Sten-Anders Ivarsson

Report on a Long-term Study of Maternal and Congenital Cytomegalovirus Infection in Sweden. Review of Prospective Studies Available in the Literature

This report summarizes knowledge accumulated in a long-term study of congenital and maternal cytomegalovirus (CMV) infection in Sweden. Some new findings are included. We considered diagnostic methods, sources of maternal infection (including occupational risks), roles of primary and secondary maternal infections, transmission to foetuses, incidence, symptoms and prognosis of established congenital infection and relative importance of such infection in infantile sensorineural deafness, microcephaly and type 1 diabetes mellitus. Virus isolation testing was done 1977-1985 on 16,474 newborns. 76 (0.5%) congenitally infected infants were found, 22/76 (29%) with transient neonatal symptoms and 11/60 (18%) with neurological symptoms by the age of 7 y. Type of maternal CMV infection was serologically determined in 62/76 cases (30 primary, 32 secondary). CNS disturbances in the infants occurred after both primary (all trimesters) and secondary maternal infections. The negative potential of secondary maternal infections might be an obstacle to preventive vaccination.

Primary and secondary maternal cytomegalovirus infections and their relation to congenital infection. Analysis of maternal sera.

ABSTRACT. 4382 new mothers were examined retrospectively with the enzymelinked immunosorbent assay (ELISA) for IgG activity to cytomegalovirus (CMV) during pregnancy. Some of them were also studied with the indirect immunofluorescence (IIF) test for CMV‐IgM antibodies. All the infants had been studied for CMV excretion within the first week of life. Nineteen of them had been shown to be congenitally infected with CMV. 1218 (28 %) women lacked CMV‐IgG activity at their first antenatal visit (usually in months III‐IV). Fourteen of them seroconverted before parturition (primary infection). Thirteen of the seroconverters were shown to develop CMV‐IgM activity. In 6 (43 %) cases the primary infection was transmitted to the offspring. The remaining 13 congenitally infected infants were born to mothers with a positive IgG‐test at their first antenatal control. Only one of these mothers had a clearly positive IgM‐test. She was shown to lack CMV‐antibodies before conception (primary infection during the first trimester). Preconceptional sera were obtained from further 4 of the 13 seropositive mothers of congenitally infected infants; all 4 had CMV antibodies before pregnancy (secondary infection during pregnancy). The combined studies of the mothers and infants revealed that 21–63 % of the congenital infections could have been caused by secondary maternal infections. Prospectively performed, the study would only have disclosed one of the three fetal CMV infections that resulted in neurological sequelae.

Long-term Outcomes of Congenital Cytomegalovirus Infection in Sweden and the United Kingdom

BACKGROUND Congenital cytomegalovirus (CMV) is an important cause of neurological problems, particularly sensorineural hearing loss, but data on long-term sequelae and the impact of nonprimary maternal infection are limited. We report updated findings on childhood outcomes from 2 large prospective studies. METHODS Pregnant women in Malmö, Sweden, and London, United Kingdom, were included between 1977 and 1986, and newborns were screened for CMV (virus culture of urine or saliva). Cases and matched controls underwent regular, detailed developmental assessments up to at least age 5 years. RESULTS One hundred seventy-six congenitally infected infants were identified among >50 000 screened (Malmö: 76 [4.6/1000 births]; London: 100 [3.2/1000 births]); 214 controls were selected. Symptoms were recorded in 11% of CMV-infected neonates (19/176) and were mostly mild; only 1 neonate had neurological symptoms. At follow-up, 7% of infants (11/154) were classified as having mild, 5% (7/154) moderate, and 6% (9/154) severe neurological sequelae. Four of 161 controls (2%) had mild impairment. Among children symptomatic at birth, 42% (8/19) had sequelae, versus 14% (19/135) of the asymptomatic infants (P = .006). All moderate/severe outcomes were identified by age 1; mild sequelae were first identified at age 2-5 years in 6 children, and age 6-7 years in 3. Among the 16 children with moderate/severe outcomes, 2 had mothers with confirmed and 7 with presumed nonprimary infection. CONCLUSIONS Moderate or severe outcomes were reported in 11% of children with congenital CMV identified through population screening, all by 1 year; all impairment detected after this age was mild. Nonprimary infections contributed substantially to the burden of childhood congenital CMV disease.

Motilin and infantile colic. A prospective study.

ABSTRACT. Two hundred and nineteen infants, consecutively born, took part in a prospective study of infantile colic from birth to 12 weeks of age. The prevalence of infantile colic in this group was 17.4%. S‐motilin was studied in 78 term infants (19 with and 59 without infantile colic) at birth (cord blood), at one day, and at 6 and 12 weeks of age, respectively. Basal motilin levels were raised both in cord blood (p<0.01) and in blood from neonates (p<0.001) who developed colic as well as in 6 week (p<0.05) and in 12‐week‐old infants with colic (p<0.01). Formula‐fed infants with colic had higher basal motilin levels than formula‐fed controls at 6 and 12 weeks of age (p<0.05). Breast‐fed infants with colic had higher basal motilin levels than breast‐fed controls at 12 weeks of age (p<0.05). The raised levels of motilin from the first day of life in infants who develop infantile colic might indicate that the gastrointestinal tract is affected in infants with infantile colic, before any symptoms of colic appear.

Maternal enterovirus infection during pregnancy as a risk factor in offspring diagnosed with type 1 diabetes between 15 and 30 years of age.

Maternal enterovirus infections during pregnancy may increase the risk of offspring developing type 1 diabetes during childhood. The aim of this study was to investigate whether gestational enterovirus infections increase the offsprings risk of type 1 diabetes later in life. Serum samples from 30 mothers without diabetes whose offspring developed type 1 diabetes between 15 and 25 years of age were analyzed for enterovirus-specific immunoglobulin M (IgM) antibodies and enterovirus genome (RNA), and compared to a control group. Among the index mothers, 9/30 (30%) were enterovirus IgM-positive, and none was positive for enterovirus RNA. In the control group, 14/90 (16%) were enterovirus IgM-positive, and 4/90 (4%) were positive for enterovirus RNA (n.s.). Boys of enterovirus IgM-positive mothers had approximately 5 times greater risk of developing diabetes (OR 4.63; 95% CI 1.22–17.6), as compared to boys of IgM-negative mothers (P < .025). These results suggest that gestational enterovirus infections may be related to the risk of offspring developing type 1 diabetes in adolescence and young adulthood.

Previous Exposure to Measles, Mumps, and Rubella--but Not Vaccination During Adolescence--Correlates to the Prevalence of Pancreatic and Thyroid Autoantibodies

Objective. This study was designed to determine whether a relationship exists between previous exposure to measles, mumps, and rubella (MMR) by natural infection or vaccination or by new immunization with MMR vaccine, and either the presence or levels of autoantibodies against thyroid cell and pancreatic β-cell antigens. Methods. Antibodies against MMR and autoantibodies against thyroglobulin, thyroid peroxidase, pancreas islet cells (ICA), islet cell surface, glutamic acid decarboxylase 65k autoantibodies, and insulin were studied before, and 3 months after, vaccination with combined MMR vaccine in 386 school children between 11 and 13 years of age. Results. The vaccination changed neither the prevalence nor the level of autoantibodies. Children with rubella antibodies before vaccination had higher levels of ICA than did the rubella seronegative children. In contrast, thyroid autoantibody levels and prevalence were lower in children with antibodies against measles, mumps, or both before vaccination than in children without those antibodies. Conclusions. Previous natural infection or vaccination against measles, mumps, or both seemed to have an inhibitory effect on the development of thyroid autoantibodies. In contrast, children with previous exposure to rubella had higher levels of ICA. No evidence was found that MMR vaccination during adolescence may trigger autoimmunity.

The impact of thyroid autoimmunity in children and adolescents with Down syndrome

The extent to which autoimmunity contributes to thyroid dysfunction in individuals with Down syndrome (DS) has not been clarified. In this study, we used the same highly sensitive method to detect both thyroid autoantibodies (thyroglobulin and thyroid peroxidase autoantibodies) in 70 children (32 M and 38 F) with DS, mean age 10. 5 y (range 1–19 y). Twenty‐seven (39%) of the patients were found to have thyroid autoantibodies, the prevalence of antibody positivity increasing with age. Of the 17 (24%) of the series who were hypothyroid (i. e. high basal TSH level and a low total‐ or free‐T4 level), 11 had thyroid autoantibodies, and another 6 with thyroid autoantibodies became hypothyroid during 13–35 months of follow‐up. Thus, the findings suggest that the majority of hypothyroid children with DS suffer from autoimmune thyroid disease.

Thyroid Gland Volume as Measured by Ultrasonography in Healthy Children and Adolescents in a Non‐Iodine Deficient Area

We performed this study to determine the normal thyroid gland size in children of various ages living in Malmo, which is an iodine-sufficient area of Sweden

Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes.

To establish the diagnostic sensitivity of and the relationships between autoantibodies to all three Zinc transporter 8 (Zinc transporter 8 autoantibody to either one, two, or all three amino acid variants at position 325, ZnT8A) variants to human leukocyte antigen (HLA)‐DQ and to autoantibodies to glutamic acid decarboxylase (GADA), insulinoma‐associated protein 2 (IA‐2A), and insulin (IAA).

Growth and pubertal development in Down syndrome

Growth retardation and gonadal insufficiency are well‐known features of Down syndrome. In this longitudinal study, 44 home‐reared children and adolescents with Down syndrome, aged 10‐24 years, living in the county of Uppsala, were followed yearly. The male patients had a mean final height above that reported previously, and a close correlation between target and final heights was found. The mean final height in the female patients was below that reported earlier. Mean peak height velocities in males and females were 8.5 and 7.3 cm year‐1, respectively, significantly lower than in healthy children. The mean ages at peak height velocity were 12.3 and 10.8 years, respectively, indicating early growth spurts. The serum follicle‐stimulating hormone concentrations, the small testes and the negative correlation between luteinizing hormone and testicular volume in the males may indicate some primary gonadal insufficiency. For the girls, mean menarcheal age corresponded closely to that of their mothers.