Background:   Porphyrias are inherited disorders with impaired heme biosynthesis. Acute intermittent porphyria (AIP) is the most common porphyria in Sweden. AIP attacks may be life-threatening. Female sex hormones are regarded as important precipitating factors. Hepatocellular carcinoma (HCC) is a severe complication in the older AIP population. The aim of the thesis was to describe the clinical expression of AIP in women, experience of hormonal contraception and hormonal replacement therapies (HRT) and of pregnancies. Secondly, we evaluated gonadotropin-releasing hormone (GnRH) agonist treatment for prevention of menstrual-cycle-related AIP attacks. Thirdly, we evaluated whether an altered sex-steroid metabolism was present in AIP women compared with controls. Finally, we evaluated the benefit of screening for HCC in AIP in a 15-year follow-up study. Methods and results: In a retrospective population-based study in northern Sweden, 166 female AIP gene carriers ≥18 years of age participated. Manifest AIP (MAIP) was reported in 55%; 82% had severe attacks and 39% had menstrual-cycle-related attacks. Hormonal contraceptives were used by 94, and 12 reported that this precipitated AIP attacks. HRT and local vaginal treatments in menopause did not precipitate AIP attacks. Only 10% reported impairment of AIP symptoms during pregnancy. In the retrospective follow-up study of GnRH-agonist treatment, 11 of 14 women improved during treatment. Porphyria attacks were triggered in two women after estradiol add-back and in 5 of 9 women after progesterone add-back. In the sex-steroid metabolism study, levels of s-progesterone, estradiol, allopregnanolone and pregnanolone during the menstrual cycle in 32 AIP gene carriers were compared with 20 healthy controls. Progesterone metabolism in the AIP group differed from controls. In the AIP group levels of allopregnanolone, but not pregnanolone, were significantly lower. In the prospective HCC screening study AIP gene carriers aged >55 years were included. On average 62 subjects participated during 15 years. HCC was diagnosed in 22 of 180 eligible AIP gene carriers in the region (male:female, 12:10, 73% MAIP). The annual incidence of HCC was 0.8%. The risk of HCC was 64-fold higher than in the general population over 50 years of age in this region, and even higher for AIP women (93-fold). Increased 3- and 5-year survival was seen in the regularly screened AIP group. Liver lab tests were not useful in HCC screening. Conclusion: The clinical expression of AIP in women is pronounced and menstrual-cycle-related attacks are common. Hormonal contraceptives can induce AIP attacks and caution is recommended. GnRH-agonist treatment can ameliorate menstrual-cycle-related attacks of porphyria. Dose findings for GnRH-agonists and add-back regimes, especially for progesterone, are intricate. Progesterone metabolism in the AIP group differs from that in healthy controls. HCC screening in AIP gene carriers >50 years of age enables early diagnosis and a possibility for curative treatments. Annual HCC screening with liver imaging is recommended in AIP gene carriers >50 years of age.

Obstetric malpractice claims, concerning delivery during a period of eight years, were analysed for motives behind disciplinary actions, and for the frequency of inappropriate oxytocin use.Failure to respond to signs of foetal distress, injudicious use of oxytocin and a failure to effect a timely delivery were the recurrent problems that accounted for the majority of disciplinary actions. Inappropriate use of oxytocin was more frequent than reported in earlier studies. (Paper I) In a case-control study, differences in the obstetric management in neonates born with and without acidaemia (umbilical artery pH < 7.05), was evaluated. Out of 28,486 deliveries during 1994–2004, 305 neonates were born with acidaemia. Uterine hyperactivity and oxytocin use were independently associated to acidaemia at birth. The increased uterine activity was related to oxytocin treatment in 75 % of cases. Pathological cardiotocographic patterns occurred significantly more often in the case group. The results indicate that guidelines on oxytocin use and foetal surveillance are not followed. The duration of bearing down is less important when uterine contraction frequency has been considered. (Paper II) In a subset of study II, cases with metabolic acidosis (umbilical artery pH < 7.05 and base deficit ≥12 mmol/L) and controls were audited for the occurrence of suboptimal intrapartum care, and the nature of such care. It was found that suboptimal care occurred in half (49%) of the cases, while it was less frequent but not uncommon among controls (13%). Suboptimal care consisted of injudicious use of oxytocin and a failure of appropriate action upon signs of foetal distress. A high rate of NICU admissions and diagnosis of encephalopathy in the case group confirms that metabolic acidosis should be avoided. We estimate that metabolic acidosis could probably have been prevented in 40-50% of the cases.(PaperIII) Women (n=103) scheduled for elective caesarean section in regional anaesthesia were randomised to 5 or 10 units oxytocin, given as an intravenous bolus (double blinded), and electrocardiograms were analysed for ST depressions as a sign of myocardial ischaemia. ST depressions were associated with oxytocin administration significantly more often in subjects receiving 10 compared with 5 units. A dose of 10 units resulted in a more marked decrease of the mean arterial blood pressure, but no difference in increase of the heartrate. There was no difference in estimated blood loss. (paper IV)

<p>Amniocentesis (AC) and chorionic villus sampling (CVS) are the principal methods for fetal karyotyping. The aim of this thesis was to evaluate psychological reactions and risks associated with the procedures.</p><p>A semi-randomised study was made on 321 women, where AC (147) and CVS (174) at 10-13 weeks’ gestation were done trans-abdominally. Spontaneous fetal loss occurred in 6.8% and 1.7% of the women in the AC and CVS groups, respectively. Repeat testing was required more often in the AC (19.0%) than in the CVS (5.2%) group.</p><p>A subgroup of 94 women answered a questionnaire prior to the procedure. Anxiety was stated as reason for invasive testing in 38% of the women. Mean scores according to the Hospital Anxiety and Depression Scale for anxiety and depression were low. Likewise, mean scores for the Impact of Event Scale, evaluating the psychological distress evoked by the procedure, were low. Yet, a number of women had higher scores, indicating a risk of clinical anxiety and depression or psychological distress. The women worried most about miscarriage, fetal injury by the procedure and waiting for the result.</p><p>Fetal, infant and maternal outcomes were evaluated in a cohort of 71 586 women aged 35 to 49 years old, with single births in Sweden during 1991 to 1996. Altogether, 21 748 were exposed to AC and 1984 to CVS. Women exposed to AC and CVS were compared with non-exposed. Outcomes were extracted from the Swedish Medical Birth Register, the Swedish Hospital Discharge Register, and the Swedish Malformation Register. An increased risk of musculo-skeletal deformities, such as club foot (OR=1.45) and hip dislocation (OR=1.22), and respiratory disturbances such as neonatal pneumonia (OR=1.29), was found for infants born in the AC group. Risk increased with earlier gestation at the procedure. Fewer women in the AC group had a normal delivery and more had a Caesarean section. Complications related to the amniotic cavity and membranes (OR=1.15), hypotonic uterine dysfunction (OR=1.12) and instrumental vaginal deliveries (OR=1.11) were more common in the AC group. No significant differences were found for the CVS group.</p><p>CVS is the method of choice for prenatal karyotyping in the first trimester. AC should not be performed before 15 weeks’ gestation. Further research to develop methods to better identify women at increased risk of chromosomal abnormal pregnancies and to develop non-invasive tests for prenatal diagnosis is needed. Thereby, the number of women exposed to invasive procedures and the adverse effects caused by these procedures can be minimised.</p>

<p>The overall aims of the study were to determine the prevalence of anaemia in women of reproductive age and to investigate the underlying causes, as well as assess the effectiveness of antenatal care (ANC) interventions for anaemia prevention. Consecutive pregnant women booking for ANC (n=2235) were screened for anaemia, followed up and screened again late in pregnancy. Basic ANC interventions included iron and folate supplementation, malaria chemoprophylaxis and referral of severe anaemia cases, and in addition staff training and education for the women and the community at the study clinic. Non-pregnant women (n=504), adolescents: pregnant (n=76), non-pregnant (n=130), and boys (n=101) were also screened for anaemia. Haematological and biochemical investigations were made on anaemic cases.</p><p>The prevalences of anaemia and severe anaemia in pregnant women were 60% and 3.8%, respectively. The adolescent pregnant women were more anaemic, with an overall prevalence of anaemia of 76%. In the non-pregnant women the prevalence was 49%. Anaemia was more prevalent in adolescent girls than in boys, and iron deficiency was the main underlying cause in all groups. In the anaemic pregnant women, malaria and other infections were more common, and Serum ferritin therefore underestimates iron deficiency.</p><p>ANC interventions achieved a significant reduction in the prevalence of severe and moderate anaemia but only a moderate reduction in overall prevalence of anaemia. Time for treatment of anaemia during pregnancy is inadequate to correct pre-existing nutritional deficiencies, and all the underlying factors are not addressed. Anaemia control must include all women of reproductive age, starting with adolescents to build up their iron stores before pregnancy. ANC supplementation should include other nutrients, and there is also a need to identify and treat infections during pregnancy. Training of ANC providers and supervision as well as improvement in the logistics and supply supplements to the clinics needs reinforcement.</p>

<p>This thesis assesses some indicators of quality for maternity care in Tanzania, using antenatal management of anaemia and hypertension and emergency obstetric care as focal points. The care of pregnant women consecutively enrolled in antenatal care (n=379) was observed and compared with quality standard criteria. From a tertiary level labour ward 741 cases of eclampsia were identified and their antenatal care analyzed. A health systems analysis was performed for 205 cases of pregnancy complications at district level.</p><p>There was inadequate equipment and drugs, inadequate staff knowledge and motivation, and incorrect measurements for investigating anaemia and hypertension in pregnancy. Hospital incidence of eclampsia at tertiary level was 200/10,000 live births, and was not modified by antenatal care. The quality observed in the antenatal programme indicated little impact on either anaemia or hypertensive complications. Compliance with obstetric referral was only 46% and all four observed maternal deaths occurred due to transport problems. The proposed process indicators for essential obstetric care were inadequate to assess the quality of care on a district level. </p><p>There is a need to address structural weaknesses, to motivate health workers and to improve training on quality improvement. More research is warranted on indicators for obstetric needs, accessibility and referral system.</p>

Amniocentesis (AC) and chorionic villus sampling (CVS) are the principal methods for fetal karyotyping. The aim of this thesis was to evaluate psychological reactions and risks associated with the procedures. A semi-randomised study was made on 321 women, where AC (147) and CVS (174) at 10-13 weeks’ gestation were done trans-abdominally. Spontaneous fetal loss occurred in 6.8% and 1.7% of the women in the AC and CVS groups, respectively. Repeat testing was required more often in the AC (19.0%) than in the CVS (5.2%) group. A subgroup of 94 women answered a questionnaire prior to the procedure. Anxiety was stated as reason for invasive testing in 38% of the women. Mean scores according to the Hospital Anxiety and Depression Scale for anxiety and depression were low. Likewise, mean scores for the Impact of Event Scale, evaluating the psychological distress evoked by the procedure, were low. Yet, a number of women had higher scores, indicating a risk of clinical anxiety and depression or psychological distress. The women worried most about miscarriage, fetal injury by the procedure and waiting for the result. Fetal, infant and maternal outcomes were evaluated in a cohort of 71 586 women aged 35 to 49 years old, with single births in Sweden during 1991 to 1996. Altogether, 21 748 were exposed to AC and 1984 to CVS. Women exposed to AC and CVS were compared with non-exposed. Outcomes were extracted from the Swedish Medical Birth Register, the Swedish Hospital Discharge Register, and the Swedish Malformation Register. An increased risk of musculo-skeletal deformities, such as club foot (OR=1.45) and hip dislocation (OR=1.22), and respiratory disturbances such as neonatal pneumonia (OR=1.29), was found for infants born in the AC group. Risk increased with earlier gestation at the procedure. Fewer women in the AC group had a normal delivery and more had a Caesarean section. Complications related to the amniotic cavity and membranes (OR=1.15), hypotonic uterine dysfunction (OR=1.12) and instrumental vaginal deliveries (OR=1.11) were more common in the AC group. No significant differences were found for the CVS group. CVS is the method of choice for prenatal karyotyping in the first trimester. AC should not be performed before 15 weeks’ gestation. Further research to develop methods to better identify women at increased risk of chromosomal abnormal pregnancies and to develop non-invasive tests for prenatal diagnosis is needed. Thereby, the number of women exposed to invasive procedures and the adverse effects caused by these procedures can be minimised.

The overall aims of the study were to determine the prevalence of anaemia in women of reproductive age and to investigate the underlying causes, as well as assess the effectiveness of antenatal care (ANC) interventions for anaemia prevention. Consecutive pregnant women booking for ANC (n=2235) were screened for anaemia, followed up and screened again late in pregnancy. Basic ANC interventions included iron and folate supplementation, malaria chemoprophylaxis and referral of severe anaemia cases, and in addition staff training and education for the women and the community at the study clinic. Non-pregnant women (n=504), adolescents: pregnant (n=76), non-pregnant (n=130), and boys (n=101) were also screened for anaemia. Haematological and biochemical investigations were made on anaemic cases. The prevalences of anaemia and severe anaemia in pregnant women were 60% and 3.8%, respectively. The adolescent pregnant women were more anaemic, with an overall prevalence of anaemia of 76%. In the non-pregnant women the prevalence was 49%. Anaemia was more prevalent in adolescent girls than in boys, and iron deficiency was the main underlying cause in all groups. In the anaemic pregnant women, malaria and other infections were more common, and Serum ferritin therefore underestimates iron deficiency. ANC interventions achieved a significant reduction in the prevalence of severe and moderate anaemia but only a moderate reduction in overall prevalence of anaemia. Time for treatment of anaemia during pregnancy is inadequate to correct pre-existing nutritional deficiencies, and all the underlying factors are not addressed. Anaemia control must include all women of reproductive age, starting with adolescents to build up their iron stores before pregnancy. ANC supplementation should include other nutrients, and there is also a need to identify and treat infections during pregnancy. Training of ANC providers and supervision as well as improvement in the logistics and supply supplements to the clinics needs reinforcement.

This thesis assesses some indicators of quality for maternity care in Tanzania, using antenatal management of anaemia and hypertension and emergency obstetric care as focal points. The care of pregnant women consecutively enrolled in antenatal care (n=379) was observed and compared with quality standard criteria. From a tertiary level labour ward 741 cases of eclampsia were identified and their antenatal care analyzed. A health systems analysis was performed for 205 cases of pregnancy complications at district level. There was inadequate equipment and drugs, inadequate staff knowledge and motivation, and incorrect measurements for investigating anaemia and hypertension in pregnancy. Hospital incidence of eclampsia at tertiary level was 200/10,000 live births, and was not modified by antenatal care. The quality observed in the antenatal programme indicated little impact on either anaemia or hypertensive complications. Compliance with obstetric referral was only 46% and all four observed maternal deaths occurred due to transport problems. The proposed process indicators for essential obstetric care were inadequate to assess the quality of care on a district level. There is a need to address structural weaknesses, to motivate health workers and to improve training on quality improvement. More research is warranted on indicators for obstetric needs, accessibility and referral system.

Introduction: Neuroactive steroids represent a class of both synthetic and naturally occurring steroids that have an effect on neural function. In addition to classical genomic mechanism by the hormones progesterone, deoxycorticosterone and testosterone 3α-OH metabolites of these hormones enhance GABAA receptor through rapid non-genomic mechanism. The site(s) of action of these neuroactive steroids namely 3α-OH-5α-pregnan-20 one, (3α,5α)-3,21-deoxycorticosterone(3α5α-THDOC) and 5α androstane-3α,17β-diol on GABAA receptor are distinct from that of benzodiazepines and barbiturate binding sites. The modulation site(s) has a well-defined structure activity relationship with a 3α-hydroxy and a 20-ketone configuration in the pregnane molecule required for agonistic action. Pregnenolone sulfate is a noncompetitive GABAA receptor antagonist and inhibit GABA activated Cl- current in an activation dependant manner. 3β-hydroxy A-ring reduced pregnane steroids are also GABAA receptor antagonist and inhibit GABAA receptor function and its potentiation induced by their 3α-diesteromers in a noncompetitive manner. Aim: The aim was to investigate if the effect of GABA, pentobarbital antagonism by bicuculline and if the effect of GABA-agonist and antagonist neuroactive steroids including pregnenolone sulfate is dependant on the α-subunits of GABAA receptor. Furthermore, the studies aimed at investigating the binding site of pregnenolone sulfate and if its effect is dependent on γ-subunit. In addition, the inhibitory effect of pregnenolone sulfate and 3β-hydroxy steroids has been characterized. We also wanted to investigate if the neuroactive steroids effect vary between the human and rat recombinant α1β2γ2L receptors and between the long (L) and short (S) variants of γ2-subunit. Method: Experiments were performed by the two electrodes voltage-clamp technique using oocytes of Xenopus laevis expressed with recombinant GABAA receptors containing α1, α4 or α5, β2, γ2L and γ2S-subunits. Results: There was no difference between the α1, α4 and α5-containing subunits regarding GABA and pentobarbital inhibition by bicuculline. GABA-activated current in the binary αβ was potent than that of ternary αβγ receptor. Unlike Zn2+ effect, inhibition by pregnenolone sulfate on the GABAA receptor is not dependant on the γ-subunit. It is likely that the 2’ residue closest to the N-terminus of the protein at M2 helix on both α1 and β2 subunit are critical to the inhibitory actions of PS and the function of Cl- channels. Point mutation at M2 helix of the β2-subunit (b2A252S) can dramatically reduce the inhibitory effect of PS on the GABAA receptors without affecting the inhibitory properties of 3β-hydroxysteroids. Agonist and antagonist steroids also varied in their efficacy between the human and rat α1β2γ2L receptor. Neuroactive steroids also showed difference between human γ2L and γ2S-containing receptor. Conclusions: GABA and pentobarbital antagonism by bicuculline is not dependant on α-subunit. Pregnenolone sulfate binding site is different from that of Zn2+. 3β-hydroxysteroids and pregnenolone sulfate inhibit GABAA receptor through different mechanisms. Neuroactive steroids also differ between species and between the long and short variant of γ- subunit.

<p>De senaste åren har antalet kejsarsnitt på humanitär indikation ökat i Sverige. Den vanligaste bidragande orsaken till detta är förlossningsrädsla. Med förlossningsrädsla menas att man känner ångest och fruktan inför sin förlossning.</p><p>Syftet med denna litteraturstudie är att belysa faktorer som kan påverka upplevelsen av förlossningsrädsla samt vilket behov av stöd förlossningsrädda kvinnor behöver. Metoden som användes var en systematisk litteraturstudie som omfattade 16 vetenskapliga artiklar. Vid granskningen av dessa artiklar bildades två huvudkategorier, dessa var; upplevelser och stöd. Resultatet visade att den vanligaste upplevelsen vid förlossningsrädsla var rädsla för smärta och oron för sin och sitt barns hälsa och välmående. Förlossningsförloppet var också något som orsakade rädsla hos vissa kvinnor. Mest utsatta för förlossningsrädsla var kvinnor som led av dålig självkänsla och tvivlade på sin prestationsförmåga. Kvinnans tidigare erfarenheter spelade en stor roll vid upplevelsen av förlossningen. Den bästa vård förlossningsrädda kvinnor kan få är stöd från sin omgivning och vårdpersonal. Den mest framgångsrika behandlingsmetod enligt denna litteraturstudie var terapi.</p><p>En slutsats blev att det är viktigt att upptäcka kvinnans förlossningsrädsla i ett tidigt stadium och att omvårdnaden är individualiserad.</p>