Mortality and morbidity in offspring of mothers with diabetes compared with a population group: a Danish cohort study with 8-35 years of follow-up.

AIMS: To assess mortality and morbidity in the offspring of mothers with diabetes compared with a control cohort of offspring of mothers without diabetes. METHODS: The mortality rate, percentage of days admitted to hospital, diagnostic categories and incidence of diabetes mellitus among 691 offspring of mothers with diabetes were compared with a control group of 168 831 offspring not exposed to maternal diabetes. Offspring of mothers with diabetes were identified from the North Jutland Pregnancy database (521 Type 1; 34 Type 2; 136 gestational diabetes) born between 1976 and 2003. Outcome data were retrieved from the National Registry of Patients with follow-up until 31 December 2011. In a subgroup with the longest hospital stay we reviewed hospital records for clinical details until 2016. RESULTS: Mortality was 1.45% in the diabetes group compared with 1.36% in the control group. In the first 2 years, offspring exposed to diabetes spent significantly more time in hospital than the control offspring, but this difference faded to an insignificant difference of 0.04% of time spent in hospital between age 2 and 8 years. The offspring of mothers with diabetes had a sixfold increased risk of developing diabetes mellitus. CONCLUSIONS: The offspring of mothers with and without diabetes had almost identical mortality. The increased morbidity was restricted to the first 2 years of life, and was primarily attributable to a few individuals with very severe but probably non-diabetes-related disease burden. The large majority of offspring of mothers with diabetes experienced health conditions similar to those not exposed to diabetes.

Maternal blood glucose in diabetic pregnancies and cognitive performance in offspring in young adulthood: a Danish cohort study.

AIMS: Maternal diabetes is a known risk factor for perinatal complications, but there are little data on consequences for long-term intellectual outcome in offspring. We assess cognitive performance in military conscripts according to maternal blood glucose levels during pregnancy. METHODS: We identified a cohort of 60 Danish male offspring of insulin-treated diabetic mothers born between 1976 and 1984 and followed this cohort to military conscription. From medical records, we extracted data on all available values of maternal blood glucose categorized as fasting and non-fasting and by day in pregnancy, together with maternal White class, smoking habits and socio-economic status. The main outcome was cognitive performance at conscription measured with a validated intelligence test. The association between maternal blood glucose level and cognitive performance was assessed by multivariate linear regression and a fitted fractional polynomial. RESULTS: Median fasting blood glucose values in the second half of pregnancy was negatively associated with cognitive scores at conscription [adjusted coefficient -1.7; 95% confidence interval (CI) -3.0; -0.4]. Restriction to only first-born sibling slightly strengthened the association (coefficient -1.9; 95% CI -3.3; -0.5), but after exclusion of two pregnancies with the blood glucose > 10 mmol/l the association became insignificant (coefficient -0.6; 95% CI -2.6; 1.4). CONCLUSIONS: Maternal blood glucose level during diabetic pregnancy is negatively associated with cognitive performance in offspring at military conscription. In pregnancies with fasting blood glucose levels below 10 mmol/l, the association is weak and considered to be without clinical relevance.

Cancer risk in users of calcium channel blockers.

Ca2+ channel blockers may cause cancer by inhibiting apoptosis or reducing intracellular Ca2+ in certain tissues. Recent findings suggest that drug users are at increased risk for cancer in general and for colon cancer in particular. We conducted a study in one Danish county of 17911 patients who received at least one prescription of Ca2+ channel blockers between 1 January 1991 and 31 December 1993. The patients were identified from records in the National Health Insurance Program, which refunds part of the price of such drugs. Cancer occurrence and rate were determined by use of the files of the Danish Cancer Registry and compared with county-specific incidence rates for various categories of cancer. During the follow-up period of up to 3 years, 412 cancers were observed among users of Ca2+ channel blockers, compared with 414 expected, to yield an age- and sex-standardized incidence ratio (SIR) of 1.00 (95% confidence interval, 0.90 to 1.10). There was no indication of an excess risk in the subgroup of likely long-term users or users of specific drugs. The SIR of colon cancer, a site of a priori interest, was 0.8 (95% confidence interval, 0.5 to 1.1) on the basis of 34 cases. Although the results are reassuring, the lack of association could reflect the relatively short follow-up after registration in the prescription database. Continued monitoring of cancer risk is planned.

Preprandial blood glucose values: influence on glycemic response studies.

Through regressional analyses on data from two glycemic response studies, the influence of various preprandial blood glucose (PPBG) values upon glycemic response is highlighted. Repeated calculations on different subsamples of meals where the PPBG was below a given value showed that the influence of PPBG upon net glycemic response not was linear in the whole PPBG range. It was found that a PPBG less than 13 mmol/L had no influence upon net glycemic response whereas PPBGs greater than 13 mmol/L were significantly negatively correlated to the net glycemic response. To obtain more valid glycemic index figures we recommend that participants with PPBG greater than 13 mmol/L are excluded from glycemic response studies and that the number of participants are increased substantially.

Risk of hospitalization resulting from upper gastrointestinal bleeding among patients taking corticosteroids: a register-based cohort study.

PURPOSE: We assessed the risk of hospitalization for upper gastrointestinal bleeding among patients using systemic corticosteroids, accounting for the use of other drugs that may increase the risk of bleeding. SUBJECTS AND METHODS: We conducted a population-based cohort study in North Jutland County, Denmark. Data on the use of corticosteroids, nonsteroidal anti-inflammatory drugs, aspirin, and anticoagulants during 1991 to 1995 were obtained from a countywide prescription database. All hospitalizations because of upper gastrointestinal bleeding were identified through the Hospital Discharge Registry. The observed numbers of patients with gastrointestinal bleeding in various exposure categories among corticosteroid users were compared with the expected number based on the North Jutland population who did not receive prescriptions for any of the drugs under study. RESULTS: A total of 45,980 patients accrued 18,379 person-years of corticosteroid use. There were 109 hospital admissions for gastrointestinal bleeding among corticosteroid users, compared with 26 expected, yielding a relative risk of 4.2 [95% confidence interval (CI): 3.4 to 5.0]. Among corticosteroid users who did not use other drugs associated with gastrointestinal bleeding, the relative risk was 2.9 (95% CI: 2.2 to 3.7). The relative risk decreased further to 1.9 (95% CI: 1.4 to 2.5) when current corticosteroid usage was compared with former usage. CONCLUSION: We observed an increased risk of hospitalization because of upper gastrointestinal bleeding among patients prescribed corticosteroids, especially among those who use other medications. Confounding from the underlying disease may also have contributed to the observed increase in risk.

Third generation oral contraceptives and heritable thrombophilia as risk factors of non-fatal venous thromboembolism.

Third generation oral contraceptives (OCs) are apparently stronger risk factors for venous thromboembolism (VTE) than other OCs, however, the increased risk may be due to confounding by indication related to differences in prescription behaviour. We estimated the risk of VTE associated with use of OCs with and without the presence of Factor V Leiden mutation, protein C-, protein S- or antithrombin deficiency. Sixty-seven cases with VTE were compared with 134 controls. The risk of VTE in the presence of thrombophilia was of the same magnitude for third generation OC users as for users of other OCs; OR: 52.5 (95% CI: 3.7-738.1) and OR: 63.3 (95% CI: 6.2-648.4), respectively. It is unlikely that confounding by indication entirely explains the risk of VTE associated with third generation OCs since the combined effect exceeds what could be explained if this source of error was the only determinant of the association.

Hospitalisation for upper gastrointestinal bleeding associated with use of oral anticoagulants.

The incidence of hospitalisation for upper GI bleeding with use of oral anticoagulants (OA) alone or in combination with other drugs was examined in a cohort of 4,204 users of OA, identified through record linkage between a population-based prescription database and a hospital discharge registry in Denmark, and compared with the incidence in the general population not exposed to OA. The standardised incidence ratio (SIR) was 2.8 (95% CI = 1.6-4.5) for use of OA alone. SIRs tended to be higher for use of OA combined with acetaminophen alone (4.4, 95% CI = 1.2-11.4), non-aspirin NSAIDs alone (8.0, 95% CI = 2.1 to 20.4) or aspirin/corticosteroids alone (3.8, 95% CI = 0.8-11.0), respectively. These results indicate that use of OA is associated with a significantly increased risk of upper GI bleeding, with still higher risks associated with the concomitant use of other medications including acetaminophen. Further research is needed to clarify the extent to which drugs interacting with oral anticoagulants may cause GI bleeding and the mechanisms through which these associations operate.

The safety of proton pump inhibitors in pregnancy.

AIM: To assess the safety of proton pump inhibitors during pregnancy. METHODS: Fifty-one pregnant women exposed to proton pump inhibitors around the time of conception or during pregnancy were compared with 13 327 controls without exposure to any prescribed drug in a population-based study based on The Pharmaco-Epidemiological Prescription Database of North Jutland and the Danish Hospital Discharge Registry. RESULTS: Three babies with malformations were found among 38 women exposed to proton pump inhibitors from 30 days before conception to the end of the first trimester. No cases of stillbirth were recorded. Crude relative risks of malformation, low birth weight and preterm delivery were 1.6 (95% CI: 0.5-5.1), 1.8 (95% CI: 0.2-13.0) and 2.3 (95% CI: 0.9-6.0), respectively. CONCLUSIONS: In this population-based follow-up study, we found no substantially elevated risk in terms of malformations, low birth weight or number of preterm deliveries in pregnancies exposed to proton pump inhibitors. However, further monitoring is warranted in order to establish or rule out a potential association between the use of proton pump inhibitors and increased risk of either cardiac malformations or preterm birth.

Outcome of pre-hospital antibiotic treatment of meningococcal disease.

OBJECTIVE: To assess the effect of pre-hospital antibiotic treatment given by general practitioners to patients with meningococcal disease. DESIGN: A 16-year population-based historical follow-up study based on referral letters and hospital records in the County of North Jutland, Denmark. SUBJECTS: 320 patients with meningococcal disease, of whom 302 were examined by a general practitioner before admission to hospital. MAIN OUTCOME MEASURES: Death. RESULTS: 44 patients (14.6%) were given antibiotic treatment by the referring general practitioner. Nine of these (20.5%) died, compared with 16 (6.2%) patients who did not receive pre-hospital antibiotic treatment. The presence of skin bleeding, petechiae, and impaired consciousness were strongly associated with case fatality. Even after adjustment for these variables the odds ratio (OR) for death in patients treated with antibiotics was high (OR = 3.2; 95% CI, 0.9-10.6). In the 15 patients with skin bleeding (ecchymoses, suggillations) the case fatality rate was 100% in patients treated with antibiotics, and 50% in patients who did not receive antibiotics before hospitalization. If skin bleeding was replaced in the models by the presence of disseminated intravascular coagulation on admission, the OR for death in patients with pre-hospital antibiotic treatment was 35.9 (95% CI, 2.9-441.8) in the presence of disseminated intravascular coagulation and 1.9 (95% CI, 0.2-19.5) in its absence. CONCLUSIONS: Pre-hospital treatment is mainly given to the most severe cases with expected high case fatality, and this confounding by indication was probably not fully adjusted for with the available data. The results contradict previous findings but provide reason to doubt the benefit of pre-hospital antibiotic treatment in patients with meningococcal disease.

Can hospital discharge diagnosis be used for surveillance of bacteremia? A data quality study of a Danish hospital discharge registry.

OBJECTIVE: To assess the data quality of septicemia and sepsis registration in a hospital discharge registry in the County of Northern Jutland, Denmark. DESIGN: Comparison of data from the discharge registry of an 880-bed, public, urban hospital in the County of Northern Jutland with data from a computerized bacteremia database at the regional department of clinical microbiology. SETTING: Urban hospital with approximately 45,000 admissions per year. PATIENTS: The study included 406 episodes of bacteremia in the bacteremia database and 83 discharges with the diagnosis of septicemia registered in the hospital discharge registry between January 1, 1994, and December 31, 1994. INTERVENTIONS: None. RESULTS: Eighteen episodes were registered in both the hospital discharge registry and the bacteremia database. Using the bacteremia database as reference standard, the sensitivity for the diagnosis of septicemia in the hospital discharge registry was 4.4% (18/406; 95% confidence intervals [CI95, 2.4%-6.4%]). By review of hospital records, we estimated the positive predictive value of septicemia registration in the hospital discharge registry as 21.7% (18/83; CI95, 12.8%-30.5%). No blood culture had been obtained in 44.4% (36/81; CI95, 33.6%-55.3%) of the cases with a discharge diagnosis of septicemia. In 33.3% (27/81; CI95, 23.1%-43.6%), the discharge diagnosis of septicemia was given, although blood cultures were negative. CONCLUSIONS: The hospital discharge registry revealed numerous misclassifications, and the system was found not suited for surveillance of, or research in, bacteremia at present.

Plasma 6-keto-PGF1 alpha, thromboxane B2 and PGE2 during diabetic ketoacidosis.

In 10 patients admitted to hospital with diabetic ketoacidosis plasma prostanoids 6-keto-PGF alpha, thromboxane B2 and PGE2 were studied before treatment and following recovery. During ketoacidosis the median plasma 6-keto-PGF1 alpha and PGE2 were significantly increased compared to those of a normal reference group: 5.2 pg/ml and 3.9 pg/ml versus 1.7 pg/ml and 0.4 pg/ml (p less than 0.01 and p less than 0.05). In response to therapy both prostanoids decreased significantly towards a normal level, 6-keto-PGF1 alpha: 0.5 pg/ml p less than 0.01 and PGE2: 0.08 p less than 0.05 respectively. The changes in plasma 6-keto-PGF1 alpha were negatively correlated to changes in pH, rho: -0.7788 p = 0.0135, whereas the changes in PGE2 were positively correlated to serum creatinine at admittance, rho: 0.6976, p = 0.0368 and to the amount of intravenous fluid and insulin used during treatment, rho: 0.7500 p = 0.0126 and rho: 0.8424, p = 0.0023 respectively. Plasma thromboxane B2 concentrations were not elevated and did not change after treatment of the ketoacidosis.

Birth outcome of 1886 pregnancies after exposure to phenoxymethylpenicillin in utero.

OBJECTIVE: To examine the risk of congenital abnormalities, preterm birth and low birth weight after exposure to phenoxymethylpenicillin in utero. METHODS: A population-based follow-up study in the County of North Jutland, Denmark. Birth outcome for 1886 women, who redeemed prescriptions for phenoxymethylpenicillin during pregnancy was compared with the outcome for 9263 women who did not redeem any prescription during pregnancy. RESULTS: The prevalence of congenital abnormalities in 654 users of phenoxymethylpenicillin with or without other drugs during the first trimester was 4.6% compared with 3.6% in the reference group, giving a prevalence odds ratio of 1.25 (95% CI: 0.84-1.86). The prevalence odds ratio was 1.35 (95% CI: 0.59-3.08) in 131 women who were exposed to phenoxymethylpenicillin only. Nine cardiovascular abnormalities were found, giving an adjusted prevalence odds ratio of 1.74 (95% CI: 0.83-3.65). The prevalence odds ratios of preterm birth and low birth weight were 0.83 (95% CI: 0.66-1.04) and 1.02 (95% CI: 0.71-1.47), respectively. CONCLUSION: We found no significantly increased risk of congenital abnormalities, including cardiovascular abnormalities, preterm birth, or low birth weight in women who purchased phenoxymethylpenicillin during pregnancy.

Homocysteine in Greenland Inuits.

Patients with homozygous homocystinuria are at greatly increased risk for development of atherosclerosis and thrombosis (1). Elevated plasma levels of homocysteine (HCY) are caused by reduced enzymatic catabolism or reduced enzymatic remethylation of HCY, due to either hereditary enzyme defects or to nutritional deficiencies of vitamins functioning as cofactors. However, several recent studies have suggested that persons with mildly elevated plasma levels of HCY also are at increased risk for coronary heart disease. (2-4). There are some indications that dietary n-3 polyunsaturated fatty acids (PUFAs) may offer protection against coronary heart disease (5-6). Several mechanisms may be involved, including beneficial effects of n-3 PUFAs on plasma lipids, platelet and leukocyte reactivity, blood pressure and vasoreactivity (7). Interestingly, Olszewski el al. recently found HCY-levels to be lowered 36% in 15 type IIa or IIb hyperlipemic men by n-3 PUFA supplementation. A possible beneficial effect of n-3 PUFA on the incidence of coronary heart disease was initially suggested from studies in Greenland Inuits by our group (8). We therefore investigated plasma levels of homocysteine in a group of traditionally living Greenland Inuits with a diet consisting mainly of marine food and with a very high content of n-3 PUFAs.

Birth outcome following maternal use of fluoroquinolones.

The aim of the study was to examine fetal risk associated with intrauterine exposure to fluoroquinolones. By using on record linkage between a Prescription Database and the Birth Registry in Denmark, the offspring of 57 users of fluoroquinolones and of 17259 patients who had no prescriptive medication during pregnancy, were compared in a cohort study. Among the users, the prevalence rate ratios of congenital abnormalities, preterm birth and low birth weight were 1.30 (95% CI: 0.30-5.30),1.53 (95% CI: 0.62-3.80) and 1.17 (95% CI: 0.15-8.90), respectively. The risk of congenital abnormalities among users of fluoroquinolones during pregnancy was close to unity. Despite these limitations of statistical analysis the study suggested that the use of fluoroquinolones during pregnancy may not be a major risk factor to the foetus.

Pre-hospital parenteral antibiotic treatment of meningococcal disease and case fatality: a Danish population-based cohort study.

OBJECTIVES: Studies about the efficiency of pre-hospital antibiotic treatment of meningococcal disease are conflicting. We examined the case fatality rate in patients with meningococcal disease treated with pre-hospital antibiotics. METHODS: A cohort study of 534 patients hospitalized with meningococcal disease from two Danish counties. Clinical data were obtained from referral letters from general practitioners and hospital records. Complete follow-up for all patient until death or discharge. RESULTS: Seventy-seven patients (16% of the patients seen by a general practitioner) received parenteral antibiotics before hospital admission; 9 (12%) of them died. Of 402 patients who did not receive pre-hospital parenteral antibiotics, 26 (7%) died. The overall risk of case fatality among antibiotic-treated patients was increased with adjusted odds ratio (OR) = 2.4 (95% CI, 1.0-5.6). Meningococcus serogroup B was associated with increased case fatality in patients who received pre-hospital parenteral antibiotics (OR = 2.6; 95% CI, 0.8-8.3) in contrast to other serogroups. In Aarhus County there were no deaths in patients who received pre-hospital parenteral antibiotics, but in North Jutland County the case fatality was high (OR = 2.9; 95% CI, 1.2-6.8). CONCLUSIONS: The efficiency of pre-hospital parenteral antibiotic treatment seems to be dependent on hospital care and may vary with the serogroup.

Glycosylated hemoglobin as predictor of adverse fetal outcome in type 1 diabetic pregnancies.

The study aimed to determine whether a consistent dose-response association can be demonstrated, after adjustment for maternal age and White classification, between glycosylated hemoglobin (HbA1c) values before conception and in the first trimester of pregnancy of insulin-dependent diabetic mothers and adverse fetal outcome (abortions and major malformations). This is a historical follow-up study based on medical records in a geographically defined catchment area. The study comprised 60 pregnancies with HbA1c determinations before pregnancy and 161 with HbA1c in the first trimester in women with type 1 diabetes admitted between 1980 and 1992. Relative risk calculations indicated a highly significant and consistent correlation between HbA1c values above 6.6% and adverse fetal outcome after adjustment for differences in maternal age and White classification. Our data support a clinically significant and consistent relationship between adverse fetal outcome and HbA1c in the first trimester of pregnancy of type 1 mothers, without any indication of a cut-off level below which further improvement in HbA1c was of minor importance.

Decreased interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids.

The effects of dietary supplementation with n-3 fatty acids on the level of cytokines and complement activation in plasma from patients with rheumatoid arthritis were examined. Thirty-two patients with active rheumatoid arthritis were included in a 12-week double-blind, randomized study of dietary supplementation with n-3 fatty acids (3.6 g per day) or placebo. The cytokines were measured in plasma before and after treatment with fish oil or placebo. In general, cytokine values at the upper limits of the calculated normal areas were found. The Interleukin-1 beta concentration in plasma was reduced significantly after 12 weeks of dietary supplementation with fish oil (p < 0.03). No significant difference was observed in the placebo group. The tumour necrosis factor alpha activity in plasma did not change significantly (p = 0.167). No significant changes were observed in the degree of complement activation. The clinical status of the patients was improved in the fish oil group, but not in the placebo group, judged by Ritchie's articular index (p < 0.02). We conclude that dietary supplementation with n-3 fatty acids results in significantly reduced plasma IL-1 beta levels in patients with rheumatoid arthritis. Even though the cytokine levels were low, the anti-inflammatory effect of n-3 fatty acids could in part be explained by their ability to decrease cytokine production.

Outcome of 328 pregnancies in 205 women with insulin-dependent diabetes mellitus in the county of Northern Jutland from 1976 to 1990.

STUDY OBJECTIVE: To determine the degree of centralization and to describe the outcome of all pregnancies among Type 1 (insulin-dependent) mothers in the county of Northern Jutland from 1976-90. DESIGN: Retrospective, hospital record based study. SETTING: Data were collected from all departments of surgery (n = 8) and obstetrics (n = 3) in the county covering 550,000 inhabitants (approx. 10% of the total Danish population). PATIENTS: Three hundred and twenty-eight consecutive, unselected pregnancies among 205 women with Type 1 diabetes mellitus admitted to the hospitals in the county from 1976-90. MAIN RESULTS: Thirty-two (11%) pregnancies were terminated with spontaneous abortions and ten (3.3%) abortions were induced for medical reasons. There were eleven (4.3%) neonatal deaths. There was no additional fetal loss within the first year of life. Eight (3.1%) babies had major and additionally six (2.4%) minor malformations. Total fetal loss was 53/297 = 18%. Twenty-eight percent of the babies were large-for-gestational age. No pregnancies terminated at primary level hospitals and only 6% at the non-sub specialized obstetrical Departments. CONCLUSION: We have achieved an almost complete centralization of the management of pregnant women with diabetes mellitus and our outcome is comparable to the results published from other regional surveys taking care of these patients.

A population-based cohort study of birth and neonatal outcome in older primipara.

OBJECTIVES: To examine the risk of adverse birth outcome in older primiparous women. METHODS: We identified 14,676 primiparae of 20 years of age or more from 1991 to 1996 using the Birth Registry in the North Jutland County, Denmark. We evaluated the risk of adverse birth outcome in the primiparous women aged 30-34 years and above 35 years using the primiparae aged 20-29 years at time of birth as reference. RESULTS: The risks of induced labor, perineotomy, stimulating contraction and vacuum extraction were significantly higher (adjusted odds ratio: 1.3 to 1.7) in the primiparae of 35 years or more. The odds ratio for cesarean section delivery was 2.1 (95% confidence interval: 1.7-2.6) and the odds ratio for delivering a low birth weight child among the primiparae of 35 years or more was 2.2 (95% confidence interval: 1.4-3.3) compared with the primiparae of 20-29 years of age. These risk estimates were independent of women's infertility treatment history. CONCLUSIONS: A negative effect of maternal age on birth and neonatal outcome may be seen even after 30 years of age and is partly related to chronic diseases. However, it is impossible to rule out selection bias, but the actual risk must be taken into consideration in antenatal care.

Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study.

OBJECTIVE: To estimate the risk of adverse birth outcome in women who take non-steroidal anti-inflammatory drugs during pregnancy. DESIGN AND SETTING: Population based cohort study and a case-control study, both based on data from a prescription registry, the Danish birth registry, and one county's hospital discharge registry. PARTICIPANTS: COHORT STUDY: 1462 pregnant women who had taken up prescriptions for non-steroidal anti-inflammatory drugs in the period from 30 days before conception to birth and 17 259 pregnant women who were not prescribed any drugs during pregnancy. CASE-CONTROL STUDY: 4268 women who had miscarriages, of whom 63 had taken non-steroidal anti-inflammatory drugs, and 29 750 primiparous controls who had live births. MAIN OUTCOME MEASURES: Incidences of congenital abnormality, low birth weight, preterm birth, and miscarriage. RESULTS: Odds ratios for congenital abnormality, low birth weight, and preterm birth among women who took up prescriptions for non-steroidal anti-inflammatory drugs were 1.27 (95% confidence interval 0.93 to 1.75), 0.79 (0.45 to 1.38), and 1.05 (0.80 to 1.39) respectively. Odds ratios for the taking up of prescriptions in the weeks before miscarriage ranged from 6.99 (2.75 to 17.74) when prescriptions were taken up during the last week before the miscarriage to 2.69 (1.81 to 4.00) when taken up between 7 and 9 weeks before. The risk estimates were no different when the analysis was restricted to missed abortions. CONCLUSIONS: Use of non-steroidal anti-inflammatory drugs during pregnancy does not seem to increase the risk of adverse birth outcome but is associated with increased risk of miscarriage.