British Journal of Obstetrics and Gynaecology April 1975. Vol. 82. pp. 293 -296.
PREGNANCY IN PATIENT§ WITH COELIAC DISEASE BY
A. D. R. OGBORN, Senior Registrar and Tutor Institute of Obstetrics and Gynaecology Hammersmith Hospital, London WIZ OHS
Summary Successful pregnancy can occur both before and after the diagnosis and treatment of gluten-sensitive enteropathy. Abortion and intrauterine growth retardation are the main associated obstetric problems but their incidence may be reduced in the more severe cases by adherence to a strict gluten-free diet and dietary supplements. The present report concerns 60 pregnancies in 25 patients with coeliac disease.
Adherence to a strict gluten-free diet was thought to be of great importance. Carbohydrate supplements were encouraged, aiming at an extra 400 calories daily. “Hycal”, containing dextrans with molecular weights up to 50000, had been found suitable when glucose tablets were poorly tolerated. Calcium gluconate may be given twice daily orally in a dose of 1 . 5 g . , adjusted to maintain a normal plasma calcium. Additional iron as ferrous sulphate, 200 mg. twice daily, and folic acid, 5 mg. twice daily, were recommended. If these supplements of iron and folk acid did not produce normal serum levels intramuscular preparations were used and this was also necessary in some patients with coeliac disease who claimed that medication in tablet form increased diarrhoea. Serum vitamin B,, levels were commonly low and cyanocobalamin was given intramuscularly three times during pregnancy, in a dose of 1000 pg. at 6,20 and 34 weeks gestation. In all but the mildest cases in remission, compound intramuscular vitamins were given weekly; a typical regime provided 100 mg. of thiamine hydrochloride, 4 mg. of riboflavine, 50 mg. of pyridoxine hydrochloride, 160 mg. of nicotinamide, 50 mg. of pantothenic acid and 500 mg. of ascorbic acid. Exacerbations of diarrhoea were controlled by hospital rest, dietary supervision and salicy-
IT has been reported that infertility and spontaneous abortion in patients with coeliac disease may be prevented by good dietary management (Morris et al., 1970; Joske and Martin, 1971), but there is remarkably little literature concerning the course and management of pregnancy. Some patients who are diagnosed and treated in childhood return to a normal diet, until there is an unexpected recurrence of symptoms, or an unsuccessful pregnancy, These circumstances provide the opportunity to compare the course and outcome of pregnancy with and without treatment using controlled diet and supportive obstetric care. Twenty-five patients have been studied at Hammersmith Hospital. They had 38 pregnancies before and 22 pregnancies after commencement of gluten-free diets. In every case the diagnosis had been confirmed by a jejunal biopsy showing total or subtotal villous atrophy. MANAGEMENT General management Most of the pregnancies reviewed took place in the period 1965 to 1973 during which time the following principles of management were evolved. Serial measurements were made of maternal weight at each visit, of haemoglobin, serum iron and calcium each month, and of vitamin B,, and folate levels to detect any deficiencies. 293
294
A. D. K. OGBORN
lazosulphapyridine (Salazopyrin) or codeine phosphate as necessary. Obstetric management Vaginal cytology and plasma progesterone estimations were used to assess progesterone status in the first 16 weeks of pregnancy because of the increased risk of spontaneous abortion. If the vaginal smear showed a poor progesterone effect 250 mg. of hydroxyprogesterone caproate was given twice a week until the 16th week of pregnancy. Intrauterine fetal growth retardation was common in this series of patients with coeliac disease. Serial estimations of urinary or plasma oestrogens, plasma progesterone and human placental lactogen together with observations of maternal weight gain (Elder et al., 1970) were of value in the third trimester for monitoring fetoplacental function and deciding the optimum time for delivery of a small-for-dates baby. Similarly, close monitoring of the fetus was maintained in labour.
RESULTS Biochemical ,findings Representative observations made on five of the patients are shown in Table I. The tendency to deficient absorption of iron, folate and vitamin B,, and consequent anaemia will be noted. Occasional low calcium levels occurred but in general the supplements provided were adequate; alkaline phosphatase values were sporadically elevated. Patients on unrestricted diet In 38 pregnancies occurring before the diagnosis or before the treatment of coeliac disease there were eight first trimester abortions (21 per cent) but no mid-trimester abortions. Six babies (16 per cent) were small-for-dates with birthweights below the 10th percentile as defined by Elder e f al. (1970). One of these, weighing only 1260 g., died from antepartum asphyxia at 33 weeks maturity. Another, weighing 1370 g., was delivered by Caesarean section at 35 weeks because of severe dysmaturity, but died on the fifth day from hyaline membrane disease. There was one premature labour at 30 weeks gestation in a patient with a very low serum folate
(1 ng./rnl.) and low serum iron (48 pg./lOOml.). The baby weighed 1590 g., survived, and made normal progress. There were 23 other babies whose birthweight was normal for the gestational age. Three patients whose coeliac disease was asymptomatic and not being treated had a total of 9 babies of normal weight. One baby of normal birthweight died an unexplained “cot death” at the age of 10 weeks. The perinatal mortality in patients on an unrestricted diet was 7 per cent. Twenty-eight out of 38 pregnancies (74 per cent) ended in the birth of a viable infant which survived the neonatal period (Table 11). Patients under treatment The treatment regime described above was developed partly as a result of experience in managing these patients, and was not implemented in full in all cases. There was only one spontaneous first trimester abortion and no cases of premature labour in 22 pregnancies in patients adhering to a strict gluten-free diet. There were 4 small-for-dates babies in the 21 treated patients (19 per cent) delivered after 28 weeks. One was an anencephalic stillbirth weighing 860 g. at 30 weeks gestation, and another was an undiagnosed hydrocephalic delivered by Caesarean section at term because of fetal distress. This baby eventually died at the age of six months. Of the 17 babies of normal weight, 16 survived; one died of antepartum anoxia at 39 weeks maturity, the loss being ascribed to placental insufficiency. The perinatal mortality rate in the treated group was 10 per cent. Nineteen out of 22 pregnancies (86 per cent) ended in the birth of a viable infant which survived the neonatal period (Table 11). Maternal weight changes At the start of pregnancy the patient’s weights were within the range 47.6 to 59.4 kg. They all gained weight during pregnancy, the average total gain being 9 * 1 kg. In 16 patients who delivered normal weight babies, the mean maternal weight gain was 12.3 kg. Between 34 weeks maturity and the time of delivery, 12 of the 16 patients gained
PREGNANCY AND COELIAC DISEASE
295
TABLEI Representative haemutological and biochemical observations in five patients with coeliac disease . . . Unrestricted diet Gluten-free diet .. _ _ _ ~ ~ ~~ _ ~_ __ ~ -~ ~ ~ ~ _ _ _ Normal Between During Between During pregnancies pregnancy range pregnancies pregnancy -. Patient t Patient 2 Patient I Patient 3 Patient 4 Patient 3 Patient 2 Patient 3 _ _ ~ Haemoglobin (g.) 13.1 12.0 8-6* 10.8* 11.1 11.3 11.5 12.6 White blood cells (per cu.mm.) 10000 18500* 17000* 6100 3000 10400 E.S.R. (Wintrobe: 4 5 54* 55' 10 4 mm./hour) Serum vitamin B12 (pg./ml.) 160-900 270 280 160 136* 60" 265 368 384 Serum folate (ng./ml.) 3-21 1.8* 2.0* 1.4* 1.8* 0.8* 3.2 3.6 6.4 Red cell folate (ng./ml.) 160-640 75* 62* 253 415 Serum iron (ug./lOO ml.) 110-130 110 20* 20* 26* 48* 80* so* 68* Serum calcium (mg./100 ml.) 8.5-10.5 9.0 8.1* 8.5 9.0 8.6 9.4 8.6 9.5 Serum inorganic phos2.54.5 3.5 3.9 2.5 3.7 2.0* 4.5 2.6 4.0 phorus (mg.) Serum alkaline phosphatase (IU/l) 30-130 70 26 100 187* 288* 90 132* 60 Serum albumin (g.) 4.4 4.2 4.0 3.7 2.2* 4.0 4.6 4.5 Serum globulin (g.) 3.6 2.9 3.0 3.3 3.2 2.3* 2.4 3.0 Blood urea (mg.) 21 16 21 23 20 14 22
-
~~~
'Abnormal values. When several values were recorded the most abnormal is given.
1 to 3 . 3 kg., the mean gain after 3 4 weeks for the 16 patients being 2 * 3 kg. In 10 patients who delivered small-for-dates babies, the mean maternal weight gain in pregnancy was 5.9 kg. and only 4 of these gained any weight after 3 4 weeks maturity. Oirtcoive of pregnancy (Table Ir) No significant differences were demonstrable
at the P = 0.05 level between the treated and untreated groups, but the apparent overall improvement in outcome with treatment is encouraging. None of the babies was found to have coeliac disease. Plasma magnesium and calcium levels in the cord blood were at the lower limit of normal in two babies, but both made normal progress and required no treatment.
TABLE I1 Details of 60 Dregnancies in 25 patients with coeliac disease Before treatment After treatment 38 22 Total pregnancies 8 (21 %) 1 (4%) Abortions Baby small-for-dates 6 (16%) 4*?(1 8 %) 24 (63Normal birthweight %) 17 (78 %) Stillbirths 1 2* 1 0 Neonatal deaths 1 Infant deaths It Perinatal mortality 7% 10%* Pregnancies ending in the birth of a viable 74 % 86 % infant which survived 28 days *1 anencephalic fetus tl hydrocephalic fetus
Totals 60 9 (15%) 10 (17%) 41 ( 6 8 % ) 3
1 2 8%
78 %
296
A. D. R. OGBORN
DISCUSSION Infertility is an occasional feature of active coeliac disease. All three such patients described by Morris et al. (1970) became pregnant when their symptoms were controlled by dietary gluten restriction. None of the 25 patients in this series had complained of infertility. Spontaneous abortion has been shown to be increased in patients with low serum folate levels (Martin et al., 1965) which may explain the 20 per cent spontaneous abortion rate in our untreated patients. Unrecognized coeliac disease is a rare cause of recurrent first trimester abortion. Joske and Martin (1971) studied 21 patients with at least three consecutive first trimester miscarriages. Three had low serum folate levels 2nd two of these were found to have previously unrecognized coeliac disease. Treatment with a gluten-free diet was followed by normal pregnancies in both of these patients. It has been suggested that conception at a time of low folic acid status might be associated with an increased incidence of fetal abnormalities (Hibbard and Smithells, 1965). In the present study, these were two abnormal infants and both were born to treated patients in whom folic acid
deficiency was less likely than in the untreated patients. A strict gluten-free diet, laboratory assessment and correction of deficiencies and serial assessment of placental function seem to improve the outcome of pregnancy in women with coeliac disease.
ACKNOWLEDGEMENTS I am grateful to Professor J. C. M. Browne, Mr. W. G. MacGregor, Mr. D. F. Hawkinsand Mr. H. Gordon for permission t o study patients under their care, and to Mr. D. F. Hawkins for guidance in the preparation of this manuscript. REFERENCES Elder, M. G., Burton, E. R., Gordon, H., Hawkins, D. F., and Browne, J. C. M. (1970): Journal of Obstetrics and Gynaecology of the British Commonwealth, 77, 481. Hibbard, E. D., and Smithells, R. W. (1965): Lancet, 1, 1254. Joske, R. A., and Martin, J. D. (1971): Journal of Obstetrics and Gynaecology of the British Commonwealth, 78, 754. Martin, R. H., Harper, T. A., and Kelso, W. (1965): Lancet, 1, 670. Morris, J. S., Adjunkiewicz, A. B., and Read, A. E. (1970): Lancet, 1, 213.
PREGNANCY IN PATIENT§ WITH COELIAC DISEASE BY
A. D. R. OGBORN, Senior Registrar and Tutor Institute of Obstetrics and Gynaecology Hammersmith Hospital, London WIZ OHS
Summary Successful pregnancy can occur both before and after the diagnosis and treatment of gluten-sensitive enteropathy. Abortion and intrauterine growth retardation are the main associated obstetric problems but their incidence may be reduced in the more severe cases by adherence to a strict gluten-free diet and dietary supplements. The present report concerns 60 pregnancies in 25 patients with coeliac disease.
Adherence to a strict gluten-free diet was thought to be of great importance. Carbohydrate supplements were encouraged, aiming at an extra 400 calories daily. “Hycal”, containing dextrans with molecular weights up to 50000, had been found suitable when glucose tablets were poorly tolerated. Calcium gluconate may be given twice daily orally in a dose of 1 . 5 g . , adjusted to maintain a normal plasma calcium. Additional iron as ferrous sulphate, 200 mg. twice daily, and folic acid, 5 mg. twice daily, were recommended. If these supplements of iron and folk acid did not produce normal serum levels intramuscular preparations were used and this was also necessary in some patients with coeliac disease who claimed that medication in tablet form increased diarrhoea. Serum vitamin B,, levels were commonly low and cyanocobalamin was given intramuscularly three times during pregnancy, in a dose of 1000 pg. at 6,20 and 34 weeks gestation. In all but the mildest cases in remission, compound intramuscular vitamins were given weekly; a typical regime provided 100 mg. of thiamine hydrochloride, 4 mg. of riboflavine, 50 mg. of pyridoxine hydrochloride, 160 mg. of nicotinamide, 50 mg. of pantothenic acid and 500 mg. of ascorbic acid. Exacerbations of diarrhoea were controlled by hospital rest, dietary supervision and salicy-
IT has been reported that infertility and spontaneous abortion in patients with coeliac disease may be prevented by good dietary management (Morris et al., 1970; Joske and Martin, 1971), but there is remarkably little literature concerning the course and management of pregnancy. Some patients who are diagnosed and treated in childhood return to a normal diet, until there is an unexpected recurrence of symptoms, or an unsuccessful pregnancy, These circumstances provide the opportunity to compare the course and outcome of pregnancy with and without treatment using controlled diet and supportive obstetric care. Twenty-five patients have been studied at Hammersmith Hospital. They had 38 pregnancies before and 22 pregnancies after commencement of gluten-free diets. In every case the diagnosis had been confirmed by a jejunal biopsy showing total or subtotal villous atrophy. MANAGEMENT General management Most of the pregnancies reviewed took place in the period 1965 to 1973 during which time the following principles of management were evolved. Serial measurements were made of maternal weight at each visit, of haemoglobin, serum iron and calcium each month, and of vitamin B,, and folate levels to detect any deficiencies. 293
294
A. D. K. OGBORN
lazosulphapyridine (Salazopyrin) or codeine phosphate as necessary. Obstetric management Vaginal cytology and plasma progesterone estimations were used to assess progesterone status in the first 16 weeks of pregnancy because of the increased risk of spontaneous abortion. If the vaginal smear showed a poor progesterone effect 250 mg. of hydroxyprogesterone caproate was given twice a week until the 16th week of pregnancy. Intrauterine fetal growth retardation was common in this series of patients with coeliac disease. Serial estimations of urinary or plasma oestrogens, plasma progesterone and human placental lactogen together with observations of maternal weight gain (Elder et al., 1970) were of value in the third trimester for monitoring fetoplacental function and deciding the optimum time for delivery of a small-for-dates baby. Similarly, close monitoring of the fetus was maintained in labour.
RESULTS Biochemical ,findings Representative observations made on five of the patients are shown in Table I. The tendency to deficient absorption of iron, folate and vitamin B,, and consequent anaemia will be noted. Occasional low calcium levels occurred but in general the supplements provided were adequate; alkaline phosphatase values were sporadically elevated. Patients on unrestricted diet In 38 pregnancies occurring before the diagnosis or before the treatment of coeliac disease there were eight first trimester abortions (21 per cent) but no mid-trimester abortions. Six babies (16 per cent) were small-for-dates with birthweights below the 10th percentile as defined by Elder e f al. (1970). One of these, weighing only 1260 g., died from antepartum asphyxia at 33 weeks maturity. Another, weighing 1370 g., was delivered by Caesarean section at 35 weeks because of severe dysmaturity, but died on the fifth day from hyaline membrane disease. There was one premature labour at 30 weeks gestation in a patient with a very low serum folate
(1 ng./rnl.) and low serum iron (48 pg./lOOml.). The baby weighed 1590 g., survived, and made normal progress. There were 23 other babies whose birthweight was normal for the gestational age. Three patients whose coeliac disease was asymptomatic and not being treated had a total of 9 babies of normal weight. One baby of normal birthweight died an unexplained “cot death” at the age of 10 weeks. The perinatal mortality in patients on an unrestricted diet was 7 per cent. Twenty-eight out of 38 pregnancies (74 per cent) ended in the birth of a viable infant which survived the neonatal period (Table 11). Patients under treatment The treatment regime described above was developed partly as a result of experience in managing these patients, and was not implemented in full in all cases. There was only one spontaneous first trimester abortion and no cases of premature labour in 22 pregnancies in patients adhering to a strict gluten-free diet. There were 4 small-for-dates babies in the 21 treated patients (19 per cent) delivered after 28 weeks. One was an anencephalic stillbirth weighing 860 g. at 30 weeks gestation, and another was an undiagnosed hydrocephalic delivered by Caesarean section at term because of fetal distress. This baby eventually died at the age of six months. Of the 17 babies of normal weight, 16 survived; one died of antepartum anoxia at 39 weeks maturity, the loss being ascribed to placental insufficiency. The perinatal mortality rate in the treated group was 10 per cent. Nineteen out of 22 pregnancies (86 per cent) ended in the birth of a viable infant which survived the neonatal period (Table 11). Maternal weight changes At the start of pregnancy the patient’s weights were within the range 47.6 to 59.4 kg. They all gained weight during pregnancy, the average total gain being 9 * 1 kg. In 16 patients who delivered normal weight babies, the mean maternal weight gain was 12.3 kg. Between 34 weeks maturity and the time of delivery, 12 of the 16 patients gained
PREGNANCY AND COELIAC DISEASE
295
TABLEI Representative haemutological and biochemical observations in five patients with coeliac disease . . . Unrestricted diet Gluten-free diet .. _ _ _ ~ ~ ~~ _ ~_ __ ~ -~ ~ ~ ~ _ _ _ Normal Between During Between During pregnancies pregnancy range pregnancies pregnancy -. Patient t Patient 2 Patient I Patient 3 Patient 4 Patient 3 Patient 2 Patient 3 _ _ ~ Haemoglobin (g.) 13.1 12.0 8-6* 10.8* 11.1 11.3 11.5 12.6 White blood cells (per cu.mm.) 10000 18500* 17000* 6100 3000 10400 E.S.R. (Wintrobe: 4 5 54* 55' 10 4 mm./hour) Serum vitamin B12 (pg./ml.) 160-900 270 280 160 136* 60" 265 368 384 Serum folate (ng./ml.) 3-21 1.8* 2.0* 1.4* 1.8* 0.8* 3.2 3.6 6.4 Red cell folate (ng./ml.) 160-640 75* 62* 253 415 Serum iron (ug./lOO ml.) 110-130 110 20* 20* 26* 48* 80* so* 68* Serum calcium (mg./100 ml.) 8.5-10.5 9.0 8.1* 8.5 9.0 8.6 9.4 8.6 9.5 Serum inorganic phos2.54.5 3.5 3.9 2.5 3.7 2.0* 4.5 2.6 4.0 phorus (mg.) Serum alkaline phosphatase (IU/l) 30-130 70 26 100 187* 288* 90 132* 60 Serum albumin (g.) 4.4 4.2 4.0 3.7 2.2* 4.0 4.6 4.5 Serum globulin (g.) 3.6 2.9 3.0 3.3 3.2 2.3* 2.4 3.0 Blood urea (mg.) 21 16 21 23 20 14 22
-
~~~
'Abnormal values. When several values were recorded the most abnormal is given.
1 to 3 . 3 kg., the mean gain after 3 4 weeks for the 16 patients being 2 * 3 kg. In 10 patients who delivered small-for-dates babies, the mean maternal weight gain in pregnancy was 5.9 kg. and only 4 of these gained any weight after 3 4 weeks maturity. Oirtcoive of pregnancy (Table Ir) No significant differences were demonstrable
at the P = 0.05 level between the treated and untreated groups, but the apparent overall improvement in outcome with treatment is encouraging. None of the babies was found to have coeliac disease. Plasma magnesium and calcium levels in the cord blood were at the lower limit of normal in two babies, but both made normal progress and required no treatment.
TABLE I1 Details of 60 Dregnancies in 25 patients with coeliac disease Before treatment After treatment 38 22 Total pregnancies 8 (21 %) 1 (4%) Abortions Baby small-for-dates 6 (16%) 4*?(1 8 %) 24 (63Normal birthweight %) 17 (78 %) Stillbirths 1 2* 1 0 Neonatal deaths 1 Infant deaths It Perinatal mortality 7% 10%* Pregnancies ending in the birth of a viable 74 % 86 % infant which survived 28 days *1 anencephalic fetus tl hydrocephalic fetus
Totals 60 9 (15%) 10 (17%) 41 ( 6 8 % ) 3
1 2 8%
78 %
296
A. D. R. OGBORN
DISCUSSION Infertility is an occasional feature of active coeliac disease. All three such patients described by Morris et al. (1970) became pregnant when their symptoms were controlled by dietary gluten restriction. None of the 25 patients in this series had complained of infertility. Spontaneous abortion has been shown to be increased in patients with low serum folate levels (Martin et al., 1965) which may explain the 20 per cent spontaneous abortion rate in our untreated patients. Unrecognized coeliac disease is a rare cause of recurrent first trimester abortion. Joske and Martin (1971) studied 21 patients with at least three consecutive first trimester miscarriages. Three had low serum folate levels 2nd two of these were found to have previously unrecognized coeliac disease. Treatment with a gluten-free diet was followed by normal pregnancies in both of these patients. It has been suggested that conception at a time of low folic acid status might be associated with an increased incidence of fetal abnormalities (Hibbard and Smithells, 1965). In the present study, these were two abnormal infants and both were born to treated patients in whom folic acid
deficiency was less likely than in the untreated patients. A strict gluten-free diet, laboratory assessment and correction of deficiencies and serial assessment of placental function seem to improve the outcome of pregnancy in women with coeliac disease.
ACKNOWLEDGEMENTS I am grateful to Professor J. C. M. Browne, Mr. W. G. MacGregor, Mr. D. F. Hawkinsand Mr. H. Gordon for permission t o study patients under their care, and to Mr. D. F. Hawkins for guidance in the preparation of this manuscript. REFERENCES Elder, M. G., Burton, E. R., Gordon, H., Hawkins, D. F., and Browne, J. C. M. (1970): Journal of Obstetrics and Gynaecology of the British Commonwealth, 77, 481. Hibbard, E. D., and Smithells, R. W. (1965): Lancet, 1, 1254. Joske, R. A., and Martin, J. D. (1971): Journal of Obstetrics and Gynaecology of the British Commonwealth, 78, 754. Martin, R. H., Harper, T. A., and Kelso, W. (1965): Lancet, 1, 670. Morris, J. S., Adjunkiewicz, A. B., and Read, A. E. (1970): Lancet, 1, 213.
