats and gastroschisis and whether maternal age modified this association. METHODS: Data came from the National Birth Defects Prevention Study (NBDPS), which included 304 isolated gastroschisis cases and 3313 controls. Dietary intake in the year prior to conception was ascertained using a food frequency questionnaire, and included total, saturated, monosaturated, and polyunsaturated fat and cholesterol. Unconditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for confounders. Age and smoking were tested as effect modifiers. RESULTS: Higher mean intakes of total energy, total fat, and cholesterol as well as the subtypes of fats were found for gastroschisis cases compared to controls. Cases were more likely to be in the middle (adjusted OR [AOR], 1.3; 95% CI, 0.9-1.9) and highest (AOR, 1.2; 95% CI, 0.8-1.7) tertile of total fat intake compared to controls. This pattern was also true for saturated fat intake. No association was found for mono or polyunsaturated fat. Cases were less likely to be in the middle (AOR, 0.6; 95% CI, 0.4-0.9) and highest (AOR, 0.8; 95% CI, 0.6-1.2) tertiles for cholesterol. There was no evidence of effect modification. CONCLUSIONS: A possible weak effect of increased risk of gastroschisis associated with higher intakes of total fat or saturated fat was found in the NBDPS; however, this did not help to explain why younger aged women are at greater risk of having an infant with this type of birth defect.     

Prevalence and characteristics of sleep apnoea in patients with stable heart failure: Results from a heart failure clinic

Background

There is much interest in the possibility that perinatal factors may influence the risk of disease in later life. We investigated the influence of maternal and perinatal factors on subsequent hospital admission for asthma in children.

Methods

Analysis of data from the Oxford record linkage study (ORLS) to generate a retrospective cohort of 248 612 records of births between 1970 and 1989, with follow-up to records of subsequent hospital admission for 4 017 children with asthma up to 1999.

Results

Univariate analysis showed significant associations between an increased risk of admission for asthma and later years of birth (reflecting the increase in asthma in the 1970s and 1980s), low social class, asthma in the mother, unmarried mothers, maternal smoking in pregnancy, subsequent births compared with first-born, male sex, low birth weight, short gestational age, caesarean delivery, forceps delivery and not being breastfed. Multivariate analysis, identifying each risk factor that had a significant effect independently of other risk factors, confirmed associations with maternal asthma (odds ratio (OR) 3.1, 95% confidence interval 2.7-3.6), male sex (versus female, 1.8, 1.7-2.0), low birth weight (1000-2999 g versus 3000-3999 g, 1.2, 1.1-1.3), maternal smoking (1.1, 1.0-1.3) and delivery by caesarean section (1.2; 1.0-1.3). In those first admitted with asthma under two years old, there were associations with having siblings (e.g. second child compared with first-born, OR 1.3, 1.0-1.7) and short gestational age (24-37 weeks versus 38-41 weeks, 1.6, 1.2-2.2). Multivariate analysis confined to those admitted with asthma aged six years or more, showed associations with maternal asthma (OR 3.8, 3.1-4.7), age of mother (under 25 versus 25-34 at birth, OR 1.16, 1.03-1.31; over 35 versus 25-34, OR 1.4, 1.1-1.7); high social class was protective (1 and 2, compared with 3, 0.72; 0.63-0.82). Hospital admission for asthma in people aged over six was more common in males than females (1.4; 1.2-1.5); but, by the teenage years, the sex ratio reversed and admission was more common in females than males.

Conclusion

Several maternal characteristics and perinatal factors are associated with an elevated risk of hospital admission for asthma in the child in later life.     

Cell-type-specific activation of c-Jun N-terminal kinase by salicylates

Salicylates inhibit signaling by tumor necrosis factor (TNF), including TNF-induced activation of mitogen-activated protein kinases (MAPKs). On the other hand, we recently showed that in normal human diploid fibroblasts sodium salicylate (NaSal) elicits activation of p38 MAPK but not activation of c-Jun N-terminal kinase (JNK). Here we show that NaSal treatment of COS-1 or HT-29 cells produced a sustained c-Jun N-terminal kinase (JNK) activation. Activation of JNK or p38 MAPK by NaSal (or aspirin) was not due to a nonspecific hyperosmotic effect because much higher molar concentrations of sorbitol or NaCl were required to produce a similar activation. Three structurally unrelated nonsteroidal antiinflammatory drugs (ibuprofen, acetaminophen, and indomethacin) failed to induce significant activation of JNK or p38 MAPK, suggesting that cyclooxygenase inhibition is not the underlying mechanism whereby salicylates induce p38 MAPK and JNK activation. Activation of JNK and p38 MAPKs may be relevant for some antiinflammatory actions of salicylates.     

Vasoactive exposures, vascular events, and hemifacial microsomia

BACKGROUND: Based on experimental evidence and clinical observations, hemifacial microsomia (HFM) is one of several structural anomalies that are postulated to result from vascular disruption. We collected data in a case-control study to identify whether vasoactive exposures or vascular events during early pregnancy affect the risk of HFM. METHODS: Cases with a diagnosis of HFM were identified at craniofacial centers in 26 cities across the United States and Canada, from 1996 to 2002. Controls were matched to cases by age and pediatrician practice. Mothers of 230 cases and 678 controls were interviewed about pregnancy events and exposures. Case and control mothers were compared for early pregnancy use of vasoactive medications, cigarettes, and alcohol; singleton or multiple gestation; and diabetes, hypertension, or vaginal bleeding in the first half of pregnancy. RESULTS: Odds ratios (ORs) were significantly increased for vasoactive mediation use (OR, 1.9 overall; OR, 4.2 among smokers), multiple gestations (OR, 10.5), and diabetes (OR, 6.0). Vaginal bleeding in the second trimester and heavy alcohol intake were associated with increased risks, but the estimates were based on small numbers and, therefore, are unstable. No associations were observed for cigarette smoking without vasoactive medication use, hypertension, and vaginal bleeding in the first trimester. CONCLUSIONS: The increased risks of HFM associated with vasoactive medication use, multiple gestations, diabetes, and second trimester vaginal bleeding appear collectively to support the hypothesis that vascular disruption is one etiology for HFM, because each of these factors is related to effects on blood vessels.     

Risk for gastroschisis in primigravidity, length of sexual cohabitation, and change in paternity

BACKGROUND: Maternal epidemiologic similarities between gastroschisis and preeclampsia have led to the objective of evaluating the risk for gastroschisis related to primigravidity, change in paternity, and length of cohabitation, considered as risk factors for preeclampsia. METHODS: The subjects were 288 newborns with isolated gastroschisis and 576 normal controls, matched by maternal age. They were ascertained in the Estudio Colaborativo Latino Americano de Malformaciones Congenitas hospital network of 10 South American countries between 1982 and 2005. Epidemiologic variables were compared among controls, between primigravidas and multigravidas, between multigravidas who had and had not changed partners, and between mothers with short and long cohabitation times with their partners. Risks associated with primigravidity, short cohabitation time, and changing paternity, as well as their combinations, were calculated. An eventual interaction between maternal age and the three risk factors was assessed. RESULTS: Only a short cohabitation time showed a significant OR for gastroschisis (OR = 2.36, 95% CI: 1.52-3.66, p < .001), whereas ORs were not significant for primigravidity (OR = 1.40, 95% CI: 0.84-2.35, p = .192) nor for changing paternity (OR = 1.20, 95% CI: 0.49-3.10, p = .752). The risk was highest for multigravidas who had changed partners (OR = 8.71, 95% CI: 2.93-21.12, p < .001), followed by multigravidas who had not changed partners (OR = 3.99, 95% CI: 1.07-15.43, p = .049), and by primigravidas (OR = 3.02, 95% CI: 1.58-5.76, p = .001), all having cohabitated for a short time. Maternal age did not modify these risks. CONCLUSIONS: Three groups at risk for a child with gastroschisis were identified, all having in common a short cohabitation time. Antigenic or "modern" lifestyle-related factors might be involved in the origin of gastroschisis.     

Early pregnancy agricultural pesticide exposures and risk of gastroschisis among offspring in the San Joaquin Valley of California

Background: Prevalence of gastroschisis has inexplicably been increasing over the past few decades. Our intent was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis. Methods: We used population‐based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California ( ). Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects. Results: Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1–5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking. Conclusion: Our study rigorously adds to the scant literature on this topic. Our a priori expectation was that we would observe certain pesticide compounds to be particularly associated with young age owing to the disproportionate risk observed for young women to have offspring with gastroschisis. We did not observe an exposure profile unique to young women. Birth Defects Research (Part A), 100:686–694, 2014. © 2014 Wiley Periodicals, Inc.     

Epidemiology of gastroschisis in metropolitan Atlanta, 1968 through 2000

BACKGROUND: An increase in the rate of gastroschisis has been documented by birth defects surveillance systems in the United States and in other countries. This study sought to evaluate historical trends in the rate of gastroschisis in Atlanta, Georgia, and to describe the epidemiology of gastroschisis over 33 years. METHODS: Gastroschisis cases were identified through the Metropolitan Atlanta Congenital Defects Program (MACDP) from 1968 through 2000. Poisson regression techniques were used to evaluate trends over time. Data on covariates were compared for three maternal age groups (< or =19, 20-24, and > or =25 years). RESULTS: From 1968 through 1975, the rate of gastroschisis was stable at 0.8 per 10,000 births. After 1975, the rate of gastroschisis was 2.3 per 10,000 births with no significant increase observed from 1976 through 2000. The rate of gastroschisis was six times higher among teenage mothers compared with mothers > or =25 years of age. Affected infants born to teenage mothers were less likely to be born to Black mothers compared to White mothers (rate ratio [RR], 0.4; 95% confidence interval [CI], 0.2-0.6). This was also true for mothers 20-24 years of age (RR, 0.5; 95% CI, 0.3-0.8) but not for mothers 25 years of age or older (RR, 1.6; 95% CI, 0.9-2.7). CONCLUSIONS: An increase in the rate of gastroschisis was observed in the mid-1970s, but no temporal trend has been observed since that time. In light of recent reports of an increasing prevalence of gastroschisis in the United States, continued monitoring of this birth defect is warranted.     

Periconceptional health and lifestyle factors of both parents affect the risk of live-born children with orofacial clefts

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO) are orofacial clefts and have a multifactorial etiology. The identification of amendable parental risk factors may contribute to a reduced occurrence of these malformations in the future. METHODS: Standardized demographic and periconceptional exposure data from 284 parents of a child with CL/P, 66 parents of a child with a CPO and 222 parents of a child without congenital malformations were collected at approximately 24 months after the periconceptional period of the index child. Univariate and multivariate logistic regression analyses were used to estimate relative risks by odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Univariate results suggest that low parental education, periconceptional maternal medication use and illnesses, paternal smoking, and first-trimester maternal common cold increased CL/P risk. Pregnancy planning and periconceptional folic acid supplementation, however, reduced CL/P risk by approximately 50% (OR, 0.5; 95% CI, 0.3-0.8) and 40% (OR, 0.6; 95% CI, 0.4-0.9), respectively. Mostly comparable results were obtained for CPO. Being a boy (OR, 2.0; 95% CI, 1.4-3.0), folic acid supplementation (OR, 0.6; 95% CI, 0.4-0.9), and low paternal education (OR, 1.6; 95% CI, 1.0-2.3) mainly determined CL/P in the multivariate analyses, compared to low paternal (OR, 4.5; 95% CI, 2.1-9.4) and maternal medication use (OR, 2.0; 95% CI, 1.0-4.0) for CPO. CONCLUSIONS: Preconceptional counseling for orofacial cleft risk assessment should pay attention to maternal medication use, periconceptional folic acid supplementation, and exposures of the father. These determinants can be amended, thereby modifying orofacial cleft risk.     

Gastroschisis, low maternal age, and fetal morbidity outcomes

OBJECTIVE: To determine if the risk for fetal growth inhibition among gastroschisis-afflicted fetuses is heightened among younger gravidas (teen mothers). METHOD: This was a retrospective cohort study on live-born infants with isolated gastroschisis delivered in New York State from 1983 through 1999. We compared infants of mature (>20 years) mothers with those of younger (<20 years) mothers with respect to the following indices of fetal morbidity outcomes: low birth weight and very low birth weight, preterm and very pre-term, and small for gestational age. We used adjusted odds ratios to approximate relative risks. RESULTS: A total of 368 infants with isolated gastroschisis were analyzed. The two groups differed in terms of mean gestational age at delivery [Mean + standard deviation(SD) for infants with gastroschisis born to mature mothers = 37.2 weeks +/- 2.8 versus 36.3 weeks + 3.6 for those of teenage mothers(p = 0.01)], as well as mean birth weight [mean birth weight +/- SD for infants with gastroschisis born to mature mothers = 2562.4 grams +548.8 versus 2367.9 grams +/- 645.2 for those of younger mothers (p = 0.004)]. Infants of teen mothers were about twice as likely to be of low birth weight (OR = 1.70; 95% CI = 1.05-2.77) and about three times as likely to be born very preterm when compared to those of mature mothers (OR = 2.80; 95% Cl = 1.02-8.00). No significant differences were observed with respect to very low birth weight, pre-term and small for gestational age. CONCLUSION: Low maternal age appears to be a risk factor for low birth weight and very preterm birth among gastroschisis-affected fetuses. This information is potentially useful for planning by care providers and in counseling affected parents.     

Resistance exercise and cyclooxygenase (COX) expression in human skeletal muscle: implications for COX-inhibiting drugs and protein synthesis

We have shown that ibuprofen and acetaminophen block cyclooxygenase (COX) synthesis of prostaglandin PGF(2alpha) and the muscle protein synthesis increase following resistance exercise. Confusingly, these two drugs are purported to work through different mechanisms, with acetaminophen apparently unable to block COX and ibuprofen able to nonspecifically block COX-1 and COX-2. A recently discovered intron-retaining COX, now known to have three variants, has been shown to be sensitive to both drugs. We measured the expression patterns and levels of the intron 1-retaining COX-1 variants (-1b1, -1b2, and -1b3), COX-1, and COX-2 at rest and following resistance exercise to help elucidate the COX through which PGF(2alpha), ibuprofen, and acetaminophen regulate muscle protein synthesis. Skeletal muscle biopsy samples were taken from 16 individuals (8M, 8F) before, 4, and 24 h after a bout of resistance exercise and analyzed using real-time RT-PCR. Relatively few individuals expressed the intron 1-retaining COX-1b variants (COX-1b1, -1b2, and -1b3) at any time point, and when expressed, these variants were in very low abundance. COX-1 was the most abundant COX mRNA before exercise and remained unchanged (P > 0.05) following exercise. COX-2 was not expressed before exercise, but increased significantly (P < 0.05) at 4 and 24 h after exercise. The inconsistent and low levels of expression of the intron 1-retaining COX-1 variants suggest that these variants are not likely responsible for the inhibition of PGF(2alpha) production and skeletal muscle protein synthesis after resistance exercise by ibuprofen and acetaminophen. Skeletal muscle-specific inhibition of COX-1 or COX-2 by these drugs should be considered.     

Paternal occupational exposures and the risk of Down syndrome.

An exploratory case-control study of paternal occupation as a risk factor for Down syndrome was conducted. With the use of the British Columbia Health Surveillance Registry, 1,008 cases of live-born Down syndrome were identified for the period 1952-73. Two controls were matched to each case by using the birth files of British Columbia. Paternal occupation was obtained from the birth notice. Elevated maternal age-adjusted relative risks of Down syndrome were found for fathers employed as janitors (odds ratio [OR] = 3.26; 95% confidence interval [C.I.] = 1.02-10.44); mechanics (OR = 3.27; C.I. = 1.57-6.80); farm managers/workers (OR = 2.03; C.I. = 1.25-3.03); material-moving equipment operators (OR = 1.88; C.I. = 0.93-3.82); food processors (OR = 1.79; C.I. = 0.96-3.31); sheet-metal workers, iron workers, and other metalworkers (OR = 1.57; C.I. = 0.92-2.69); and sawmill workers (OR = 1.43; C.I. = 0.90-2.66). This large study provides new leads for further evaluation of the role of paternal exposures in the etiology of Down syndrome.     

Biosynthesis of amphetamine analogs in plants

Amphetamine analogs are produced by plants in the genus Ephedra and by Catha edulis, and include the widely used decongestants and appetite suppressants pseudoephedrine and ephedrine. A combination of yeast (Candida utilis or Saccharomyces cerevisiae) fermentation and subsequent chemical modification is used for the commercial production of these compounds. The availability of certain plant biosynthetic genes would facilitate the engineering of yeast strains capable of de novo pseudoephedrine and ephedrine biosynthesis. Chemical synthesis has yielded amphetamine analogs with myriad functional group substitutions and diverse pharmacological properties. The isolation of enzymes with the serendipitous capacity to accept novel substrates could allow the production of substituted amphetamines in synthetic biosystems. Here, we review the biology, biochemistry and biotechnological potential of amphetamine analogs in plants.     

Maternal cigarette smoking, Down syndrome in live births, and infant race.

Previous studies have suggested that maternal smoking is negatively associated with a Down syndrome live birth. We analyzed the data of the U.S. Perinatal Collaborative Study in a search for racial variation in Down syndrome risk factors. There were 22 cases in 25,346 live births to smoking mothers (4/10,780 blacks, 18/13,320 whites, and 0/1,246 other races) and 42/29,130 live births to nonsmoking mothers (24/14,665 blacks, 14/11,694 whites, and 4/2,771 others). The crude overall rates per 1,000 live births were 0.4 in black smokers and 1.6 in black nonsmokers but 1.4 in white smokers and 1.2 in white non-smokers. Adjusted for maternal age, the summary relative risk for a Down syndrome live birth to a smoking mother was 0.2 in blacks (95% interval 0.1-0.7) but 1.2 in whites (95% interval 0.6-2.5). Stratification on variables associated with socioeconomic status or gestational age at time of entry into the study did not alter the racial difference. A comparison of smokers with those who never smoked revealed essentially the same trends. Among all nonsmokers the ratio of the maternal age-adjusted risks for a Down syndrome live birth in whites compared with blacks was 0.7 (95% interval 0.3-1.3), and among all smokers this ratio was 3.6 (95% interval 1.3-9.9). If the results are not attributable to statistical fluctuation or undetected confounding, then differences in the probability of intrauterine survival of the Down syndrome fetus would appear to be one plausible explanation for the difference.