Lactose handling by women with lactose malabsorption is improved during pregnancy

Clin Invest Med 1996; 19 (6): 416-26.

[résumé]

Drs. Salomon and Szilagyi are supported by a grant from the Dairy Bureau of Canada, and Dr. Seidman is the recipient of a Chercheur boursier clinicien Research Scholarship Award from the Fonds de la recherche en santé du Québec.

(Original manuscript submitted Dec. 4, 1995; received in revised form May 17, 1996; accepted May 28, 1996)

Paper reprints may be obtained from: Dr. Ernest Seidman, Department of Gastroenterology, Hôpital Sainte-Justine, #A-714, 3175 Côte Sainte-Catherine, Montreal QC H3T 1C5; tel 514 345-4626; fax 514 345-4999

• Abstract
• Résumé
• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgements
• References

Design: Prospective study of lactose intolerance among pregnant women with and without lactose malabsorption.

Setting: Gastroenterology service of the Sir Mortimer B. Davis­Jewish General Hospital, Montreal.

Patients: Thirty-three pregnant women, of whom 18 had lactose malabsorption, 12 did not and 3 were excluded.

Outcome measures: Lactose breath hydrogen (BH2) concentration after ingestion of lactose or lactulose; comparison before and after delivery of area under the curve (AUC) for lactose, oral­cecal transit time (OCTT) for lactulose, lactose-BH2-derived transit time and estimated dietary lactose consumption.

Results: After weaning (at a median time of 9 months after delivery), 28 of the women returned for follow-up. Of the 12 who could absorb lactose before delivery, 4 could no longer absorb lactose. Of the other 16 women, lactose intolerance worsened in 12, remained the same in 2 and improved in 2. The AUC was greater (p < 0.005), the maximal BH2 concentration was higher (p = 0.004) and the number of women whose BH2 concentration peaked was fewer (p < 0.025) post partum than before delivery. The women's symptoms during and after lactose BH2 tests were also greater post partum. The OCTT (based on the lactulose BH2 test) was shorter post partum (p = 0.001). Transit time derived from lactose BH2 tests was also shorter, but not significantly so. The OCTT was not inversely correlated with the change in AUC before and after delivery, but the lactose-BH2-derived transit time was inversely correlated. Pregnant women consumed more lactose before delivery than afterward (p < 0.004).

Conclusions: Women with lactose malabsorption handle lactose better than usual in late pregnancy. Slow intestinal transit and bacterial adaptation to increased lactose intake may be primarily responsible.

Devis : Étude prospective de l'intolérance au lactose chez des femmes enceintes avec et sans malabsorption du lactose.

Cadre : Service de gastroentérologie de Sir Mortimer B. Davis­Jewish General Hospital à Montréal.

Sujets : Trente-trois femmes enceintes avec (n = 18) ou sans malabsorption du lactose (n = 12). Trois sujets furent exclus.

Variables mesurées : Concentration d'hydrogène dans l'haleine après charge en lactose (BH2) après ingestion de lactose ou de lactulose; comparaison avant et après la grossesse de la surface sous la courbe pour le lactose, du temps de transit oro-caecal (TTOC) pour le lactulose, du temps de transit dérivé d'après le lactose-BH2 et conservation estimée de lactose dans la diète.

Résultats : Après sevrage (survenue médiane : 9 mois après l'accouchement), 28 sujets furent réévalués. Parmi les 12 sujets qui absorbaient le lactose avant l'accouchement, 4 ne l'absorbaient plus. Parmi les 16 autres sujets, la tolérance au lactose augmenta (n = 12), resta stationnaire (n = 2), ou s'améliora (n = 2). Dans la période post-partum, il y avait une plus grande surface sous la courbe (p < 0.005), la concentration maximale de BH2 était plus grande (p = 0.004) et le nombre de femmes dont la concentration de BH2 atteint un pic plus petit (p < 0.025) qu'avant l'accouchement. De plus, c'est dans la période post-partum que les symptômes pendant et après les épreuves au lactose BH2 étaient plus marqués. Le TTOC, évalué d'après le test au lactulose BH2, était également plus court mais cette différence n'était pas significative. Il n'y avait pas de corrélation inverse entre le TTOC et la variation dans la surface sous la courbe tant avant qu'après l'accouchement. Par contre, le temps de transit évalué d'après le lactose BH2 était en corrélation inverse avec cette variable. Les femmes enceintes consommèrent plus de lactose avant qu'après l'accouchement (p < 0.004).

Conclusion : Chez les femmes avec malabsorption du lactose, le maniement du lactose se fait mieux en fin de grossesse qu'en temps normal. Ceci pourrait s'expliquer par un temps de transit intestinal plus lent et par une adaptation bactérienne à une ingestion accrue de lactose.

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In humans and animals, the ability to absorb lactose diminishes with age, and the loss of lactase along the upper jejunal mucosa occurs in a mosaic pattern in people with lactose malabsorption.[2­4] Depending on the rate of enzyme loss, people may have different tolerance thresholds.[5] As well, various pathologic conditions can transiently impair lactose absorption.[6,7] In the 1960s and 1970s, when the World Health Organization distributed milk powder to Third World countries, it was observed that increased intake of lactose gradually improved lactose handling.[2] However, it has been clearly established that lactase is not an inducible enzyme in humans.[8] Various mechanisms, including post-translational lactase modification and intestinal bacterial adaptation to a high lactose intake, have been postulated to account for improved lactose handling in certain conditions.[2,9] Recently, prolonged intestinal transit resulting from yogourt consumption has been shown to mitigate symptoms of lactose intolerance.[10]

In pregnancy, the gut appears to be primed to transiently enhance absorption of certain nutrients.[11­14] A study of Guatemalan women followed through pregnancy and post partum found that there was a substantial improvement in lactose handling as pregnancy progressed. The authors felt that this improvement was due to intestinal adaptation.[15] We undertook a prospective study to ascertain whether lactose handling is improved in pregnancy and to determine the mechanisms underlying this adaptation. We examined the possible influence of intestinal transit, hormonal alterations and consumption of dairy products during pregnancy.

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Methods

Patients

Breath hydrogen and blood tests

On the first day, exhaled BH2 concentration was measured after the woman ingested 50 g of lactose in 200 mL of water. On a subsequent day (usually within 24 to 48 hours), the breath test was repeated after ingestion of 10 g of lactulose as a 10% solution in water. BH2 concentration was measured each half hour for lactose and each 10 minutes for lactulose, for 3 hours. At each time point, the mean of three BH2 concentration measurements was used to analyse data. The baseline value was calculated from values for the first three intervals. A 10-ppm rise in the BH2 concentration above baseline was considered a positive response.[16] The peak hydrogen level was defined as the highest value at any time interval after which a decrease in hydrogen concentration was observed.

On the basis of the lactulose BH2 test, the oral­cecal transit time (OCTT) was calculated as follows:[17]

OCTT = changes in t (t0-tp) - 10 minutes where changes in t = the time interval from t0 until hydrogen levels exceed 10 ppm above baseline (tp).

To compare BH2 concentrations before and after delivery, the calculated baseline concentration for each subject was subtracted from BH2 concentrations at each time interval. Baseline values never exceeded 20 ppm, and prepartum and postpartum values were comparable (mean 7.6, standard error of the mean [SEM] 1.1 ppm v. mean 8.35, SEM 1.4 ppm, respectively). Lactose BH2 concentrations prepartum and post partum were compared by calculating the area under the curve (AUC) for 3 hours. The area was calculated by summing calculated squares and triangles at each time interval. The transit time during lactose testing was estimated as the first sustained rise in BH2 to at least 10 ppm above baseline.

During lactose BH2 measurements, symptoms experienced by subjects were recorded at 30-minute intervals and scored as follows: diarrhea (the most objective symptom) was given a score of 3; abdominal pain 2; and excessive gas, bloating or distension 1. Scores from each of the six time intervals were summed, yielding a maximum possible score of 42 (from 30 minutes to 3 hours after lactose ingestion). An estimate of symptom scores after the lactose BH2 test was also obtained. All subjects were asked to record delayed symptoms and report them when they returned the following day. Subjects who could not return in 24 hours were contacted 1 to 3 days after testing to submit their record of symptoms. Symptoms caused by lactulose ingestion were not scored.

All BH2 measurements were performed with the use of a hand-held electrochemical hydrogen analyser (EC 60 Hydrogen Breath Monitor Vitalograph, Bedfont Inc., Lenexa, Kan.). This model uses a sealed electrochemical sensor that can detect hydrogen in ppm (v/v) in a range of 0 to 2000 ppm. The validity of electrochemical sensors for BH2 measurement has been previously established by comparison with gas chromatography.[18,19] We previously established an intrasubject variability of 22% for BH2 measurements in a group of nine age-matched control women.[20]

Lactose consumption and clinical tolerance

All subjects were asked whether they had consumed more, less or about the same amount of lactose-containing products (mainly dairy foods) during pregnancy as post partum. Semiquantitative ranks were set to range from -3 to +3 (where 0 = same, -3 = a lot less and +3 = a lot more). To estimate the validity of this method of ranking, we compared the subjective answers with the diet diary in a subgroup of 10 women, as outlined above. Overall, only 2 women's subjective reporting did not match the actual diet recall scores. There was one case of over-estimation and one of underestimation. We therefore considered that our subjective questionnaire was about 80% accurate in reflecting true changes in lactose consumption between pregnancy and post partum, after weaning.

Statistical analysis

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Results

Demographic and clinical characteristics of the initial group of 33 women are presented in Table 1. Of these women, 18 initially had lactose malabsorption, 12 did not, 2 did not produce hydrogen after ingesting lactose during the study period, and 1 did not undergo lactose BH2 tests, as discussed above. Tests were repeated after the women resumed their regular menstrual cycles and had stopped breast-feeding. This time point was a median of 9 months post partum, and ranged from 2.5 to 14.5 months. Tests were always carried out within 2 weeks of the subjects' last menstrual period, to coincide with the follicular phase of the cycle. The mean estradiol level was 295.8 pmol/L (SEM 6.3 pmol/L) and mean progesterone level was 1.13 nmol/L (SEM 0.11 nmol/L).

Of the 12 pregnant women initially found to have normal lactose absorption, 4 were found to have lactose malabsorption post partum. Two of the 4 women were from ethnic groups with a high prevalence of lactose malabsorption (1 was Jewish and 1 was African-American), and the other 2 were from groups with a low prevalence of lactose malabsorption (1 was French-Canadian and 1 was east European). Two of the 4 women experienced mild symptoms during or after the 3-hour study period whereas 2 remained asymptomatic prepartum and post partum. The other 8 women were all from groups with a low prevalence of lactose malabsorption (French- or English-Canadian). Two had mild bloating after the lactose BH2 tests were completed.

Of the initial 18 women with lactose malabsorption, only 1, of French-Canadian descent, was from a population group with a low prevalence of lactase insufficiency. As stated previously, 2 of the women with lactose malabsorption failed to return for postpartum tests. Of the remaining women, 12 had a greater AUC after BH2 tests post partum than during pregnancy, two had a smaller AUC post partum, and two had an almost identical AUC post partum (Table 2).

When the prepartum and postpartum AUCs of the 16 women with lactose malabsorption were compared, the difference was statistically significant (prepartum mean 3816.9, SEM 577.4, 95% confidence interval [CI] 2685.2 to 4948.6 v. postpartum mean 6490.4, SEM 925.0, 95% CI 4677.4 to 8303.4, p < 0.005). Since the four subjects discussed above were judged to have latent lactose malabsorption, their results were combined with those of the group of 16. Further analysis is based on the full group of 20 unless otherwise stated. Recomparison of the AUCs for the full group remained statistically significant (prepartum mean 3094.0, SEM 567.0, 95% CI 1982.7 to 4205.3 v. postpartum mean 5660.4, SEM 839.5, 95% CI 4016 to 7304.8, p = 0.001). A comparison of lactose BH2 concentrations prepartum and post partum is shown in Fig. 2. The peak or maximal value of BH2 concentration during pregnancy was significantly lower than that post partum (mean during pregnancy 49.2 ppm, SEM 5.5 ppm, 95% CI 38.4 to 60.0 ppm v. mean post partum 78.3 ppm, SEM 8.4 ppm, 95% CI 61.8 to 94.8 ppm, p = 0.003). These values differ from those shown in Fig. 2 because they are based on the 16 original women with lactose malabsorption rather than the full group of 20. Furthermore, the number of subjects who achieved a peak BH2 concentration during pregnancy was significantly higher than the number post partum (chi² = 5.625, p < 0.025, values obtained with 16 rather than 20 subjects).

In terms of symptoms during the 3-hour lactose BH2 test, 9 women had more symptoms post partum than during pregnancy, 5 had fewer and 6 had similar symptoms or lack of symptoms. The mean symptom score post partum (7.7, SEM 8.7) was higher than during pregnancy (4.4, SEM 1.3). However, this difference did not quite reach statistical significance (p = 0.07). There was, however, a positive and significant correlation between symptom scores and AUCs post partum (r = 0.557, p < 0.01). The correlation during pregnancy was not significant (r = 0.364, p = 0.12). Evaluation of patients' subjective assessment of symptoms after lactose BH2 tests showed that only 2 subjects' lactose handling improved post partum whereas 13 subjects' lactose handling worsened and 5 subjects without symptoms had unchanged scores (mean symptom score during pregnancy 3.4, SEM 0.8, CI 1.8 to 2.5 v. mean symptom score post partum 8.1, SEM 1.5, CI 5.2 to 11.0, p = 0.003). Comparison of the number of women who felt better during pregnancy (13) with the number who felt better post partum (2) was significant as well (p < 0.005).

Comparison of OCTT prepartum and post partum for the entire group is reported elsewhere.20 However, the OCTT for the subgroup of women with lactose malabsorption is reported separately here to determine its impact on observed changes in lactose handling. The OCTT, as measured by lactulose BH2 concentration, was significantly longer in pregnancy (104.7 min, SEM 10.1 min, 95% CI 94.6 to 124.5 min) than post partum (71.6 min, SEM 7.6 min, 95% CI 56.7 to 86.5 min, p < 0.01, Table 3). The estimated transit time with lactose was also longer during pregnancy (91.9 min, SEM 7.0 min) than post partum (73.1 min, SEM 8.6 min). However, this difference did not reach significant levels (p = 0.12). A negative correlation between transit time, as measured during lactose BH2 tests, and AUC was noted during pregnancy (r = -0.652, p < 0.005) and post partum (r = -0.629, p < 0.003). However, there was no significant correlation between OCTT and AUC either during pregnancy or post partum. No significant correlation was found between OCTT and transit time measured with the use of lactose BH2 tests during pregnancy (p = 0.26) or post partum (p = 0.31). Similarly, we compared symptoms and OCTT or lactose-BH2-derived transit time during pregnancy and post partum. No significant correlations were found between these variables.

In the subgroup of 10 women who completed a detailed diet questionnaire, the daily lactose-intake score was significantly higher during pregnancy than post partum. Their mean lactose-intake score in pregnancy was 16.0, SEM 3.15, 95% CI 9.8 to 22.2, and the mean score post partum was 6.3, SEM 0.99, 95% CI 4.4 to 8.2 (p = 0.003). Of the 10 women, 8 were classified as having lactose malabsorption. Six consumed more lactose during pregnancy, whereas the other 2 had an equivalent lactose intake during pregnancy and post partum.

For the full group of 20, the estimated subjective change in lactose intake from pregnancy to the postpartum period was a score of -3 in 5 women, -2 in 2 women, -1 in 7, 0 in 4 and +1 in 1 woman. One woman was unavailable for interview. Thus, 14 out of 19 women (73.4%) consumed more lactose during pregnancy than afterward.

There was no significant correlation between changes in diet score and in the AUC for lactose from pregnancy to the postpartum period (r = -0.28, p = 0.23).

Changes in free thyroxine levels between pregnancy and the postpartum period did not correlate with changes in AUC between these periods. There was also no correlation between gravidity and changes in AUC between pregnancy and the postpartum period.

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Discussion

Milk remains an important source of protein, calcium and vitamins as well as energy, even in those with lactase insufficiency. These people continue to absorb nutrients despite evidence of lactose malabsorption.[2,25] Therefore, continued milk consumption is a desirable goal, particularly in areas with an inadequate food supply.

Our study, although small, clearly shows that advanced pregnancy alters lactose BH2 concentrations in women with lactose malabsorption.

The 3-hour time period for testing may have contributed to the failure to detect a significant rise in BH2 levels in two subjects. According to Strocchi and associates,[16] if studies are carried for 7 or 8 hours, a 93% sensitivity and 93% specificity for diagnosing lactose malabsorption is achieved. Therefore, measurements beyond 3 hours may have revealed a BH2 rise in our two subjects. We felt, however, that it was unethical to expect pregnant women to fast for more than 3 waking hours after an overnight fast of at least 12 hours.

A potential confounding influence on our observations is the interference of methane production in hydrogen production. Methane is found to increase hydrogen consumption[26,27] and is thought to lead to false-negative or falsely low hydrogen concentrations.[28,29] Increased methane production may therefore impair hydrogen production and lead to reduced symptoms. However, we are not aware of any studies showing altered methane production in pregnancy. Furthermore, recent re-evaluation of the possible confounding effects of methane on hydrogen concentration and interpretation showed that the influence is negligible.[30]

We believe that lactose handling is improved during pregnancy, on the basis of the following observations. Four of the women in our study were redefined as having lactose malabsorption post partum; the AUC for lactose BH2 was significantly smaller during pregnancy than post partum; peak hydrogen concentration was significantly lower and the number of women who achieved this value significantly higher during pregnancy than post partum; subjects had significantly fewer symptoms during pregnancy than post partum; and a significant number of women felt better during pregnancy.

Symptom scores were found to have a weak correlation with AUC post partum, although a significant correlation was observed during pregnancy. In our preliminary report, the summation of BH2 concentration also correlated with symptom score, both during pregnancy and post partum.[31]

A direct relation between AUC and quantity of malabsorbed carbohydrate has been reported.[32­34] However, we are unable to determine whether absorption or only tolerance improved. Nevertheless, our study confirms the results of a study by Villar and associates,[15] in which the number of lactose-tolerant women increased progressively during pregnancy. The prospective nature of Villar and associates' study makes it highly unlikely that our observations are a function of aging. Repetition of studies after a median of only 9 months is unlikely to be affected by an age-related change in intestinal lactase levels.[8]

There are several hypotheses that may account for improved lactose handling during pregnancy.

Hormonal changes that occur during pregnancy may directly influence intestinal lactase levels. We and others have reported lower, albeit normal-range, free thyroxine levels during pregnancy.[20,35,36] Thyroxine is known to affect both intestinal transit[37] and lactase activity.[38] In rats, free thyroxine inhibits intestinal lactase messenger RNA.[39] Since lactose intolerance in humans is aggravated by hyperthyroidism,[23] a similar inhibition of lactase mRNA may occur. Low levels of free thyroxine during pregnancy may play a permissive role in full lactase expression. The changes in hormone levels do not need to be excessive, since the small bowel may be quite sensitive to small alterations in thyroxine levels.[40] Despite the lack of a significant correlation between altered levels of free thyroxine and AUCs in our study, a permissive effect of free thyroxine cannot be ruled out.

Progesterone, levels of which are markedly elevated during pregnancy, may also play a role in increasing intestinal lactase levels. There is evidence that progesterone plays a maturation role in lactase in the human fetus.[41] In animals, high levels of progesterone may induce intestinal lactase,[42] although in humans they likely do not.[43] Progesterone also increases villus height in rats, thus expanding the mucosal surface and the amount of lactase available.[44] In this study, we cannot rule out an intestinal effect of progesterone. Thus, the possible effect of both thyroid-stimulating hormone and progesterone on human intestinal lactase remains to be elucidated.

Changes in OCTT may alter intestinal absorptive capabilities or reduce the rate of delivery of carbohydrate to the colon. Clinically, rapid transit in hyperthyroidism has been implicated in steatorrhoea[45] and lactose intolerance.[23] Rapid intestinal transit and loss of gastric delay of emptying is also implicated in lactose malabsorption that occurs after gastrectomy.[46] The converse, prolonged transit, could enhance absorption and lead to reduced lactose BH2 levels. We and others have shown that OCTT is consistently and significantly prolonged during pregnancy.[20,47,48] Although no correlation between OCTT and lactose BH2 transit was observed, a significant negative correlation between AUC and lactose BH2 transit was noted. Such a relation has been previously reported.[49] Since the osmotic effect of unabsorbed lactose and lactulose is likely similar, a closer correlation in transit times may be observed with ingestion of lower lactose concentrations. The influence of decreasing the lactose load on the transit time was indeed observed by Ladas, Papanikos and Arapakis.[49] Conversely, prolonging OCTT by taking loperamide improved symptoms in a dose-dependent fashion and significantly reduced the AUC for hydrogen in euthyroid men challenged with a 50-g lactose load.[50]

It has been observed that continued lactose ingestion, despite lactose intolerance, mitigates symptoms.[2,51­53] However, Gilat and associates8 showed that the improvement in milk consumption in healthy, lactose-intolerant men over a 12-month period was not associated with changes in intestinal lactase levels, and that disposition of malabsorbed carbohydrates is likely mediated by colonic bacterial flora.[9] Experimentally, Permann, Modler and Olson[54] showed that hydrogen production was directly related to fecal pH. Lower pH likely reflects higher production of short-chain fatty acids, a principal bacterial metabolite of salvaged carbohydrate. However, under low-pH conditions, hydrogen production is inhibited. Hetzler and Savaiano[55] recently showed that bacteria rapidly adapt to lactose feeding after 2 weeks, with dramatic reduction in hydrogen production and symptoms. In this study, we observed that pregnant women ingest more food containing lactose during pregnancy than post partum. The consistent and continued ingestion of dairy products, despite initial intolerance, sets up conditions favouring bacterial adaptation.

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Conclusions

Whatever the mechanisms, the knowledge that lactose handling improves in many women as pregnancy progresses may aid in dietary counselling for lactose-intolerant women who are pregnant.

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Acknowledgements

We thank Dr. Ronald Schondorf and Ms. Antoinette Colacone for assistance with statistical work, and Dr. Ronald G. Barr for helpful discussions. We also thank Mr. Rocco Starnino and Ms. Donalda Buchanan for technical assistance, and Ms. Florence Lurie for preparing the manuscript.

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