Perinatal mortality and maternal health in rural China

Background and context Since the economic reforms of 1978, China has been acclaimed as a remarkable economy, achieving 9% annual growth per head for more than 25 years. However, China's health sector has not fared well. The population health gains slowed down and health disparities increased. In the field of health and health care, significant progress in maternal care has been achieved. However, there still remain important disparities between the urban and rural areas and among the rural areas in terms of economic development. The excess female infant deaths and the rapidly increasing sex ratio at birth in the last decade aroused serious concerns among policy makers and scholars. Decentralization of the government administration and health sector reform impacts maternal care. Many studies using census data have been conducted to explore the determinants of a high sex ratio at birth, but no agreement has been so far reached on the possible contributing factors. No study using family planning system data has been conducted to explore perinatal mortality and sex ratio at birth and only few studies have examined the impact of the decentralization of government and health sector reforms on the provision and organization of maternal care in rural China. Objectives The general objective of this study was to investigate the state of perinatal health and maternal care and their determinants in rural China under the historic context of major socioeconomic reforms and the one child family planning policy. The specific objectives of the study included: 1) to study pregnancy outcomes and perinatal health and their correlates in a rural Chinese county; 2) to examine the issue of sex ratio at birth and its determinants in a rural Chinese county; 3) to explore the patterns of provision, utilization, and content of maternal care in a rural Chinese county; 4) to investigate the changes in the use of maternal care in China from 1991 to 2003. Materials and Methods This study is based on a project for evaluating the prenatal care programme in Dingyuan county in 1999-2003, Anhui province, China and a nationwide household health survey to describe the changes in maternal care utilization. The approaches used included a retrospective cohort study, cross sectional interview surveys, informant interviews, observations and the use of statistical data. The data sources included the following: 1) A cohort of pregnant women followed from pregnancy up to 7 days after birth in 20 townships in the study county, collecting information on pregnancy outcomes using family planning records; 2) A questionnaire interview survey given to women who gave birth between 2001 and 2003; 3) Various statistical and informant surveys data collected from the study county; 4) Three national household health interview survey data sets (1993-2003) were utilized, and reanalyzed to described the changes in maternity care utilization. Relative risks (RR) and their confidence intervals (CI) were calculated for comparison between parity, approval status, infant sex and township groups. The chi-square test was used to analyse the disparity of use of maternal care between and within urban and rural areas and its trend across the years in China. Logistic regression was used to analyse the factors associated with hospital delivery in rural areas. Results There were 3697 pregnancies in the study cohort, resulting in 3092 live births in a total population of 299463 in the 20 study townships during 1999-2000. The average age at pregnancy in the cohort was 25.9 years. Of the women, 61% were childless, 38% already had one child and 0.3% had two children before the current pregnancy. About 90% of approved pregnancies ended in a live birth while 73% of the unapproved ones were aborted. The perinatal mortality rate was 69 per thousand births. If the 30 induced abortions in which the gestational age was more than 28 weeks had been counted as perinatal deaths, the perinatal mortality rate would have been as high as 78 per thousand. The perinatal mortality rate was negatively associated with the wealth of the township. Approximately two thirds of the perinatal deaths occurred in the early neonatal period. Both the still birth rate and the early neonatal death rate increased with parity. The risk of a stillbirth in a second pregnancy was almost four times that for a first pregnancy, while the risk of early neonatal deaths doubled. The early neonatal mortality rate was twice as high for female as for male infants. The sex difference in the early neonatal mortality rate was mainly attributable to mortality in second births. The male early neonatal mortality rate was not affected by parity, while the female early neonatal mortality rate increased dramatically with parity: it was about six times higher for second births than for first births. About 82% early neonatal deaths happened within 24 hours after birth, and during that time, girls were almost three times more likely to die than boys. The death rate of females on the day of birth increased much more sharply with parity than that of males. The total sex ratio at birth of 3697 registered pregnancies was 152 males to 100 females, with 118 and 287 in first and second pregnancies, respectively. Among unapproved pregnancies, there were almost 5 live-born boys for each girl. Most prenatal and delivery care was to be taken care of in township hospitals. At the village level, there were small private clinics. There was no limitation period for the provision of prenatal and postnatal care by private practitioners. They were not permitted to provide delivery care by the county health bureau, but as some 12% of all births occurred either at home or at private clinics; some village health workers might have been involved. The county level hospitals served as the referral centers for the township hospitals in the county. However, there was no formal regulation or guideline on how the referral system should work. Whether or not a woman was referred to a higher level hospital depended on the individual midwife's professional judgment and on the clients' compliance. The county health bureau had little power over township hospitals, because township hospitals had in the decentralization process become directly accountable to the township government. In the township and county hospitals only 10-20% of the recurrent costs were funded by local government (the township hospital was funded by the township government and the county hospital was funded by the county government) and the hospitals collected user fees to balance their budgets. Also the staff salaries depended on fee incomes by the hospital. The hospitals could define the user charges themselves. Prenatal care consultations were however free in most township hospitals. None of the midwives made postnatal home visits, because of low profit of these services. The three national household health survey data showed that the proportion of women receiving their first prenatal visit within 12 weeks increased greatly from the early to middle 1990s in all areas except for large cities. The increase was much larger in the rural areas, reducing the urban-rural difference from more than 4 times to about 1.4 times. The proportion of women that received antenatal care visits meeting the Ministry of Health s standard (at least 5 times) in the rural areas increased sharply from 12% in 1991-1993 to 36% in 2001-2003. In rural areas, the proportion increase was much faster in less developed areas than in developed areas. The hospital delivery rate increased slightly from 90% to 94% in urban areas while the proportion increased from 27% to 69% in rural areas. The fastest change was found to be in type 4 rural areas, where the utilization even quadrupled. The overall difference between rural and urban areas was substantially narrowed over the period. Multiple logistic regression analysis shows that time periods, residency in rural or urban areas, income levels, age group, education levels, delivery history, occupation, health insurance and distance from the nearest health care facilities were significantly associated with hospital delivery rates. Conclusions 1. Perinatal mortality in this study was much higher than that for urban areas as well as any reported rate from specific studies in rural areas of China. Previous studies in which calculations of infant mortality were not based on epidemiological surveys have been shown to underestimate the rates by more than 50%. 2. Routine statistics collected by the Chinese family planning system proved to be a reliable data source for studying perinatal health, including still births, neonatal deaths, sex ratio at birth and among newborns. National Household Health Survey data proved to be a useful and reliable data source for studying population health and health services. Prior to this research there were few studies in these areas available to international audiences. 3.Though perinatal mortality rate was negatively associated with the level of township economic development, the excess female early neonatal mortality rate contributed much more to high perinatal mortality rate than economic factors. This was likely a result of the role of the family planning policy and the traditional preferences for sons, which leads to lethal neglect of female newborns and high perinatal mortality. 4. The selective abortions of female foetuses were likely to contribute most to the high sex ratio at birth. The underreporting of female births seemed to have played a secondary role. The higher early neonatal mortality rate in second-born as compared to first-born children, particularly in females, may indicate that neglect or poorer care of female newborn infants also contributes to the high sex ratio at birth or among newborns. Existing family planning policy proved not to effectively control the steadily increased birth sex ratio. 5. The rural-urban gap in service utilization was on average significantly narrowed in terms of maternal healthcare in China from 1991 to 2003. This demonstrates that significant achievements in reducing inequities can be made through a combination of socio-economic development and targeted investments in improving health services, including infrastructure, staff capacities, and subsidies to reduce the costs of service utilization for the poorest. However, the huge gap which persisted among cities of different size and within different types of rural areas indicated the need for further efforts to support the poorest areas. 6. Hospital delivery care in the study county was better accepted by women because most of women think delivery care was very important while prenatal and postnatal care were not. Hospital delivery care was more systematically provided and promoted than prenatal and postnatal care by township hospital in the study area. The reliance of hospital staff income on user fees gave the hospitals an incentive to put more emphasis on revenue generating activities such as delivery care instead of prenatal and postnatal care, since delivery care generated much profits than prenatal and postnatal care . Recommendations 1. It is essential for the central government to re-assess and modify existing family planning policies. In order to keep national sex balance, the existing practice of one couple one child in urban areas and at-least-one-son a couple in rural areas should be gradually changed to a two-children-a-couple policy throughout the country. The government should establish a favourable social security policy for couples, especially for rural couples who have only daughters, with particular emphasis on their pension and medical care insurance, combined with an educational campaign for equal rights for boys and girls in society. 2. There is currently no routine vital-statistics registration system in rural China. Using the findings of this study, the central government could set up a routine vital-statistics registration system using family planning routine work records, which could be used by policy makers and researchers. 3. It is possible for the central and provincial government to invest more in the less developed and poor rural areas to increase the access of pregnant women in these areas to maternal care services. Central government together with local government should gradually provide free maternal care including prenatal and postnatal as well as delivery care to the women in poor and less developed rural areas. 4. Future research could be done to explore if county and the township level health care sector and the family planning system could be merged to increase the effectiveness and efficiency of maternal and child care. 5. Future research could be done to explore the relative contribution of maternal care, economic development and family planning policy on perinatal and child health using prospective cohort studies and community based randomized trials. Key words: perinatal health, perinatal mortality, stillbirth, neonatal death, sex selective abortion, sex ratio at birth, family planning, son preference, maternal care, prenatal care, postnatal care, equity, China

On the environmental genetics of depressive symptoms : Focus on two serotonergic genes

Depression is a complex psychiatric disorder influenced by several genes, environmental factors, and their interplay. Serotonin receptor 2A (HTR2A) and tryptophan hydroxylase 1 (TPH1) genes have been implicated in vulnerability to depression and other psychiatric disorders, but the results have been inconsistent. The present study examined whether these two genes moderated the influence of different depressogenic environmental factors on subthreshold depressive symptoms (assessed on a modified version of Beck s Depression Inventory, BDI) and depression-related temperament, i.e., harm avoidance (assessed on the Temperament and Character Inventory, TCI). The environmental factors included measures of childhood and adolescence exposure, i.e., maternal nurturance and parental socioeconomic status, and adulthood social circumstances, i.e., perceived social support and urban/rural residence. The participants were two randomly selected subsamples (n = 1246, n = 341) from the longitudinal population-based Cardiovascular Risk in Young Finns study (n = 3596). Childhood environmental factors were assessed when the participants were 3 to 18 years of age, and three years after the baseline. Adulthood environmental factors and outcome measures were assessed 17 and 21 years later when the participants were 21 to 39 years of age. The T102C polymorphism of the HTR2A gene moderated the association between childhood maternal nurturance and adulthood depressive symptoms, such that exposure to high maternal nurturance predicted low depressive symptoms among individuals carrying the T/T or T/C genotypes, but not among those carrying the C/C genotype. Likewise, high parental SES predicted low adulthood harm avoidance in individuals carrying the T/T or T/C genotype, but not in C/C-genotype carriers. Individuals carrying the T/T or T/C genotype were also sensitive to urban/rural residence, such that they had lower depressive symptoms in urban than in rural areas, whereas those carrying the C/C genotype were not sensitive to urban/rural residence difference. HTR2A did not moderate the influence of social support. TheA779C/A218C haplotype of the TPH1 gene was not involved in the association between childhood environment and adulthood outcomes. However, individuals carrying A alleles of the TPH1 haplotype were more vulnerable to the lack of adulthood social support in terms of high depressive symptoms than their counterparts carrying no A alleles. Furthermore, individuals living in remote rural areas and carrying the A/A haplotype had higher depressive symptoms than those carrying other genotypes of the TPH1. The findings suggest that the HTR2A and TPH1 genes may be involved in the development of depression by influencing individual s sensitivity to depressogenic environmental influences.

Preadolescents and Their Mothers as Oral Health-Promoting Actors : Non-biologic Determinants of Oral Health among Turkish and Finnish Preadolescents

Is oral health becoming a part of the global health culture? Oral health seems to turn out to be part of the global health culture, according to the findings of a thesis-research, Institute of Dentistry, University of Helsinki. The thesis is entitled as “Preadolescents and Their Mothers as Oral Health-Promoting Actors: Non-biologic Determinants of Oral Health among Turkish and Finnish Preadolescents.” The research was supervised by Prof.Murtomaa and led by Dr.A.Basak Cinar. It was conducted as a cross-sectional study of 611 Turkish and 223 Finnish school preadolescents in Istanbul and Helsinki, from the fourth, fifth, and sixth grades, aged 10 to 12, based on self-administered and pre-tested health behavior questionnaires for them and their mothers as well as the youth’s oral health records. Clinically assessed dental status (DMFT) and self-reported oral health of Turkish preadolescents was significantly poorer than the Finns`. A similar association occurred for well-being measures (height and weight, self-esteem), but not for school performance. Turkish preadolescents were more dentally anxious and reported lower mean values of toothbrushing self-efficacy and dietary self-efficacy than did Finns. The Turks less frequently reported recommended oral health behaviors (twice daily or more toothbrushing, sweet consumption on 2 days or less/week, decreased between-meal sweet consumption) than did the Finns. Turkish mothers reported less frequently dental health as being above average and recommended oral health behaviors as well as regular dental visits. Their mean values for dental anxiety was higher and self-efficacy on implementation of twice-daily toothbrushing were lower than those of the Finnish. Despite these differences between the Turks and Finns, the associations found in common for all preadolescents, regardless of cultural differences and different oral health care systems, assessed for the first time in a holistic framework, were as follows: There seems to be interrelation between oral health and general-well being (body height-weight measures, school performance, and self-esteem) among preadolescents: • The body height was an explanatory factor for dental health, underlining the possible common life-course factors for dental health and general well-being. • Better school performance, high levels of self-esteem and self-efficacy were interrelated and they contributed to good oral health. • Good school performance was a common predictor for twice-daily toothbrushing. Self-efficacy and maternal modelling have significant role for maintenance and improvement of both oral- and general health- related behaviors. In addition, there is need for integration of self-efficacy based approaches to promote better oral health. • All preadolescents with high levels of self-efficacy were more likely to report more frequent twice-daily toothbrushing and less frequent sweet consumption. • All preadolescents were likely to imitate toothbrushing and sweet consumption behaviors of their mothers. • High levels of self-efficacy contributed to low dental anxiety in various patterns in both groups. As a conclusion: • Many health-detrimental behaviors arise from the school age years and are unlikely to change later. Schools have powerful influences on children’s development and well-being. Therefore, oral health promotion in schools should be integrated into general health promotion, school curricula, and other activities. • Health promotion messages should be reinforced in schools, enabling children and their families to develop lifelong sustainable positive health-related skills (self-esteem, self-efficacy) and behaviors. • Placing more emphasis on behavioral sciences, preventive approaches, and community-based education during undergraduate studies should encourage social responsibility and health-promoting roles among dentists. Attempts to increase general well-being and to reduce oral health inequalities among preadolescents will remain unsuccessful if the individual factors, as well as maternal and societal influences, are not considered by psycho-social holistic approaches.

Socioeconomic Status, Occupational Factors and Lifestyle as Predictors of Hospitalisation for Back Disorders

The aim of this dissertation was to examine the determinants of severe back disorders leading to hospital admission in Finland. First, back-related hospitalisations were considered from the perspective of socioeconomic status, occupation, and industry. Secondly, the significance of psychosocial factors at work, sleep disturbances, and such lifestyle factors as smoking and overweight was studied as predictors of hospitalisation due to back disorders. Two sets of data were used: 1) the population-based data comprised all occupationally active Finns aged 25-64, and included hospitalisations due to back disorders in 1996 and 2) a cohort of employees followed up from 1973 to 2000 having been hospitalised due to back disorders. The results of the population-based study showed that people in physically strenuous industries and occupations, such as agriculture and manufacturing, were at an increased risk of being hospitalised for back disorders. The lowest hospitalisation rates were found in sedentary occupations. Occupational class and the level of formal education were independently associated with hospitalisation for back disorders. This stratification was fairly consistent across age-groups and genders. Men had a slightly higher risk of becoming hospitalised compared with women, and the risk increased with age among both genders. The results of the prospective cohort study showed that psychosocial factors at work such as low job control and low supervisor support predicted subsequent hospitalisation for back disorders even when adjustments were made for occupational class and physical workload history. However, psychosocial factors did not predict hospital admissions due to intervertebral disc disorders; only admissions due to other back disorders. Smoking and overweight predicted, instead, only hospitalisation for intervertebral disc disorders. These results suggest that the etiological factors of disc disorders and other back disorders differ from each other. The study concerning the association of sleep disturbances and other distress symptoms with hospitalisation for back disorders revealed that sleep disturbances predicted subsequent hospitalisation for all back disorders after adjustment for chronic back disorders and recurrent back symptoms at baseline, as well as for work-related load and lifestyle factors. Other distress symptoms were not predictive of hospitalisation.

Early growth and adult health: focus on blood pressure, glucose tolerance status and body composition

Theory of developmental origins of adult health and disease proposes that experiences during critical periods of early development may have consequences on health throughout a lifespan. Thesis studies aimed to characterize associations between early growth and some components of the metabolic syndrome cluster. Participants belong to two epidemiological cohorts with data on birth measurements and, for the younger cohort, on serial recordings of weight and height during childhood. They were born as singletons between 1924-33 and 1934-44 in the Helsinki University Central Hospital, and 500 and 2003 of them, respectively, attended clinical studies at the age of 65-75 and 56-70 years, respectively. In the 65-75 year old men and women, the well-known inverse relationship between birth weight and systolic blood pressure (SBP) was confined to people who had established hypertension. Among them a 1-kg increase in birth weight was associated with a 6.4-mmHg (95% CI: 1.0 to 11.9) decrease in SBP. This relationship was further confined to people with the prevailing Pro12Pro polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPARγ2) gene. People with low birth weight were more likely to receive angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB, p=0.03), and, again, this relationship was confined to the carriers of the Pro12Pro (p=0.01 for interaction). These results suggest that the inverse association between birth weight and systolic BP becomes focused in hypertensive people because pathological features of BP regulation, associated with slow fetal growth, become self-perpetuating in adult life. Insulin resistance of the Pro12Pro carriers with low birth weight may interact with the renin-angiotensin system leading to raised BP levels. Habitual physical activity protected men and women who were small at birth, and thus at increased risk for the development of type 2 diabetes, against glucose intolerance more strongly. Among subjects with birth weight ≤3000 g, the odds ratio (OR) for glucose intolerance was 5.2 (95% CI: 2.1 to 13) in those who exercised less than 3 times per week compared to regular exercisers; in those who scored their exercise light compared with moderate exercisers (defined as comparable to brisk walking) the OR was 3.5 (1.5 to 8.2). In the 56-70 year old men a 1 kg increase in birth weight corresponded to a 4.1 kg (95% CI: 3.1 to 5.1) and in women to a 2.9 kg (2.1 to 3.6) increase in adult lean mass. Rapid gain in body mass index (BMI), i.e. crossing from an original BMI percentile to a higher one, before the age of 2 years increased adult lean mass index (LMI, lean mass/height squared) without excess fat accumulation whereas rapid gain in BMI during later childhood, despite the concurrent rise in LMI, resulted in a relatively higher increase in adult body fat mass. These findings illustrate how genes, the environment and their interactions, early growth patterns, and adult lifestyle modify adult health risks which originate from early life.

Defects in tricarboxylic acid cycle enzymes Fumarate hydratase and Succinate dehydrogenase in cancer

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a recently characterized cancer syndrome which predisposes to cutaneous and uterine leiomyomas as well as renal cell carcinoma (RCC). Uterine leiomyosarcoma (ULMS) has also been observed in certain Finnish HLRCC families. The predisposing gene for this syndrome, fumarate hydratase (FH), was identified in 2002. The well-known function of FH is in the tricarboxylic acid cycle (TCAC) in the energy metabolism of cells. As FH is a novel cancer gene, the role of FH mutations in tumours is in general unknown. Similarly, the mechanisms through which defective FH is associated with tumourigenesis are unclear. The loss of a wild type allele has been observed in virtually all HLRCC patients tumours and the FH enzyme activities are either totally lost or remarkably reduced in the tissues of mutation carrier patients. Therefore, FH is assumed to function as a tumour suppressor. Mutations in genes encoding subunits of other TCAC enzyme SDH have also been reported recently in tumours: mutations in SDHB, SDHC, and SDHD genes predispose to paraganglioma and pheochromocytoma. In the present study, mutations in the SDHB gene were observed to predispose to RCC. This was the first time that mutations in SDHB have been detected in extra-paraganglial tumours. Two different SDHB mutations were observed in two unrelated families. In the first family, the index patient was diagnosed with RCC at the age of 24 years. Additionally, his mother with a paraganglioma (PGL) of the heart and his maternal uncle with lung cancer were both carriers of the mutation. The RCC of the index patient and the PGL of his mother showed LOH. In the other family, an SDHB mutation was detected in two siblings who were both diagnosed with RCC at the ages of 24 and 26 years. Both of the siblings also suffered PGL. All these tumours showed LOH. Therefore, we concluded that mutations in SDHB predispose also for RCC in certain families. Several tumour types were analysed for FH mutations to define the role of FH mutations in these tumour types. In addition, patients with a putative cancer phenotype were analysed to identify new HLRCC families. Three FH variants were detected, of which two were novel. One of the variants was observed in a patient diagnosed with ULMS at the age of 41 years. However, LOH was not detected in the tumour tissue. The FH enzyme activity of the mutated protein was clearly reduced, being 43% of the activity of the normal protein. Together with the results from an earlier study we calculated that the prevalence of FH mutations in Finnish non-syndromic ULMS is around 2.4%. Therefore, FH mutations seem to have a minor role in the pathogenesis on non-syndromic ULMS. Two other germline variants were detected in a novel tumour type, ovarian mucinous cystadenoma. However, tumour tissues of the patients were not available for LOH studies and therefore LOH status remained unclear. Therefore, it is possible that FH mutations predispose also for ovarian tumours but further studies are needed to verify this result. A novel variant form of the FH gene (FHv) was identified and characterized in more detail. FHv contains an alternative first exon (1b), which appeared to function as 5 UTR sequence. The translation of FHv is initiated in vitro from exons two and three. The localization of FHv is both cytosolic and nuclear, in contrast to the localization of FH in mitochondria. FHv is expressed at low levels in all human tissues. Interestingly, the expression was induced after heat shock treatment and in chronic hypoxia. Therefore, FHv might have a role e.g. in the adaptation to unfavourable growth conditions. However, this remains to be elucidated.

Effects of living crown reduction on needle element status of Scots pine

A wide range of biotic and abiotic factors, operating over different time perspectives and intensities, cause defoliation and a rapid decrease in the crown size of trees. Scleroderris canker disease [Gremmeniella abietina (Lagerb.) Morelet] has caused widespread crown reduction and tree mortality in Scots pine (Pinus sylvestris L) in forests in Scandinavia during the last three decades. In the 1980's, attempts were made to show, on the basis of the higher foliar N and S concentrations of affected pines in the diseased area, that sulphur and nitrogen deposition predispose trees to G. abietina. Unfortunately, in many studies on defoliated trees, exceptionally high or low needle mineral nutrient concentrations are still often interpreted as one of the causes of tree injury and not, conversely, as the result. In this thesis, three different field experiments, with foliar analysis as the main study method, were conducted in order to asses the possible long-term effects of living crown reduction on the needle nutrient concentrations of Scots pine trees in southern Finland. The crown ratio and length of the living crown were used to estimate the amount of defoliation in the reduced canopies. The material for the partial studies was collected and a total of 968 foliar samples were analysed individually (15-17 elements/sample) on a total of 488 sample trees (140 diseased, 116 pruned and 232 control trees) during the years 1987-1996 in 13 Scots pine stands. All the three experiments of this thesis provided significant evidence that severe, disease-induced defoliation or artificial pruning of the living branches can induce long-lasting nutritional changes in the foliage of the recovering trees under the typical growing conditions for Scots pine. The foliar concentrations of all the 17 mineral nutrients/elements analysed were affected, to a varying degree, by artificial pruning during the following three years. Although Scots pine, as an evergreen conifer, is considered to have low induced chemical responses to defoliation, this study proved experimentally under natural forest conditions that severe artificial pruning or disease-induced defoliation of Scots pine trees may induce biologically significant changes in the concentrations of most of the important macro- and micronutrients, as well as of carbon, in refoliated needles. Concerning the studies in this thesis, I find the results significant in providing new information about the long-term effects of rapid living crown reduction on the foliar nutrient and element status of Scots pine trees. Key words: Foliar analysis, defoliation, needle loss, pruning, nutrients, Pinus sylvestris, Gremmeniella abietina

Venous thromboembolism during pregnancy and the impact of thrombophilia in pregnancy complications

Venous thromboembolism (VTE) is the greatest single cause of maternal mortality in pregnant women in developed countries. Pregnancy is a hypercoagulable state and brings about an enhanced risk of deep venous thrombosis (DVT) in otherwise healthy women. Traditionally, unfractionated heparin (UFH) has been used for treatment of DVT during pregnancy. We showed in our observational study that low molecular weight heparin (LMWH) is as effective and safe as UFH in the treatment of DVT during pregnancy. Although DVT during pregnancy is often massive, increasing the risk of developing long-term consequences, namely post-thrombotic syndrome (PTS), only 11% of all patients had confirmed PTS 3 4 years after DVT. In our studies the prevalence of PTS was not dependent on treatment (UFH vs LMWH). Low molecular weight heparin is more easily administered, few laboratory controls are required and the hospital stay is shorter, factors that lower the costs of treatment. Cervical insufficiency is defined as repeated very preterm delivery during the second or early third trimester. Infection is a well-known risk factor of preterm delivery. We found overpresentation of thrombophilic mutations (FV Leiden, prothrombin G20210A)among 42 patients with cervical insufficiency compared with controls (OR 6.7, CI 2.7 18.4). Thus, thrombophilia might be a risk factor of cervical insufficiency possibly explained by interaction of coagulation and inflammation processes. The presence of antiphospholipid (aPL) antibodies increases the risk for recurrent miscarriage (RM). Annexins are proteins which all bind to anionic phospholipids (PLs) preventing clotting on vascular phospholipid surfaces. Plasma concentrations of circulating annexin IV and V were investigated in 77 pregnancies at the beginning of pregnancy among women with a history of RM, and in connection to their aPL antibody status. Control group consisted unselected pregnant patients (n=25) without history of adverse pregnancy outcome. Plasma levels of annexin V were significantly higher at the beginning (≤5th week) of pregnancy in women with aPL antibodies compared with those without aPL antibodies (P=0.03). Levels of circulating annexin V were also higher at the 6th (P= 0.01) and 8th week of pregnancy in subjects with aPL antibodies (P=0.01). Results support the hypothesis that aPL could displace annexin from anionic phospholipid surfaces of syncytiotrophoblasts (STBs) and may exert procoagulant activities on the surfaces of STBs Recurrent miscarriage (RM) has been suggested to be caused by mutations in genes coding for various coagulation factors resulting in thrombophilia. In the last study of my thesis were investigated the prevalence of thrombomodulin (TM) and endothelial protein C receptor polymorphism EPCR among 40 couples and six women suffering RM. This study showed that mutations in the TM or EPCR genes are not a major cause of RM in Finnish patients.

Bone health and vitamin D status in children with motor disability and adults with intellectual disability

Osteoporosis is not only a disease of the elderly, but is increasingly diagnosed in chronically ill children. Children with severe motor disabilities, such as cerebral palsy (CP), have many risk factors for osteoporosis. Adults with intellectual disability (ID) are also prone to low bone mineral density (BMD) and increased fractures. This study was carried out to identify risk factors for low BMD and osteoporosis in children with severe motor disability and in adults with ID. In this study 59 children with severe motor disability, ranging in age from 5 to 16 years were evaluated. Lumbar spine BMD was measured with dual-energy x-ray absorptiometry. BMD values were corrected for bone size by calculating bone mineral apparent density (BMAD), and for bone age. The values were transformed into Z-scores by comparison with normative data. Spinal radiographs were assessed for vertebral morphology. Blood samples were obtained for biochemical parameters. Parents were requested to keep a food diary for three days. The median daily energy and nutrient intakes were calculated. Fractures were common; 17% of the children had sustained peripheral fractures and 25% had compression fractures. BMD was low in children; the median spinal BMAD Z-score was -1.0 (range -5.0 – +2.0) and the BMAD Z-score <-2.0 in 20% of the children. Low BMAD Z-score and hypercalciuria were significant risk factors for fractures. In children with motor disability, calcium intakes were sufficient, while total energy and vitamin D intakes were not. In the vitamin D intervention studies, 44 children and adolescents with severe motor disability and 138 adults with ID were studied. After baseline blood samples, the children were divided into two groups; those in the treatment group received 1000 IU peroral vitamin D3 five days a week for 10 weeks, and subjects in the control group continued with their normal diet. Adults with ID were allocated to receive either 800 IU peroral vitamin D3 daily for six months or a single intramuscular injection of 150 000 IU D3. Blood samples were obtained at baseline and after treatment. Serum concentrations of 25-OH-vitamin D (S-25-OHD) were low in all subgroups before vitamin D intervention: in almost 60% of children and in 77% of adults the S-25-OHD concentration was below 50 nmol/L, indicating vitamin D insufficiency. After vitamin D intervention, 19% of children and 42% adults who received vitamin D perorally and 12% of adults who received vitamin D intramuscularly had optimal S-25-OHD (>80 nmol/L). This study demonstrated that low BMD and peripheral and spinal fractures are common in children with severe motor disabilities. Vitamin D status was suboptimal in the majority of children with motor disability and adults with ID. Vitamin D insufficiency can be corrected with vitamin D supplements; the peroral dose should be at least 800 IU per day.