Ovarian steroid hormones are neuroactive steroids with widespread actions in the brain, and are thus able to influence mood, behavior and cognition. In this thesis the effects of progesterone withdrawal and the direct effects of the progesterone metabolite allopregnanolone are evaluated. Allopregnanolone, through binding to the GABAA receptor complex, enhances inhibitory neurotransmission, thus exerting anxiolytic, sedative and antiepileptic effects. The acoustic startle response (ASR) is a withdrawal reflex evoked by sudden or noxious auditory stimuli, and can be measured in humans as an eye blink. ASR is significantly increased in several anxiety disorders, and notably also during progesterone withdrawal. Sensorimotor gating can be assessed by measuring prepulse inhibition of the startle response (PPI). The CNS circuits regulating PPI are sensitive to hormone fluctuations. GABAergic drugs are involved in cognitive impairment and animal studies have indicated that allopregnanolone may inhibit learning. The main purpose of this research was to evaluate the behavioral effects of progesterone withdrawal on the startle response and sensorimotor gating in PMDD patients and healthy controls, in healthy third trimester pregnant women and healthy postpartum women. A second aim was to evaluate allopregnanolone effects on memory and cognition in healthy women and also on the startle response and PPI. We found that PMDD patients have an increased startle response across the menstrual cycle and a deficiency in sensorimotor gating during the late luteal phase. Ovarian steroids affect sensorimotor gating; pregnant women have lower levels of PPI than late postpartum women. Acutely administered allopregnanolone did not affect the ASR or PPI. Allopregnanolone impairs episodic memory in healthy women. In conclusion, our studies suggest that ovarian steroids, including allopregnanolone, do not influence the startle response. Ovarian steroids affect sensorimotor gating; pregnancy, a condition with high levels of ovarian steroids, suppresses PPI. Theoretically, the variability in PPI across reproductive events is due to effects mediated by the progesterone or estradiol receptors but is not mediated by allopregnanolone. PMDD patients display decreased PPI during the late luteal phase, suggesting underlying pathophysiology in common with other anxiety disorders. The most vulnerable memory system, the episodic memory, is impaired by the allopregnanolone in healthy women.

Vaginismus is a sexual pain disorder, where spasm of musculature of the outer third of the vagina interferes with intercourse. Vaginismus exists in two forms: total vaginismus, where intercourse is impossible, and the more seldom described partial vaginismus, in which intercourse is possible but painful. The aim of the thesis was to develop a useful definition of partial vaginismus for both clinical and scientific purposes; to describe the prevalence of partial vaginismus among women with superficial coital pain; to report on symptoms and clinical findings in women with partial vaginismus; and to present treatment results for women with vaginismus. In a clinical sample of 224 women with superficial coital pain, we found a great overlap of the clinical diagnoses of partial vaginismus (PaV) and vulvar vestibulitis (VVS) (nowadays called provoked vestibulodynia); 102 women had both PaV and VVS. All women with VVS had vaginismus. Partial vaginismus was more common in all our samples than total vaginismus. sEMG of pelvic floor muscles was found to be of no value in distinguishing women with partial vaginismus with or without vulvar vestibulitis (PaV+/-VVS) (n=47) from each other or from an asymptomatic group (n=27). Women with PaV+/-VVS (n=53) reported not only burning pain but also itch during a standardized penetration situation (sEMG of pelvic floor muscles), while asymptomatic women (n=27) did not. In most cases, the appearance of burning pain preceded the appearance of itch. In a retrospective interview study, 24 women with PaV+/-VVS reported pain after intercourse more often than pain during penetration at the onset of the problem. When the women ceased having intercourse, both symptoms were equally common. Intensity of pain during penetration increased dramatically from very low at onset of the problem to very high when the women ceased having intercourse, while intensity of pain after intercourse was already high at onset of the problem and increased to very high when the women ceased having intercourse. Pain after intercourse in women with PaV+/-VVS was described as burning and/or smarting and lasted in mean for two hours, while pain during penetration was described with words like sharp/incisive/bursting and lasted for one minute. At long-term follow-up (more than three years) of a group of women treated with cognitive behaviour therapy for vaginismus (n=59, response rate 44/59 on a questionnaire), a majority were able to have and enjoy intercourse. The proportion of women with positive treatment outcome was, however, associated to the definition of treatment outcome. An ability to have intercourse at end of therapy was maintained at follow-up. Every tenth women with vaginismus healed spontaneously after thorough assessment. Conclusion: Partial vaginismus was more common in our studies than total vaginismus, and all women with vulvar vestibulitis had partial vaginismus. Women with PaV+/-VVS reported not only burning pain during standardized penetration but also itch. When the problem started in women with PaV+/-VVS, pain after intercourse was more common than pain during penetration. Pain after intercourse was described as longlasting and burning and/or smarting, while pain during penetration was described as short and sharp/incisive/bursting. Long-term follow-up results of a series of women treated with CBT for vaginismus show good treatment outcome.

Different modes of assisted ventilation were investigated in cats before and after lung lavage and after instillation of surfactant. The activity of single units of slowly adapting pulmonary stretch receptors (PSRs) in the vagal nerve and the integrated phrenic nerve activity were recorded. The instantaneous impulse frequency (fimp) of PSRs was calculated and related to transpulmonary pressure (Ptp), tidal volume (Vt) and the calculated energy storage of the lung (ΣP*ΔV). Respiratory rate (RR), inspiratory and expiratory time, and Vt were measured, and their coefficients of variation were calculated. During assist control (A/C) ventilation with different pressure waveforms, PNA was shorter and lower in amplitude with squarewave pressure waveform than with linear and sinusoidal pressure waveforms in cats with normal lungs, concomitantly with earlier peak fimp during inspiration and prolonged fimp during expiration. The type of pressure waveform can thus influence the spontaneous breathing effort during A/C ventilation. Proportional assist ventilation (PAV) is a new mode of assisted ventilation which servo-controls the applied airway pressure continuously in proportion to the breathing effort. After lung lavage and surfactant instillation, PAV improves ventilation markedly, with lower PNA and oesophageal pressure deflection and higher RR and variability of breathing, compared to CPAP. In addition, an earlier and higher maximal fimp was observed during PAV. Under conditions of low work and maintained control of breathing, PAV seems to be an attractive mode of ventilatory support. Low-threshold (LT) and high-threshold (HT) PSRs respond to the surfactant content of the lung partly independent of Ptp and Vt in spontaneously breathing cats, implying a possible effect of surfactant on PSRs. The PSR fimp normalized to ΣP*ΔV confirmed these findings and showed that LT and HT PSRs are intrinsically the same. After instillation of surfactant, compliance and PSR activity increased, but the breathing still remained shallow and rapid, suggesting a control of breathing less dominated by PSR activity.

This investigation was undertaken to examine effects of motor skill intervention in children with motor difficulties consistent with developmental co-ordination disorder (DCD) diagnosed in child health care before school entrance, to analyse the parents' descriptions of their children, and to follow up the children's motor status in a short-term perspective. Thirteen studies on the effects of motor skill intervention were submitted to a meta-analysis (Study I). Thirty-seven children who at age 5 to 6 years were diagnosed as having motor difficulties consistent with DCD were enrolled in an experimental investigation of effects of group motor skill intervention on motor skills (Study II) and on self-perceived competence (Study III). The parents' descriptions of their children were obtained at an interview (Study IV). The children's motor status was re-examined when they were 7 to 8 years old (Study V). Motor skill intervention, using the Specific Skills approach, in a group setting or in a home programme, 3 to 5 times per week, was found beneficial for children with DCD who were older than 5 years of age. The non-specific group motor skill intervention influenced the number of children with borderline motor difficulties who changed to having no motor difficulties, and seemed to enhance awareness of motor competence. Parents whose children had definite motor difficulties were more inclined to support their children in physical activity, and reported worry and uncertainty. The children had not changed their motor status at the age of 7 to 8 years. The children with definite motor difficulties, in particular, continued to have these difficulties. Children who when 5 to 6 years old have motor difficulties and who score at the 5th percentile or below at the Movement ABC motor test, seem to need active support in joyful motor learning situations to reduce unwillingness and displeasure.

In this study 165 Swedish parents of young children with Downs’s syndrome (DS) were investigated regarding their perception of the quality of the first information and support received after the birth of the child. The parents’ opinions were compared with clinical routines at the paediatric clinics regarding these issues. Strong clinical ambitions fell short, however, since 70 % of the parents felt insufficiently informed; 56 % felt unsupported, and the timing of the disclosure varied between 0 hour to >5 days. On the basis of a grounded theory analysis the parents’ written narratives regarding the quality of the first information and support were analysed to better understand the reasons underlying the parental dissatisfaction. Criticisms were raised by the parents concerning: the low communication skills by professionals; the lack of privacy; too much negative information; and an unmet desire to early meet other DS parents. The implications of being DS parents regarding their daily life were examined by measuring parental health, stress, sense of coherence, employment and sick leave rates. Results were compared with those in a randomly selected group of parents of healthy age-matched children. The similarities between the DS and control parents were more pronounced than the differences regarding divorce rates, siblings in the family, time spent on child care, employment and sick leave rates, and their self-perceived health, stress, and sense of coherence. However, self-perceived health of the DS mothers was impaired and stress was increased. A small group of DS parents (5 mothers and 1 father) had an extremely high rate of sick leave and no such group was seen in the control parents. In addition, the DS mothers stayed at home because of the child’s sickness most frequently and the DS fathers stayed at home for this reason more than control mothers. Conclusions: Existing guidelines for optimal first information and support of new parents of children with DS are not always followed in Sweden. Qualitative clinical improvements from the parents’ perspective are proposed. Most DS parents live an ordinary family life in respect to the measured parameters, but the risk for health deterioration, particularly in DS mothers, might need attention.

Background Screening by cytology has been highly effective in reducing the incidence and mortality from squamous invasive cervical cancer (ICC), but the effectiveness is less established regarding non-squamous ICC and regarding women above screening ages and below 30 years of age. Cervical cancer still occurs despite the presence of an organised screening programme. A substantial proportion of screened women with ICC are reported to have had previous abnormal cytology findings. The significance of negative cytology with limited evaluation is not quite determined, the most effective management of women with low-grade abnormalities is controversial, and evaluation of long-term effect of different treatment methods is limited. Aims To identify possible areas of improvements in the prevention of cervical cancer by evaluating the effectiveness of the Swedish cervical screening programme, and by exploring risk factors for ICC in the cytological screening histories and in the management of women with abnormal cytology findings. Methods The screening histories of all ICC cases in Sweden 1999-2001 (n=1230) and of five population-based control women per case were reviewed, using data from the Swedish Cancer Registry, the national population register, the Swedish national cervical screening quality register, histopathological reports and questionnaires to clinicians. The risk of cervical cancer according to screening histories 0.5-6.5 years before cancer diagnosis was estimated as odds ratios (ORs) in logistic regression models with 95% confidence interval (CI) (Paper I). Risk related to different cytological reports was assessed in women below 67 years of age with cytology (n=572, n=3569) in Paper II. The initial follow-up of women with abnormal or unsatisfactory cytology reports (n=159, n=258) was evaluated in Paper III, and further investigation and treatment of abnormalities (n=143 cases, n=176 controls) in Paper IV. Results The cancer cases were above screening ages (31%), had not been screened according to recommendations (33%), had negative cytology (23%), or had previous positive screening tests (13%). No screening within the recommended interval increased the risk of squamous (OR 2.97, 95% CI 2.51-3.50) as well as non-squamous cancer (OR 1.59, 95% CI 1.20-2.11), and increased the risk in all ages. Negative cytology with partially obscuring factors and unsatisfactory cytology increased the risk of subsequent early stage ICC. All cytological abnormalities increased the risk of ICC, and women with glandular atypia or atypia in cells of uncertain origin carried a particularly high risk (OR 11.69, 95% CI 7.02-19.46). After a low-grade squamous abnormal smear finding, further investigation with biopsy was more effective than repeated cytology (OR 0.46, 95% CI 0.24-0.89). Lack of biopsy increased the risk in women with both low-grade and high-grade squamous abnormalities. Neither repeat cytology, nor biopsy, decreased the risk in women with glandular atypia or atypia in cells of uncertain origin. Treatment decreased the risk, even when the biopsy before treatment was negative or showed low-grade atypia only. Ablative therapy was less effective than excision and laser conisation was the most effective therapy. Conclusions Improved adherence to screening recommendations and including older women at increased risk in the programme would have significant cancer preventive gains. Women with negative cytology with limited evaluation and with unsatisfactory cytology may need further evaluation. Assessment with biopsy should be recommended for women with low-grade as well as high-grade squamous abnormalities. The diagnosing of precancer lesions and the identification of women in need of treatment warrant improvements, in particular in cases of glandular or “other” atypia in cytology. Treatment techniques need further evaluation.

2-Methoxyestradiol (2-ME), a metabolite of 17β-estradiol, is a potent antitumor and antiangiogenesis agent in vitro and in vivo. This study aimed to investigate the effects of 2-ME on human cervical and endometrial cancers in vitro and in vivo. Human cervical cancer HeLaS3 cells, endometrial cancer HEC-1-A and RL-95-2 cells, and severe combined immune deficient (SCID) mice were used. On cervical cancer HeLaS3 cells, 2-ME inhibited the cell growth which is accompanied by apoptosis via iNOS pathway and by G2/M cell cycle arrest. 2-ME had slight effects on normal cervical epithelial cells. In vivo on SCID mice, 2-ME (75 mg/kg p.o.) inhibited the growth of human cervical carcinoma by 34% (p < 0.05) and showed slight side effects to liver and spleen. On human endometrial cancer cells (HEC-1-A and RL-95-2 cells), 2-ME inhibited the growth by blocking cell cycle progress in S- and G2/M-phase in both cell types, and by inducing apoptosis in HEC-1-A cells and by causing necrosis in RL-95-2 cells. 2-ME had no effects on normal endometrial cells. The apoptotic effect, in HEC-1-A cells, was prevented by iNOS-inhibitor 1400W and eliminated by Caspase-inhibitor Z-VAD-FMK. The necrosis, on RL-95-2 cells, was due to a severe disruption of the mitochondrial membrane potential. Unfortunately, 2-ME had no significant effects on endometrial cancer xenografts. It showed slight toxicity to liver, spleen and proliferative effect on uterus. In conclusion, 2-ME inhibits the growth of human cervical and endometrial cancer cells in vitro. However, a weaker anti-tumor effect was observed in our animal model and 2-ME was slightly toxic to liver and spleen. Considering the proliferative effect on uterus, 2-ME might not be a suitable therapeutic agent in gynecological tumors.

The experience of pregnancy and childbirth is a central life event with special implications for women at high risk. This thesis describes the meaning of pregnancy, childbirth and midwifery care in four qualitative interview studies based on the lifeworld theory. Women were interviewed during pregnancy and within one week after childbirth. Midwives were interviewed concerning midwifery care for women at high risk. In an intervention study, childbirth experience as reported through a post partum questionnaire was compared between women receiving standard care and women who had formulated a birth plan preceded by a questionnaire on their expectations and feelings about childbirth. The findings emphasise that childbearing women at high risk live in an extremely vulnerable situation. The vulnerability is obvious in the use of an individual birth plan, where negative feelings become more frequent in women at high risk than in those with normal pregnancy and childbirth. During pregnancy the women feel a moral commitment towards the child, including feelings of objectification and of exaggerated responsibility. During an obstetrically complicated childbirth the essential meaning is the women’s desire to be recognised and affirmed as individual persons. Like women with normal pregnancy and childbirth, they need an emotionally present midwife who sees, give trust and supports. Good midwifery care of childbearing women at high risk is synthesised as "genuine caring in caring for the genuine". The ethos of caring constitutes the basis of caring. Women’s transition during pregnancy and childbirth is described as a genuinely natural process. Midwives have a special responsibility to encourage and preserve this process within women at high risk. The caring relationship is the core and the most essential tool in the care. Distinctive features in the midwifery care are embodied knowledge, physical as well as emotional presence, sensitivity, a mutual dialogue including shared control between midwife and woman, and confirmation and support of the genuine in each woman. The midwifery care is a struggle and a balance between natural and medical perspectives.

Background: Pelvic organ prolapse (POP) is a relatively common condition. In Sweden, the overall estimated prevalence of POP in the female population is 31% and the prevalence of symptomatic prolapse is 8–15%. The prevalence of POP increases with age. The lifetime risk of undergoing pelvic floor surgery is estimated to 11%. The aim of this thesis was to investigate outcomes of vaginal hysterectomy for treatment of prolapse; to study outcomes of cystocele repair surgery and patient satisfaction related to different anaesthesia methods; to explore women’s experiences of vaginal prolapse; and to investigate what is known regarding POP prior to surgery and healthcare-seeking behaviour. Methods: In the Swedish National Quality Register for Gynaecological Surgery (Gynop-register), 941 women were identified who underwent vaginal hysterectomy for prolapse from 1997 to 2005 and 1,364 women were identified who underwent cystocele repair surgery from 2006 to 2009. In-depth interviews were performed with 14 women with vaginal prolapse. Interview data were analyzed with a qualitative content analysis. To investigate women’s knowledge about POP and healthcare-seeking behaviour, a questionnaire was developed, validated and distributed to women with planned surgery for POP. Women undergoing hysterectomy or incontinence surgery were used as reference groups. Results: Severe complications after vaginal hysterectomy occurred in 3% of cases. Sexual activity was improved after vaginal hysterectomy, the number of women reported to have intercourse increased by 20% (p = 0.006). Subjective symptoms of urinary incontinence and overactive bladder were resolved in 50% of the women. De novo stress incontinence was reported by 11% of the women. Use of local anaesthesia (LA) in reconstruction of cystocele showed advantage over other forms of anaesthesia. Length of hospital stay, duration of use of postoperative pain-killing drugs, and time to return to daily activity were shorter among women who underwent surgery with LA compared to other forms of anaesthesia. Patient satisfaction was not related to methods of anaesthesia. In an interview study, the process from recognition the symptoms to seeking healthcare was highlighted. Two categories, “obstacles” and “facilitators” to seeking health care, were identified. One of the obstacles was lack of information on POP in the public domain. The main facilitators were feeling sexually unattractive and impaired physical ability due to POP. Some findings from the interview study were further explored in the questionnaire study. One out of five women with vaginal prolapse did not know that the symptoms were related to prolapse before consulting their physician. Over 30% of the women in the incontinence group were embarrassed to talk about incontinence, and they were unaware that it could be treated. The most frequent description of vaginal prolapse was vaginal bulging. Women in the prolapse group had significantly less access to information through brochures and public media than women in the incontinence group (p < 0.001). Conclusion: Short-term follow-up after vaginal hysterectomy showed that sexual activity and urinary symptoms had improved. Cystocele surgery using LA showed no disadvantage compared to surgery using other anaesthesia methods. POP surgery can therefore be performed safely with LA. Information on prolapse should be easily accessible to improve the possibility for women of gaining knowledge and thereby overcoming obstacles to seeking medical advice. Healthcare professionals have a significant role to play in informing women about symptoms and available treatment options.

Background: In high-income countries, hospital length of stay after a normal birth has gradually decreased correspondingly to length of stay in care of other patients. A short stay provides a greater opportunity for autonomy and an increased sense of participation, but it may involve great challenges satisfying parental guidance as well as on the possibility of preventing, discovering, and treating neonatal medical conditions. Aim: This study evaluates postnatal care based on cost calculations, risk assessments, and parents’ satisfaction with care. Methods: Questionnaires were sent to 1 122 new mothers and her partner during 1998-1999. For the summary of utilization of health care services during the first 28 days postdelivery, the participants were linked with registry data from the hospital administration system for mothers and newborns (n= 773). The answers were also used to describe new parents’ experiences with postnatal care (n = 1 479). The costs for five postnatal care models were estimated, including three care options: Maternity Ward, Family Suite, and Early Discharge. Data about neonatal readmissions and death within 28 days was retrieved from the Swedish Medical Birth Register, the Swedish Hospital Discharge Registry, and the Swedish Cause-of-Death Register between 1999 and 2002 (n = 197 898). This data was related to data about postnatal follow-up practices from all 48 Swedish delivery wards. Results: The readmission rate for the mothers was similar among the various care options, and there was no difference in utilization of health care or breastfeeding outcome due to type of maternity care. As a proxy for morbidity, the readmission rate for the newborns was influenced by postdelivery follow-up routines as routine neonatal examination timing. Depending on the proportion of mothers receiving care at the Maternity Ward, the costs differed significantly between the various care models, while parents’ preferences complied with the cost-minimizing option Family Suite. Most mothers and fathers (70%) were satisfied with the overall impression of the postnatal care, but 72% were dissatisfied with at least one particular topic. A main finding was that the parents experienced a close emotional attachment, an affinity that was not always supported by the staff. The father was not treated as a principal character even though the parents wanted the father’s to be involved and recognized. Conclusions: Since the postnatal care options are not always the most cost minimizing and postnatal routines influence neonatal morbidity and parental satisfaction, the postnatal services need to be improved. Without increasing risks or costs, every postnatal care option ought to meet the families’ need for support, security, autonomy, and attachment with each other.