Brief Critical Reviews May 7996: 146-152

Maternal Obesity Increases Congenital Malformations

There has been growing evidence that maternal obesity is associated with an increased risk of congenital malformations, particularly of neural tube defects. Two new studies confirm this rela- tionship and indicate that it is independent of pos- sible covariant confounders such as maternal age, socioeconomic status, education, smoking, and vitamin intake, including folic acid. There is a suggestion that folic acid loses its protective benefit in overweight and obese mothers. These new findings add to a long list of obstetric mor- bidities, and show a steep gradient with increas- ing maternal fatness and point to the urgent need to prevent excess weight gain in young women.

Almost forty years ago Kalter and Warkany re- viewed a substantial literature associating maternal undernutrition with an increased occurrence of con- genital malformations in mammals.’ There has since been intensive research in this field, which has led, for instance, to the wide acceptance that preconcep- tional supplementation with folic acid is effective in reducing the incidence of neural tube defects (NTDs) in newborns.2 More recently, there have been reports that overnutrition, as evidenced by ma- ternal obesity, may also cause congenital defects, particularly of the central nervous system (CNS).

An early clue emerged from a retrospective case-controlled study of 833 birth defects occurring in South Wales between 1964 and 1966.3 In line with the interests of this era, the analysis concen- trated on poor maternal diet as a possible etiologic factor and reported that affected cases had a higher frequency of “not balanced” and “doubtful” diet quality during the first trimester of pregnancy. This was most pronounced for CNS defects, especially anencephaly. It was also noted that mothers with anencephalic babies were significantly heavier than controls (p < 0.05).

Twenty years later, in 1990, Naeye published a more convincing analysis based on 2504 major con- genital malformations (not subdivided by type) oc- curring in 56,000 pregnancies in the 1959-66 Col- laborative Perinatal Study conducted in hospitals

This review was prepared by Andrew Prentice, Ph.D., and Gail Goldberg, B.Sc., at the MRC Dunn Clinical Nutrition Centre, Hills Road, Cambridge, UK.

from various regions of the United state^.^ When analyzed according to maternal body mass index (BMI), congenital malformations were significantly more common in mildly overweight (BMI 25-30 kg/m2; p < 0.001) and in obese women (BMI > 30 kg/m2; p < 0.001) relative to thin women as the referent group. This correlation between maternal fatness and birth defects was independent of other factors in the study known to be associated with congenital malformations, specifically advanced maternal age, cigarette smoking, and twins. The 40% increased risk for all types of malformations in Naeye’s analysis might have concealed stronger associations with CNS defects.

In 1994 Waller and colleagues also reported an association between maternal obesity and malfor- mat ion~.~ Using a case-controlled study of 836 ma- jor birth defects occurring in California and Illinois, they showed a significantly increased risk of NTDs in obese (BMI 31-37 kg/m2) and severely obese (BMI > 38 kg/m2) women (odds ratios [OR] 1.8 [95% CI 1.0-3.21 and 3.0 [CI 1.2-7.71 respective- ly). For all women with BMI > 31 kg/m2, the crude OR for NTDs was 2.1 (CI 1.3-3.4) decreasing to 1.8 (CI 1.1-3.0) after adjustment for age, race, mother’s education, and family income.

This report was challenged by Haddow and Pal- omaki who referred to other data sets that had been collected in the course of prenatal screening for open NTDs and that failed to record significantly raised mean or median maternal body weights in affected pregnancies.6 However, such an approach has been dismissed as being insufficiently sensitive to detect effects at the extremes of body eight.^

A U.S. study based on 307 affected cases and 2755 controls has reported a significantly increased OR for spina bifida and anencephaly in obese wom- en (OR = 2.2, CI 1.0-4.8) after adjusting for ma- ternal age, education, smoking status, alcohol use, and vitamin use.8

Most recently, two papers have been published side-by-side in the Journal of the American Medical Association. Shaw and colleagues report data from the California Birth Defects Monitoring Program? This was a population-based case-control study of 538 cases of NTDs and 539 nonaffected controls. Table 1 shows that risk estimates increased with in- creasing maternal BMI. The authors then divided the sample into obese and nonobese women using

146 Nutrition Reviews, Vol. 54, No. 5

Table 1. Risk of NTD-affected Pregnancies Among Women by Maternal BMI

Case Control BMI Mothers Mothers Odds Ratio (kg/m2) No No (95% CI) <16 0 2 0 16-17 17 28 0.7 (0.4-1.3) 18 33 34 1 . 1 (0.6-1.8) 19-27 35 1 392 Reference 28-30 53 31 1.9 (1.2-3.1) 3 1-37 32 24 1.5 (0.8-2.7) >38 14 6 2.6 (0.9-7.7)

OR = odds ratio; CI = confidence interval. Adapted from Shaw et al.9

the Institute of Medicine's cutoff of 29 kg/m2. On this basis the OR for NTDs in obese women was 1.9 (CI 1.3-2.9). Simultaneous adjustment for ma- ternal age, education, gravidity, vitamin use, and al- cohol use did not alter the OR.

Table 2 reveals a tendency for the association between obesity and NTDs to be stronger for wom- en who took periconceptional vitamins (including folic acid) and who did not diet before pregnancy or in the first trimester. Thus, lack of folic acid use or an excess of restrictive dieting was not the ex- planation for the increased NTD risk among women with a BMI > 29 kg/m2. In fact, the opposite was observed. Further analysis of total energy intake, percent of energy from fat, and vitamin and zinc use revealed that the obesity-NTD association did not appear to be related to these dietary variables.

Exploration of other potential explanations (pre- existent or gestational diabetes, high blood pressure, use of diet pills, low pregnancy weight gain, known NTD syndromes, and previous history of NTD pregnancies) did not alter the OR of 1.9 observed overall.

The other JAMA paper, by Werler and col- leagues, compared 604 NTD cases with 1658 in- fants with non-NTD major malformations.1° For most of these cases, maternal height was not ascer- tained so the analysis was performed using weight alone. Multivariate relative risks (adjusted for ma- ternal age, education, income, liveborn versus aborted, and daily folate intake) increased from 1.9 (CI 1.2-2.9) for women weighing 80-89 kg to 4.0 (CI 1.6-9.9) for women weighing 100 kg or more (p C 0.001 for trend). Similar trends were observed when the sample was subdivided into women with estimated periconceptional folate intakes above and below the recommended intake of 400 &day. In normal-weight women, those consuming high folate intakes had a relative risk of NTDs of 0.6 (CI 0.4- 0 . Q in line with previous findings concerning the protective effects of folic acid. However, in women

Table 2. Risk Estimates for NTDs in Lean vs Obese Women by Category of Potential Covariates and Case Phenotypes

Odds Ratio (95% CI)

Overall 1.9 (1.3-2.9) Used vitamin containing folic acid in

3 mo before to 3 mo after concep- tion

No 1.9 (0.9-3.9) Yes 3.4 (1.1-11.4) Began use after 1st trimester 1.7 ( 1 .O-3.0)

Diet to lose weight 3 mo before con- ception

No 2.2 (1.4-3.5) Yes 1 . 1 (0.4-2.9)

Diet to lose weight in 1st trimester No 1.9 (1.3-2.9) Yes 1.3 (0.3-6.6)

Case phenotype Anencephaly 1.4 (0.9-2.4) Spina bifida 2.2 (1.4-3.3) Other 4.9 (2.0-12.7)

CI = confidence interval. Adapted from Shaw et al.9

weighing more than 70 kg, folate had no significant protective effect. In a small subsample of 88 af- fected cases collected since 1992, maternal heights were recorded (allowing calculation of BMI) and 93 unaffected controls were incorporated. The analysis combined the unaffected babies and the non-NTD malformations as the control group. This subset also revealed increased risks of NTD with increasing fat- ness: relative risks were 1.7 (CI 0.9-3.2), 1.9 (CI 0.9-4.2), and 2.8 (CI 1.1-6.7) for BMI 24.0-27.9, 28.0-3 1.9 and >32.0 kg/m2, respectively.

In view of these latest reports there now seems to be strong evidence that maternal obesity is a risk factor for congenital malformations involving the CNS. The association is not readily explained by any known social, dietary, or medical confounders and appears to be quite independent of folate intake, suggesting that it might arise from a specific patho- physiologic disturbance of obesity. The many met- abolic and endocrine changes associated with obe- sity provide numerous potential candidates. Of par- ticular concern is the finding that folic acid seems to lose its protective effect in overweight women.I0 This finding must be treated as provisional but is in line with a clinical trial of zinc supplementation in which efficacy in reducing low birth weight infants was achieved only in nonobese women."

Although the increased risk of NTDs in obesity is rather modest (about double), this may become

Nutrition Reviews, Vol. 54, No. 5 147

Table 3. Perinatal Mortality Rates with Increasing Maternal Pregravid Weight According to Categories of Additional Risk Factors

Pregnancy Risk Factors Thin Normal Overweight Obese

Maternal Age 10-18 years 7.8 7.0 3.6" 10.5d Age 35-50 years 1.4 4.8" 12.2" 23.4' Smoking 18.4 21.0 22.3d 39.3" Low socioeconomic status 10.2 11.1 14.7b 27.8" Diabetes 1.2 1.6 1.4 11.1" Low pregnancy weight gain 12.9 5.6" 1o.w 13.6 Hypertensive disorders 4.9 4.8 5.2 10.9" Black 16.2 2 1.4" 30.3" 38.5"

Fetal Preterm births 30.4 34.4d 40.6" 79.7"

Born at 24-30 weeks 16.2 18.7d 22.7" 46.2" Born at 31-37 weeks 14.2 15.7 1 7.gd 33.5"

Full-term births 6.9 13.9" 15.4" 41.2" Major congenital defects 4.8 7.8" 8.6" 14.4" Birth trauma - - - 0 Twins 2.2 3.4d 3.9' 6.5"

Neonatal Respiratory distress 5.4 4.2 3.8 9.6b

All cases 37.3 48.3" 55.9" 120.9"

Perinatal mortality = fetal plus neonatal deathdl000 births. Thin = <20 kg/m2; Normal = 20-24 kg/m2; Overweight = 25-30 kg/m2; Obese = >30 kg/m2. Chi-squared test: a = p < 0.001; b = p < 0.005; c = p < 0.02; d = p < 0.05. Adapted fron N a e ~ e . ~

an increasingly important issue as obesity rates es- calate in affluent societies. Latest estimates from the United States indicate a national average prevalence of obesity of 33% in women and rates close to 50% in certain ethnic and regional subgroups.I2 In the United Kingdom, obesity rates have doubled in a single decade.I3

This latest evidence implicating obesity in the causation of birth defects adds to a long list of other detrimental effects of excess fatness in pregnancy. Naeye's analysis of the Collaborative Perinatal Study provides the best data. Table 3 shows that perinatal mortality was heavily influenced by ma- ternal fatness almost irrespective of other risk fac- tors. For instance, in older gravidas, perinatal mor- tality rates were 1.4/1000 in thin women and 23.4/1000 in obese women, a 16-fold increase. For women with diabetes mellitus, perinatal mortality was 1.2/1000 in thin women and 11.1/1000 in obese women. For preterm births the perinatal mortality rates were 30.4 and 79.7/1000, and for full-term births they were 6.9 and 41.2/1000 for thin and obese women respectively. These trends arose from an increasing frequency and an increasing case fa- tality rate for the various risk factors. The obser- vation that preterm babies born to obese women had lower survival chances had been noted in a previous study from Cambridge, UK.I4 In Naeye's analysis,

the only risk factor that did not interact unfavorably with obesity was low pregnancy weight gain. How- ever, even here the obese women showed higher perinatal mortality rates than the normal women, and the effect only appears neutral when referenced to the thin women in whom low pregnancy weight gain is, not surprisingly, a particular risk factor.

Considering all cases, irrespective of other risk factors, the perinatal mortality rates rose progres- sively from 37.3 to 120.9 per thousand. Calculations of attributable risk showed that preterm birth was responsible for nearly half of this mortality increase. The difference in preterm births between thin and obese women was 80% attributable to acute cho- rioamnionitis and twins.

In addition to these effects on perinatal mortal- ity, there are numerous other associated morbidities and obstetric complications associated with obesi- ty.I5-l7 A recent publication from France provides a compelling example of just how steep the increasing risk curve is for pregnancy complications and gives an indication of the consequent drain on health ser- vice resources (Table 4).18 For example, there was a ninefold gradient for hypertension, a 12-fold gra- dient for toxemia, a 24-fold gradient for gestational diabetes, a fivefold gradient for cesarean section, a 24-fold gradient for outpatient hospitalization, a 14-fold gradient for inpatient hospitalization, and

148 Nutrition Reviews, Vol. 54, No. 5

Table 4. Obesity and incidence of Maternal Complications During Pregnancy

Massively Normal Overweight Obese Obese p value

Number of subjects 54 48 34 30 Hypertension (70) 9.3 33.3" 54.6" 79.3" <0.0001 Toxemia (%) 3.7 17.8 30.3" 42.9" <0.0001 Gestational diabetes (%) 1.9 12.3 39.4" 44.8" <0.0001 Insulin (% patients) 0 2.1 12.1" 20.7" <0.001 Insulin (% diabetics) 0 16.8 30.7" 46.2" <0.001 Urinary infection (%) 16.7 8.7 29.0 37.5 <0.02 Preterm labor (%) 14.8 13.0 22.6 28.0 NS Cesarian section (7') 9.3 16.7 15.1 42.9" < o m 2 1st cesarian section (%) 7.4 10.4 5.9 33.3" <0.006

Hospitalization 45.5" 61.5" <0:0001 Outpatients (%) 7.4 33.3"

Inpatients (%) 9.3 33.3" 36.4" 66.6" <0.0001

Outpatients (days) 0.2 1.5" 2.9" 4.7" <O.OOol Inpatients (days) 0.6 2.9" 3.7" 8.6" <O.OOol

Hospitalization

Overall costb 5.7 9.6" 11.0" 18.4" <O.OOo 1

Normal = 18-24.9 kg/m2; Overweight = 25-29.9 kg/m2; Obese = 30-34.9 kg/m2; Massively obese = >35 kg/m2. a = significantly different from normal weight group. b = cost assessed as equivalent outpatient hospitalization. Adapted from Galtier-Dereure et a1.I8

more than a 3-fold gradient in overall costs. These data are supported and augmented by a very recent analysis from Miami in which strong gradients were observed for many of the same factors and for ad- ditional factors such as thromboembolic disease, chorioamnionitis, wound infection, and need for convalescent and intensive care.I9

This is a disturbing litany of risks, and all in- dicators point to the situation becoming much worse in the future as the prevalence of obesity continues to rise. Naeye has pointed out that for decades there has been little progress in preventing premature births, partly because the biggest contributor, acute chorioamnionitis, cannot currently be p re~en ted .~ The prevalence of diabetes and gestational diabetes is rising unchecked. Furthermore, older gravidas are becoming more frequent as many women delay the start of a family, and dizygotic twins are increasing in frequency as the result of widespread use of fer- tility drugs. Each of these interact with maternal obesity to produce high-risk pregnancies. The pre- vention of excess weight gain in adolescents and young women would be the most effective possible intervention. Strategies to achieve this are urgently required and should command considerable fund- ing, since the economic benefits in reducing the bur- den of illness both during and outside pregnancy would be substantial.

1. Kalter H, Warkany J. Experimental production of con-

genitql malformations in mammals by metabolic pro- cedures. Physiol Rev 1959;39:69-82

2. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991 ;338:131-7

3. Richards IDG. Congenital malformations and envi- ronmental influences in pregnancy. Brit J Prev SOC Med 1969;23:218-25

4. Naeye RL. Maternal body weight and pregnancy out- come. Am J Clin Nutr 1990;52:273-79

5. Waller DK, Mills JL, Simpson JL, Cunningham GC, Conley MR, Lassman MR, et al. Are obese women at higher risk for producing malformed offspring? Am J Obstet Gynecol 1994;170:541-8

6. Haddow JE, Palomaki GE. Is maternal obesity a risk factor for open neural tube defects? Am J Obstet Gy- necol 1995; 172:245-6

7. Waller D, Mills JL, Rhoads GG, Simpson JL, Cun- ningham GC. Is maternal obesity a risk factor for open neural tube defects? (Reply). Am J Obstet Gy- necol 1995;172:246-7

8. Watkins M, Scanlon K, Mulinare J, Khoury M. Is ma- ternal obesity a risk factor for anencephaly and spina bifida? Am J Epidemiol 1994;139:SI 1

9. Shaw GM, Velie EM, Schaffer D. Risk of neural tube defect-affected pregnancies among obese women. J Am Med Assoc 1996;275: 1093-6

10. Werler MM, Louik C, Shapiro S, Mitchell AA. Pre- pregnant weight in relation to risk of neural tube de- fects. J Am Med Assoc 1996;275:1089-92

11. Goldenberg RL, Tamura T, Neggers Y, et al. The ef- fect of zinc supplementation on pregnancy outcome. J Am Med Assoc 1995;274:463-8

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12. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson 16. Gross T, Sokol RJ, King KC. Obesity in pregnancy: CL. Increasing prevalence of overweight among US risks and outcome. Obstet Gynecol 1980;56:446-50 adults: The National Health and Nutrition Examina- 17. Abrams BF, Parker J. Overweight and pregnancy tion Surveys 1960 to 1991. J Am Med Assoc complications. Int J Obesity 1987;12:293-303 1994;272:205-11 18. Galtier-Dereure F, Montpeyroux F, Boulot P, Bringer

J, Jaffiol C. Weight excess before pregnancy: com- 13. Prentice AM, Jebb SA. Obesity in Britain: gluttony or sloth? Br Med J 1995;311:437-9

plications and cost. Int J Obesity 19953 9:443-8 14. Lucas A, Morley R, Cole TJ. Maternal fatness and viability of preterm infants. Med J 1988;296: 19. Edwards LE, Hellerstedt WL, Alton IR, Story M, Hi- 1495-7 mes JH. Pregnancy complications and birth out-

15. Garbaciak JA, Richter MD, Miller S, Barton JJ. Ma- comes in obese and normal-weight women: effects ternal weight and pregnancy complications. Am J of gestational weight change. Obstet Gynecol Obstet Gynecol 1985;152:23845 1996;87:389-94

The Mechanism of Uptake of Ascorbic Acid into Osteoblasts and Leukocytes

Ascorbic acid is taken up into osteoblast cells by a saturable, stereospecific, Na+-dependent trans- porter, accumulating ascorbic acid to a level 100- fold that in the medium. The ascorbic acid uptake rate correlated with intracellular hydroxyproline synthesis. A second, distinct mechanism has also been described for accumulation of ascorbic acid into neutrophils and myeloid leukemia cells. This appears to be Na+-independent and relies on the glucose transporter GLUT1 to ferry dehydroas- corbic acid (DHA) into cells and then to trap it as ascorbic acid to a high concentration.

~~ ~

The mechanism of transport of L-ascorbic acid (AA) into cells has recently been studied intensively be- cause of, among other reasons, the high level of accumulation of AA into cells compared to the sur- rounding medium.

Two different transporters appear to exist-one for uptake into connective tissue cells such as os- teoblasts and fibroblasts (Na+-dependent transport) and the second, which is less widespread, for uptake into leukocytes (neutrophils and myeloid leukemia cells "a+-independent transport]).

The precise cofactor role of AA in the hydrox- ylation of peptide-bound proline to hydroxyproline in collagen in connective tissue has been known for decades. More recently, Franceschi and Iyer' dis- covered that AA-dependent formation of the colla- gen matrix itself is essential for induction of differ- entiation of osteoblast cells.

The mechanism of uptake and accumulation of AA into mouse preosteoblast cells in culture has

This review was prepared by George Wolf, D.Phil., at the Department of Nutritional Sciences, University of California at Berkeley, Berkeley, CA 94720-31 04.

been explored by Franceschi et a1.* Uptake of la- beled AA was Na+-dependent, suppressed by an ex- cess of unlabeled AA, and inhibited by anion trans- port inhibitors such as sulfinpyrazone. There was a rapid rise in intracellular AA within minutes and after 5-10 hours, concentrations were as high as 9- 11 mM. Efflux also was Na+-dependent and sulfin- pyrazone sensitive. The uptake was found to be stereospecific, since D-isoascorbic acid was taken up 20-fold less than AA. Kinetic experiments showed the uptake to be saturable, with a K, of 30 pM.

When the cells were prelabeled with ['Hlproline, hydroxyproline synthesis in collagen was detected 30 minutes after incubation with 100 pM AA, and rose steeply for 10 hours. In short- term incubations (5 hours) of preosteoblasts with 20 pM AA, intracellular AA levels showed complete correlation with hydroxyproline synthesis; both were Na+-dependent and inhibited by sulfinpyra- zone, the cell-surface inhibitor of anion transport. Because the K, of the purified prolyl hydroxylase is 360 P M , ~ the transporter that takes up AA from the medium at 100 pM (the physiologic concentra- tion of AA in serum) is essential if the intracellular accumulation of AA of 300-400 pM is to be achieved. Below this concentration, proline hydrox- ylation and collagen synthesis would be insignifi- cant. Long-term incubation (6 days) was found to result not only in AA accumulation, stereospecific for the L-isomer, and stimulation of hydroxyproline synthesis, but also in the induction of alkaline phos- phatase activity. This enzyme is a marker for dif- ferentiation of the preosteoblasts in response to the deposition of the collagen matrix.'

Leukocytes have been reported to take up AA in the oxidized form as dehydroascorbic acid (DHA) by means of the glucose transporter." This is not the case for preosteoblasts.2 Uptake of [14C]AA was not in-

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