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.

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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)

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The incidence of allergic diseases is increasing, possibly due to a reduced intensity and diversity of microbial stimulation. More knowledge is needed on the immunological mechanisms underlying the eczema preventive effect of pre- and postnatal probiotic supplementation. The pregnancy period seems to be of essential importance, since both epidemiological and experimental animal studies show the importance of microbial exposure during gestation on allergy prevention. We have performed a study where the probiotic lactic acid producing bacteria Lactobacillus reuteri was supplemented to pregnant women, at risk of having an allergic infant. The pregnant mothers received the study product from gestational week 36 until delivery, and the infants then continued with the same product until one year of age. The probiotic, as compared with placebo, supplemented infants had less IgE-associated eczema at two years of age. In order to investigate how the supplementation affected the immune system peripheral blood was collected and immune cells were stimulated with common allergens and TLR ligands. The probiotic treated group responded with a more regulated response to allergens and TLR2 ligands in comparison to the placebo supplemented group. We also investigated how the probiotic supplementation affected the epigenetic methylation pattern in circulating T helper cells during infancy, observing the most pronounced effects at birth. In a follow up study, supplementation was started earlier to possibly gain a stronger allergy preventive effect via changes in maternal immune regulation. Supplementation with Lactobacillus reuteri and ω-3 fatty acids started at gestational week 20 and throughout pregnancy. After 20 weeks of supplementation, some immunomodulatory effects among circulating activated regulatory T cells and a subpopulation of monocytes were noted. Several systemic immune modifying effects of pregnancy were observed. In summary, probiotics show several immunomodulatory effects in infants and pregnant women. However, more research is needed to better understand the effects of the probiotic supplementation to aid future identification of more efficacious allergy preventive strategies.

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Abstract Aim: To map first-time mothers experiences of breastfeeding support provided by maternal health care, birth center and BB. Method: A quantitative survey with a cross-sectional design. The criterias to be included was first-time mothers who breastfed or wished to breastfeed and gave birth to a full-term child in the last two years. Data were collected through a web survey published on Facebook. A comfort selection was chosen and data were analyzed with descriptive statistics. Comparisons were made between two age groups Results: A total of 197 first time mothers were answered in the survey. Group 1 consisted of first-time mothers aged 21-30 years and Group 2 consisted of first-time mothers aged 31-42 years. The breastfeeding support included written, verbal and practical guidance. Positive and negative factors in breastfeeding support were identified. Both differences but mainly similarities were identified among first-time mothers’ experiences of breastfeeding support. It was 70,3% of the entire population who wanted more information about breastfeeding. A difference was that Group 2 generally estimated lower breastfeeding support compared with Group 1. Conclusion: The breastfeeding support was estimated quite low by both age groups. Almost half of the first-time mothers considered themselves to receive the best breastfeeding support from sources other than maternal health care, childbirth and BB. This indicates that the breastfeeding support that first-time mothers received was insufficient. First-time mothers requested more information about breastfeeding. High attendance of the midwife and individual guidance were positive factors.   Keywords: breastfeeding, experiences, midwives, mothers, support.

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