Objectives: To study indicators specifically reflecting the reproductive health of Ukrainian women and to analyse factors behind the indicators. Methods: Induced abortion and maternal mortality were studied in some countries/regions of the former Soviet Union, using official statistics. Abortion rates, contraceptive practices and intentions in Ukrainian women were analysed by a large self-completion survey in 1996, and by a classroom questionnaire to first year medical students in 1999 in Donetsk, Ukraine. Totally, 1694 women and 689 students participated. Perinatal mortality was studied, applying the Nordic-Baltic perinatal death classification to all cases in the Donetsk region in 1997-98 (n=1126) and in Denmark in 1996 (n=540). Clinical guidelines, use of technology and rates of interventions in the two regions were analysed. Results: Abortion remains a major method of fertility control and abortion-related mortality contributes to maternal deaths. Perinatal mortality rate is twice as high in the Donetsk region as in Denmark. A substantial proportion of sexually active women do not practice contraception. Modern methods of contraception are not widely used. There is a lack of knowledge in reproductive health issues and negative attitude to OCs. There is a positive attitude towards abortion as an acceptable fertility control method and of having abortion instead of using OCs or IUD. Poor economy is an obstacle to the use of contraceptive methods associated with a cost. Lack of experience with contraception reduces the intention to use any method in the future. Being single, younger than 19 years, living with parents, having a positive attitude towards abortion as fertility control method, having a history of previous childbirth and/or abortion are important factors associated with pregnancy termination. Antepartum deaths of growth-retarded fetuses, intrapartum and neonatal deaths associated with asphyxia are more common in Ukraine than in Denmark, particularly among premature infants. Lack of evidence-based clinical guidelines and adequate resources for fetal monitoring during pregnancy and labour, together with negative attitudes towards, and limited resources for, instrumental delivery, contribute to high perinatal mortality. Conclusion: Better reproductive education/information of all strata of society is needed. Implementation of evidence-based guidelines in perinatal medicine, where international collaboration can be of great value, should be a matter of high priority.

The appropriateness of universal screening for gestational diabetes mellitus (GDM) has been strongly questioned, since it does not satisfy ethical principles for screening. The aims of these studies were to determine the prevalence of GDM, expressed in terms of impaired glucose tolerance (IGT) and diabetes mellitus (DM), to evaluate different screening models using traditional anamnestic risk factors and repeated random B-glucose, to determine whether GDM increases risks for maternal complications such as preeclampsia, and to determine whether IGT during pregnancy, if left untreated, is associated with increased maternal or neonatal morbidity. Of 4,918 pregnant non-diabetic women attending maternal health care, 73.5% agreed to have a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed in 1.7%, IGT in 1.3% and DM in 0.4%. Traditional risk factor criteria were fulfilled by 15.8%. Prior GDM and a prior macrosomic infant showed the highest association with GDM. No selective or two-step universal screening model would have detected all cases of GDM. A constructed model comprising prior GDM, a prior LGA/macrosomic infant, or a cut-off random B-glucose level of 8 mmol/l as an indication for OGTT reduced the need for OGTT to 7.3% compared to the selective screening model with traditional risk factors. Such a universal two-step screening model had 100% sensitivity for DM, and 44.7% sensitivity for IGT. The Swedish Medical Birth Register was used to evaluate GDM as risk factor for preeclampsia. GDM occurred in 0.8% and preeclampsia in 2.9% of 430,852 singleton pregnancies. There is an independent and significant association between GDM and preeclampsia. Obesity is a major confounding factor, but cannot explain the total excess risk. In a prospective population-based case-control study 213 women with untreated IGT during pregnancy were identified. For each case, four controls were recruited from the same delivery department. The analyses confirmed that maternal and fetal morbidity were increased in the cases in terms of cesarean section rate, pre-term delivery, Erb’s palsy and admission to NICU. There was a marked, independent increase in the proportion of LGA infants (OR 7.3; 95% CI 4.1-12.7). To determine whether treatment has an effect when IGT is diagnosed during pregnancy, a randomized study is required.

Antenatal care has been associated with improved maternal and perinatal outcomes but there is no agreement on the most effective model in terms of content as well as the number and timing of visits. A cluster randomised controlled trial was conducted in a rural area of Zimbabwe to assess a 5-visit goal-oriented antenatal care model against standard care. In the same population was also determined the sensitivity of factors used for risk screening to predict pregnancy complications and the effectiveness of the referral system in managing women with identified risk markers or pregnancy complications. Pregnancy records of 10 572 out of total 13 517 recruited women were available for analysis. The new model did not change the number of visits but resulted in better use of health care. The classical risk screening system had low predictive value and identified too large a risk group for referral. Nulliparous women had an increased risk for pregnancy complications whereas women with previous uncomplicated pregnancies were at low risk of complications even with high parity. Multiparous women with previous complications had an increased risk of complications but better utilisation of health care services for delivery reduced adverse perinatal outcomes. There was a functional referral system in Gutu and women complied with referral indications but efficiency of the system was reduced by failure of care providers to comply with referral recommendations. Antenatal care can be improved in a rural setting through a focussed programme and the unpredictability of many pregnancy complications limits the value of antenatal risk screening. Until universal access to essential obstetric care facilities is attained in low resource settings, a critical re-examination of risk factors could avoid overburdening the referral system.

The effects of environmental contaminants in humans and animals are of great concern. Some contaminants are endocrine disruptors that may interfere with the endogenous hormonal signalling and disturb, for example, reproductive organs and functions. Primary uterine myometrial cells originating from women and Baltic grey seals were exposed to some polychlorinated biphenyls (PCBs) and their metabolites. Even though human and Baltic grey seal myometrial cells responded differently to the tested PCBs, the results indicate that PCBs can influence myometrial cell proliferation in vitro. The prevalence of uterine leiomyomas was investigated among 257 Baltic grey seals. Leiomyomas were only present in females older than 22 years, at a prevalence of 65%. Proliferation in leiomyoma cells was detected in individuals lacking ovarian proliferation support, suggesting the presence of an exogenous stimulant. By taking into account temporal alterations in the contaminant burden of the seals, PCB exposure was found to be associated with leiomyoma prevalence. In conclusion, PCB exposure may be related to uterine leiomyoma development and proliferation in Baltic grey seals in vivo. Human endometrial endothelial cells (HEECs) were exposed to some endocrine disruptors, and the effects of the endocrine disruptors on cell proliferation and viability were studied. All evaluated endocrine disruptors decreased HEEC proliferation and most also decreased HEEC viability. Further studies revealed that the reduction in HEEC proliferation after exposure to o,p’-DDT was associated with differential expression of mRNA involved in proliferation, defence response, and lipid and cholesterol metabolism compared to untreated HEEC. In conclusion, these studies suggest that endocrine disruptors affect cultured cells from the female reproductive tract of humans and grey seals, and may have deleterious effects on proliferation, viability, and genes involved in defence response, and lipid or cholesterol metabolism.

Many women experience miscarriage every year. Every fourth woman who has given birth reports that she has previous experience of miscarriage. In a study of all women in the Swedish Medical Birth Register 1983-2003, we found that the number of cases of self reported miscarriage had increased in Sweden during this 21 year period. This increase can be explained by the introduction of sensitive pregnancy tests around 1990, as well as an increase in the mean age of the mothers, by approximately 3 years, during the observation period. The risk of miscarriage is 13% with the first child. With subsequent pregnancies, the risk of miscarriage is 8%, 6% and 4% with the second, third and fourth child, respectively. Thirteen of these women who had suffered a recent miscarriage were interviewed four months later, and their feelings of guilt and emptiness were explored. Their experience was that they wanted their questions to be answered, and that they wanted others to treat them as the mothers to be that they felt themselves to be. They also experienced the need for time to grieve their loss. Measurement of grief by means of the Perinatal Grief Scale (PGS) is used in research but has also been proposed for clinical use. We have translated this psychological instrument to Swedish, back-translated and tested it in a small pilot study. In a randomized controlled study, women with early miscarriage were allocated, either to a structured visit (study group) or a regular visit (control group) to a midwife. The structured visit was conducted according to the Swanson caring theory. We could conclude that the structured visit had no significant effect on grief compared to the regular visit, as measured using the PGS. However, women with the sub-diagnosis missed abortion have significantly more grief four months after early miscarriage, regardless of visit type. We also performed a content analysis of the tape-recorded structured follow-up visit. The code-key used was Bonanno and Kaltman’s general grief categorization. Women’s expression of grief after miscarriage was found to be very similar to the grief experienced following the death of a relative. Furthermore, the grief was found to be independent of number of children, women’s age, or earlier experience of miscarriage. Conclusions: Every fourth woman who gives birth reports that she has also experienced early miscarriage. The experience of these women is that they have suffered a substantial loss and their reaction is grief similar to that experienced following the death of a relative. / On the day of the public defence of the doctoral thesis the status of article III was In Press and article IV was In Press.

In the past decades there has been an improvement in the medical treatment of children born preterm or with reduced foetal growth. This has resulted in a much higher survival rate of these children, but also in a higher number of surviving children with chronic conditions. These changes have, in turn, increased interest in investigating the connection between birth-characteristics and outcomes in later life. The overall aim of the present thesis was to study the relations between birth-characteristics, subsequent hospitalisations, and childbearing by means of data available in Swedish population-based registries. The study population in this thesis consisted of women (and men in Paper III) born in 1973-75 according to the Medical Birth Register and the Total Population Register. Information available in other registries, such as the Hospital Discharge Register, was obtained by individual record linkage. In Paper I, 148,281 women, alive and living in Sweden at 13 years of age, were included. Of the women, 4.1% were born preterm and 5.4% were born small for gestational age, and approximately 30% of all women had given birth between 13 and 27 years of age. We found that reduced foetal growth and possibly preterm birth were related to the likelihood of giving birth during the study period. The intergenerational effects of preterm birth and reduced foetal growth were investigated in Paper II and the study population consisted of 38,720 mother-offspring pairs. An intergenerational effect of reduced foetal growth was found, and reduced foetal growth in the mother also increased the risk for preterm birth in the child. Paper III was concerned with 304,275 men and women living in Sweden at 13 years of age. Of these men and women, 30% were hospitalised during adolescence and early adulthood (i.e. between 12 and 23 years of age). We found that men and women born small for gestational age or preterm were more likely to be hospitalised, and that those born small for gestational age seemed to be more at risk compared to those born preterm. Finally, in Paper IV, the relation between hospitalisations during adolescence and the likelihood of giving birth was studied in 142,998 women living in Sweden at 20 years of age. We found that a majority of the causes of hospitalisation during adolescence were positively connected to the likelihood of giving birth between 20 and 27 years of age. The relations presented in Papers I-IV were evident although socio-economic characteristics were adjusted for.

Hyaluronan is an important component of the lung extracellular matrix, with a high capacity for water immobilization, but information on perinatal changes in the lung hyaluronan concentration and their association with changes in the lung water content is limited. In this study, conducted both in rabbit pups and in human infants, we investigated changes in the hyaluronan concentration and distribution in the lung and in the lung water content after preterm or term birth, and changes produced by common antenatal and postnatal pathological conditions and treatments. In rabbit pups, we found a gradual decrease in lung hyaluronan concentration and in the intensity of alveolar hyaluronan staining with advancing gestational age at birth in late gestation, but no further changes during the first 7-9 days of life. The lung water content was uniformly high before birth, but decreased significantly after preterm delivery or at birth at term. Postnatal exposure of newborn preterm or term rabbit pups to hyperoxia for 4-9 days resulted in an increase in both lung hyaluronan concentration and lung water content. This was accompanied by more intense hyaluronan staining, mainly in the alveolar walls. Antenatal exposure of rabbit pups to betamethasone or terbutaline resulted in a lower lung hyaluronan concentration at preterm birth, associated with less intense hyaluronan staining in alveolar walls, without altering the lung water content. Betamethasone exposure had a maximal effect at 25 days of gestation (term = 31 days), decreasing thereafter with advancing gestation, while terbutaline exposure resulted in a gradually increasing effect during late gestation, with a maximum at 29 days. In deceased infants born at a gestational age of < 32 weeks, the lung hyaluronan concentration at death was most strongly associated with the gestational age at birth. It also covaried with sex, antenatal steroid administration, intrauterine bleeding, mode of delivery, birth weight, IRDS, and surfactant treatment. In infants born at a gestational age of > 33 weeks there was a weaker association between lung hyaluronan concentration and gestational age. In this group, the lung hyaluronan concentration was associated with administration of a high concentration of oxygen, and covaried with maximal ventilatory pressure, and lung water content.

Background: Depressive and anxiety disorders are common health problems, affecting women at least twice as often as men. Although some studies have been made on pregnant women or, especially, in the postpartum period, most of these studies have been performed on small samples, mainly specific risk groups such as teenage mothers, women of low socioeconomic status and certain ethnic groups. Also, there is a lack of studies on antenatal and postpartum depression and/or anxiety using diagnostic criteria adhering to the Diagnostic and Statistical Manual of Mental disorders, fourth edition (DSM-IV). Aims and methods: The aims were to estimate the point prevalence of mood, anxiety and eating disorders, based on DSM-IV criteria, in an unselected population during the second trimester of pregnancy, and to assess the obstetric and neonatal outcome, as well as the health care consumption during pregnancy, delivery and the early postpartum period among women with a psychiatric disorder, compared to healthy subjects. Finally, we aimed to investigate depression and anxiety, and associated maternal characteristics and events through pregnancy and the postpartum period in the same group of women. The Primary Care Evaluation of Mental Disorders (PRIME-MD) was used for assessment of psychiatric disorders during the second trimester of pregnancy and three to six months after delivery. From October 2nd, 2000, to October 1st, 2001 all women attending the second trimester routine ultrasound-screening at two different hospitals in northern Sweden (at Umeå University Hospital and at Sunderby Central Hospital) were approached for participation in the study. After delivery, data were extracted from the medical records of the mothers and their offspring to evaluate obstetric and neonatal outcome. Three to six months after delivery, the women who had an antenatal depression and/or anxiety were contacted for an assessment using the PRIME-MD. The same procedure was made in a control group, consisting of 500 women, randomly selected among those who did not have any psychiatric diagnosis according to the PRIME-MD investigation during the second trimester of pregnancy. Results and conclusions: Of the 1555 women in the study population, 220 (14.1%) had one or more PRIME-MD diagnoses. Living single, low socioeconomic status, smoking, multiparity and a body mass index of 30 or more were significantly associated with a psychiatric diagnosis in the second trimester of pregnancy. Women with antenatal depression and/or anxiety more often suffered from nausea and vomiting during pregnancy were more often on sick leave, and they visited their obstetrician more often than healthy subjects, specifically because of fear of childbirth and premature contractions. Also, they were more commonly delivered by elective caesarean section, had an increased use of epidural analgesia and reported a longer self-experienced duration of labor. Severe complications of pregnancy, delivery, and the early postpartum period were not affected by antenatal depression and/or anxiety. There was no significant difference in neonatal outcome depending on antenatal depressive or anxiety disorder. Fewer cases of depressive and/or anxiety disorders were prevalent postpartum, but there was a significant shift from a majority of sub-threshold diagnoses during pregnancy to full DSM-IV diagnoses during the postpartum period. Previous psychiatric disorder and living singly were significantly associated with both a new-onset and a postpartum continuation/recurrence of depression and/or anxiety. Postpartum continuation/recurrence of a psychiatric disorder was additionally associated with smoking, obesity, and adverse obstetric events.

Progesterone metabolites as allopregnanolone, isoallopregnanolone and tetrahydrodeoxy-corticosterone (THDOC) are increased in the luteal phase of the menstrual cycle, throughout pregnancy and during stress. Allopregnanolone and THDOC are neurosteroids with 3α-hydroxy, 5α-configurations and positive modulating effect on the GABAA receptor. They have similar properties and effect, and share the same binding sites on the GABAA receptor. Isoallopregnanolone has a 3β-hydroxy, 5α-configuration and a diverse effect as a proposed antagonist to both allopregnanolone and THDOC. Neurosteroids are thought to exert their effect predominantly at extrasynaptic GABAA receptors, containing for example α4- or α5-subunits. Such receptors are involved in the tonic response. Different subunits have diverse distribution pattern in the brain and are involved in different functions. The α5-subunit, mainly expressed in the hippocampus, is involved in learning, while α4 is more widespread and involved in e.g. anxiety and anaesthesia. The aim of the present thesis was to contribute to the knowledge about selected progesterone metabolites and their effects on learning and tolerance development, as well as their metabolism. Also basic characteristics between different α-subunits of the GABAA receptor were evaluated. The thesis shows that the effect of bicuculline and pentobarbital is not dependent on the α-subunit isoform of the GABAA receptor expressed in oocytes. Acute tolerance developed after allopregnanolone-induced anaesthesia with a decrease at both mRNA and protein levels of the GABAA receptor α4-subunit in the thalamus VPM nucleus. A negative correlation between the α4 mRNA and the increased dose of allopregnanolone needed to maintain the anaesthesia level was also shown. In addition, allopregnanolone induces a learning impairment in the Morris water maze test, when high concentrations of allopregnanolone are present in the brain. This impairment is not possible to reverse by isoallopregnanolone. In α5β3γ2L-transfected HEK-293 cells THDOC induces a baseline shift of its own and also potentiate the GABA-current. Neither of those THDOC effects can be inhibited by isoallopregnanolone. Instead isoallopregnanolone shows an agonistic effect on the THDOC-potentiation of the GABA-response. The main allopregnanolone metabolites identified, 5α-DHP and isoallopregnanolone, as well as allopregnanolone itself are mainly localized to the brain after an i.v. injection. After an isoallopregnanolone injection there is a more even distribution of the given steroid and the metabolites between plasma and brain. There is an epimerisation between isoallopregnanolone and allopregnanolone and vice versa. In conclusion, the present thesis shows that the α4-subunit in the thalamus VPM nucleus is likely to be involved in the acute tolerance development against allopregnanolone and that allopregnanolone-induced learning impairment is likely to be hippocampus dependent. The lack of antagonistic effect of isoallopregnanolone on the THDOC-induced α5β3γ2L-GABAA response, together with epimerisation of isoallopregnanolone to allopregnanolone, could explain why isoallopregnanolone does not work as an antagonist to the allopregnanolone-induced learning impairment in a hippocampus dependent learning task.

These studies were undertaken to investigate risks of maternal and perinatal complications in pregnant women with chronic hypertensive disease, and to investigate future risk of preeclampsia in women born small for gestational age (SGA). Population based cohort studies using the Swedish Medical Birth Register from different years were performed. The maternal complications mild and severe preeclampsia, gestational diabetes and abruptio placenta were studied in a population of 681 515 women, with a prevalence of 0,5% for chronic hypertension. Risk estimates were adjusted for differences in maternal characteristics as age, parity, BMI, ethnicity and smoking habits. Chronic hypertensive women wore found to have significantly increased risks of all complications. The perinatal complication SGA was studied in a population of 560 188, with a prevalence of 0,5% for chronic hypertension. Risk estimates were adjusted for differences in maternal characteristics and for the secondary complications mild and severe preeclampsia. Chronic hypertensive women were found to suffer a significantly increased risk of giving birth to an offspring that is SGA. The perinatal complication fetal/infant mortality was studied in a population of 1 222 952 with a prevalence of 0,6% for chronic hypertension. Risk estimates were adjusted for differences in maternal characteristics and for the complications mild and severe preeclampsia, gestational diabetes, abruptio placenta and offspring being SGA In the analysis an effect modification by gender was included. Chronic hypertensive women were found to have a significantly increased risk for stillbirth and neonatal death in male, but not in female, offspring. Thus a clear gender difference in mortality was revealed. The risk of mortality of offspring was mediated by severe preeclampsia, abruptio placenta and offspring being SGA. Mild preeclampsia and gestational diabetes did not affect the risk. No increased risk of post neonatal mortality was found. A generation study was performed in 118 634 girls of which 5.8% were born SGA. Their future risk for mild and severe preeclampsia in first pregnancy was analysed. Risk estimates were adjusted for age, smoking, BMI and for preeclampsia in the mothers while pregnant with the study population. Women who were born SGA were shown to have a significantly increased risk for severe preeclampsia, but not for mild preeclampsia.