Recurrent pregnancy loss: couples' perspectives on their need for treatment, support and follow up.

STUDY QUESTION: What do couples referred to or attending a recurrent pregnancy loss (RPL) clinic believe they need in terms of treatment, support and follow up? SUMMARY ANSWER: Men and women wish for more information, earlier access to treatment, support and follow up that is sensitive to their history of pregnancy loss (PL), includes both members of the couple, and acknowledges the psychological impact of RPL. WHAT IS KNOWN ALREADY: Previous research has highlighted women's dissatisfaction with medical care provided post-PL and their desire for medical professionals to have increased awareness about PL and recognition of the psychological impact of PL. Less is known about the needs of the male partner, the needs of those experiencing RPL and whether the needs differ during different reproductive stages. STUDY DESIGN, SIZE, DURATION: Over a 2-month period in 2017-2018, 13 couples who were referred to the national RPL program in Copenhagen, Denmark were qualitatively interviewed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were heterosexual couples with at least three consecutive PLs before 12 weeks' gestation with no children or one child prior to the PLs, not currently pregnant, and willing to be interviewed in English. Couples were interviewed together in a semi-structured format. Data were analyzed using thematic analysis. Invitations (n = 30) were sent to couples recently referred to the RPL program who indicated an interest in participating and 17 couples contacted the interviewer to schedule an interview. Due to cancellations, 15 interviews were held. Data from 13 interviews that met the study criteria were used for the current analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The participants had experienced a median of three PLs (range 3-6). Both men and women described the cumulative effect of RPL with an increase in pressure and exhaustion by the third and subsequent losses. Inclusion of the male partner in consultations and treatment was seen as important. Men felt pressured to remain positive and support their partners despite their own feelings of loss. The findings showed that couples desired reliable and accurate information about RPL. They wished for recognition from the medical community that RPL has a significant psychological impact, and stressed that effective treatment should include both members of the couple, with attention to both physical and psychological aspects of the RPL and should be tailored to their current reproductive stage, in order to help them cope with the negative impact of RPL and the anxiety associated with conception and another pregnancy. LIMITATIONS, REASONS FOR CAUTION: Participants were self-selected thus findings cannot be generalized to all couples with RPL. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study addressing the needs of the female and male partners in couples suffering from RPL. The findings highlight a disconnect between couples' perceived needs and their experience of medical care after RPL. This may be partly due to a discrepancy in couples' and medical professionals' perceptions of the PLs. The findings highlight that medical professionals need to take a holistic and couple-focused approach in their treatment of RPL and include attention to the psychological impact and cumulative effect of the multiple PLs on the couple. The results underscore the need for informational resources and psychological support for couples experiencing RPL, tailored to their reproductive stage. STUDY FUNDING/COMPETING INTEREST(S): EK was funded by a Travel/Training Fellowship from ReproUnion, co-financed by the European Union, Interreg V ÖKS. No other competing interests were declared. TRIAL REGISTRATION NUMBER: N/A.

Recurrent pregnancy loss: what is the impact of consecutive versus non-consecutive losses?

STUDY QUESTION: Is there a different prognostic impact for consecutive and non-consecutive early pregnancy losses in women with secondary recurrent pregnancy loss (RPL)? SUMMARY ANSWER: Only consecutive early pregnancy losses after the last birth have a statistically significant negative prognostic impact in women with secondary RPL. WHAT IS KNOWN ALREADY: The risk of a new pregnancy loss increases with the number of previous pregnancy losses in patients with RPL. Second trimester losses seem to exhibit a stronger negative impact than early losses. It is unknown whether the sequence of pregnancy losses plays a role for the prognosis in patients with a prior birth. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study of pregnancy outcome in patients with unexplained secondary RPL included in three previously published, Danish double-blinded placebo-controlled trials of intravenous immunoglobulin (IvIg) conducted from 1991 to 2014. No other treatments were given. Patients with documented explained pregnancy losses (ectopic pregnancies and aneuploid miscarriages) were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 168 patients included in the trials, 127 had secondary RPL and experienced a subsequent live birth or unexplained pregnancy loss in the first pregnancy after giving informed consent to participate in the trials (the index pregnancy). Data analyzed by multivariate analysis included the independent variables age, the number of early pregnancy losses before and after the last birth, respectively and a second trimester pregnancy loss before or after the last birth, respectively. The outcome variable was unexplained loss in the index pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In patients with secondary RPL, both a late and each early loss before the last birth did not significantly influence the risk of a new pregnancy loss in the index pregnancy: incidence rate ratio (IRR) 1.31 (95% CI 0.62-2.77) and IRR 0.88 (95% CI 0.70-1.11), respectively. In contrast, the impact on risk of pregnancy loss conferred by a late and by each early pregnancy loss occurring after the birth was significant: IRR 2.15 (95% CI 1.57-2.94, P < 0.0001) and IRR 1.14 (95% CI 1.04-1.24, P = 0.002), respectively. LIMITATIONS, REASONS FOR CAUTION: Of the patients, 48% were treated with IvIg, which could influence the results. However, allocation to IvIg was random and prognostic variables were equally distributed in IvIg and placebo-treated patients. WIDER IMPLICATIONS OF THE FINDINGS: A birth in women with secondary RPL eradicates the negative prognostic impact of previous pregnancy losses and this finding is important for our understanding of the pathogenesis. It indicates that only consecutive pregnancy losses should count in the definition of RPL. STUDY FUNDING/COMPETING INTERESTS: There was no particular funding for this study. The authors declare that there is no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable for two of the included randomized controlled trials. For the last trial: Clinical.Gov NCT00722475.

Angiogenic factors and the lectin pathway of complement in women with secondary recurrent pregnancy loss.

The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, -2, -3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss.

HLA-DRB1 polymorphism in recurrent pregnancy loss: New evidence for an association to HLA-DRB1*07.

Many cases of recurrent pregnancy loss (RPL) defined as ≥3 consecutive pregnancy losses are suggested to be caused by an aberrant maternal immune response against the fetus or trophoblast. Human leukocyte antigen (HLA)-DRB1 and -DQB1 polymorphisms are associated with most autoimmune disorders and studies of HLA-DBB1 polymorphism in RPL patients are thus relevant. In previous studies, the HLA-DRB1*03 allele was found with increased prevalence in RPL patients. We wanted to clarify whether HLA-DRB1 alleles indeed were associated with RPL among women of Caucasian descent. A total of 1078 women with unexplained RPL and 2066 bone marrow donors were HLA-DRB1-typed and subsets were also HLA-DQB1 typed. All patients were initially HLA-DRB1-typed by DNA-based low-resolution techniques and subsets of patients and all controls were typed by high-resolution techniques. Among patients, the HLA-DRB1*07 allele frequency was significantly increased compared with controls; OR 1.29 (95 % CI 1.09-1.52), p < 0.0025; after correction for multiple comparisons pc = 0.031. The HLA-DRB1*07/*07 genotype was highly increased in patients with RPL compared with controls: OR 2.27 (1.31-3.93), p = 0.0027. The frequency of the HLA-DRB1*07 phenotype in RPL patients had increased significantly (p = 0.002) in three studies from our group published 1994-2021. The allele frequency of HLA-DRB1*03 was not increased in RPL patients compared with controls; OR 0.96 (0.83-1.12). In conclusion, the previous association between HLA-DRB1*03 and RPL could not be confirmed in our study whereas an association to HLA-DRB1*07 was detected for the first time. Since the latter association is a new finding, it should be confirmed in future studies.

An alternative placement of implantable central venous access systems.

A modified technique of inserting an implantable venous access system in the inferior epigastric vein is described. This route can be used in cases where the jugular or subclavian veins are unsuitable. After exposure of the inferior epigastric vein in the lower part of the rectus sheath, the catheter is placed in the vein with its tip at the junction to the iliac vein, with the aid of fluoroscopy and x-ray contrast. Protrusion of the tip into the lumen of the iliac vein is avoided. The technique was successful in four of the five patients where an attempt was made to insert the catheter. In the fifth case the vein was too narrow to allow catheterization. In the four cases where the catheter was successfully inserted there were no complications. This technique may allow use of the inferior vena cava for venous access without the high risk of intravenous thrombosis which is inherent with current methods.

Implantable drug delivery systems in computed tomography and magnetic resonance imaging--a comparison between titanium and stainless steel.

The effect of implantable drug delivery systems on computed tomography (CT) and magnetic resonance imaging (MRI) was investigated in a phantom and in two patients. The implantable systems of identical construction consisted either of medical grade titanium alloy or stainless steel. Images of a phantom showed artefacts of the stainless steel port in both CT and MRI. These artefacts were substantially reduced in images of the titanium port. Similar results were found in situ in two patients.

Enzyme activities and adenine nucleotide content in aorta, heart muscle and skeletal muscle from uraemic rats.

A prominent feature of arterial and myocardial lesions in uraemia is necrosis of the smooth muscle cells. In this study the possibility of detecting metabolic disturbances before necroses appear was investigated. The investigation was made on rats with moderate uraemia (mean serum creatinine 165 mumol/l) of 12 weeks duration. Enzyme activities and concentrations of adenine nucleotides were measured in aorta, heart and skeletal muscles. Histological examination disclosed no changes in these organs. Hexokinase, an important glycolytic enzyme, showed decreased activity in the skeletal muscle and aorta, whereas the hexosemonophosphate shunt enzyme glucose-6-phosphate dehydrogenase remained unchanged. The aspartate aminotransferase was increased in the skeletal muscle. Fat metabolism was not disturbed as reflected by unchanged activity of hydroxyacyl-CoA-dehydrogenase. Adenylatekinase which is important for the energy supply showed markedly increased activities in all tissues examined from the uraemic rats. Decreased ATP levels were found in the heart muscle and the aorta of the uraemic animals, whereas the total pool of adenosine phosphates remained unchanged in all tissues. The animal model described offers a useful means of detecting early changes in uraemia and should be useful for studying the effects of different treatments of uraemic complications.

The aortic content of glycosaminoglycans, hydroxyproline and calcium in experimental uraemia with special reference to parathyroidectomy and vitamin-D treatment.

The contents of the various glycosaminoglycan (GAG) fractions, hydroxyproline and calcium in the thoracic aorta from the rat were studied. The effect on these contents of induced uraemia (3/4 kidney resection) combined with parathyroidectomy and/or 1-alpha-hydroxycholecalciferol (1-alpha-OH-D3) treatment was evaluated. Confirming earlier results increased levels of GAGs (predominately of chondroitin and dermatan sulphate) were found in the aortae of uraemic rats. The present study showed that parathyroidectomy or treatment with 1-alpha-OH-D3 did not significantly further alter the aortic content of GAGs in uraemic rats. Arteriosclerotic changes (calcifying medial necrosis) were only found in non-parathyroidectomized uraemic rats given 1-alpha-OH-D3. The aorta from these rats had a lower total content of GAGs, mainly due to a decrease in hyaluronic acid, than that from uraemic rats without calcifications. The aortic content of calcium was lowest in uraemic parathyroidectomized rats. Treatment with 1-alpha-OH-D3 increased this content, which was augmented 100-200-fold when calcifications were present. No correlation between the aortic contents of calcium and GAGs was found. There was a statistically significant correlation between the aortic content of calcium and the serum calcium X phosphate product. A significantly lower content of hydroxyproline was found in uraemic non-parathyroidectomized rats given 1-alpha-OH-D3, especially in those with arteriosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on oesophagitis--no evidence for pyloric incompetence as a primary etiological factor. a scintigraphic study with 99Tcm-Solco-HIDA.

Duodeno-gastric bile reflux was studied by means of a non-invasive scintigraphic technique in 15 patients with symptomatic oesophagitis. The fate of an intravenously administered, bile-excreted radiopharmaceutic, 99Tcm-Solco-HIDA, was followed with a gamma camera. In 12 patients with an intact pylorus and in one patient operated upon by truncal vagotomy and pyloroplasty no evidence of bile reflux to the stomach was found. One of two patients earlier operated upon by a Billroth I gastrectomy had scintigraphic evidence of a severe bile reflux. We conclude that duodeno-gastric bile reflux is uncommon in patients with hiatal hernia and oesophagitis, and hence that normally pyloric incompetence is of minor importance for the development of this disorder.

Tissue calcification and alkaline phosphatase activity in uraemic rats.

The activity and localization of alkaline phosphatase activity (AP) in aorta and heart, and the incidence of calcifications in aorta, heart and kidney as well as cardial fibrosis were studied in uraemic rats treated with 1,25-dihydroxycholecalciferol (1,25-DCHH) and Nifedipine. 1,25-DHCC treatment elevated the serum Ca x P product and aggravated the development of renal and aortic calcifications and cardial fibrosis. Nifedipine did not protect against calcifications, but decreased the incidence of cardial fibrosis. The activity of AP was increased in the thoracic aorta in uraemia independent of 1,25-DHCC or Nifedipine treatment or presence of calcification. No changes of the AP activity were found in the heart.

Uraemic and 1-alpha-hydroxycholecalciferol induced aortic lesions.

Aortic alterations in uraemic rats were studied ultrastructurally. The main changes consisted of degeneration and necrosis of smooth muscle cells and occurrence of extracellular calcifications. These alterations were aggravated when 1-alpha-hydroxycholecalciferol (1-alpha-OH-D3) was given in a slightly hypercalcaemic dose. Parathyroidectomy prevented, to some degree, the development of ultrastructurally demonstrable changes; this effect was abolished when 1-alpha-OH-D3 was given. The influence of 1-alpha-OH-D3 and parathyroidectomy on the aorta in uraemia was not solely a function of their effect on the serum calcium X phosphate product. Bodies composed of concentrically arranged (target-like) ring formations (1,200-6,000 A in diameter), possibly originating from degenerated smooth myocytes, were observed in the aortae of uraemic rats. These bodies may represent the matrix for initial calcification in the ground substance. The calcium salt deposits in the target-like bodies disappears when the tissues are stored in glutaraldehyde solutions for a long period of time. Calcifications were normally only found extracellularly, and it is proposed that the target-like bodies may locally initiate the calcification process.

The effect of vitamin D treatment on decreased levels of ATP and energy charge in the thoracic aorta of uraemic rats.

The contents of ATP, ADP, AMP and calcium in the thoracic aorta were determined in rats with moderate uraemia, and in rats with the same degree of uraemia following treatment with 1,25-dihydroxycholecalciferol (1,25-DHCC). The contents of ATP, ADP and total nucleotides were decreased in the thoracic aorta in the uraemic rats but not in uraemic rats following 1,25-DHCC treatment. The content of calcium in the aorta increased substantially in uraemic rats given 1,25-DHCC. The results indicate that the development of arterial calcifications in uraemic rats following vitamin D treatment is dissociated from an impaired energy metabolism, since vitamin D may simultaneously restore impaired energy metabolism and accumulate calcium in the aortic wall.

Vascular complications in the Ehlers-Danlos syndrome.

The Ehlers-Danlos syndrome is a rare condition, which usually is easily recognized. In one type of this disease, type IV, arterial fragility dominates, and the syndrome may remain undiscovered until the patient has a traumatic or spontaneous arterial rupture. Two cases with a fatal outcome are presented in order to emphasize some important aspects in the management of these patients.

Scintigraphic assessment of biliary reflux into the residual stomach after subtotal gastrectomy and gastrojejunostomy.

A method is described for evaluating biliary reflux into the gastric remnant after subtotal gastrectomy, avoiding naso- or orogastric intubation. Gamma camera detection and continuous recording of the distribution and possible gastric reflux of 99Tcm-HIDA after intravenous injection was employed, before and after stimulation of bile flow by a fatty meal. The technique is simple and specific, but further clinical evaluation is needed.

Arterial calcifications in uraemic rats treated with 1-alpha-hydroxycholecalciferol and parathyroidectomy.

The effect of 1-alpha-hydroxycholecalciferol (1-alpha-OH-D3) on the incidence of arterial calcifications, and the influence of parathyroidectomy on the effect of this vitamin D treatment, were studied in uraemic rats. Uraemia was induced by 3/4 kidney resection, and parathyroidectomy was achieved by electrocoagulation. 1-alpha-OH-D3 in a dose of 3, 10 or 125 ng/100 g body weight (b.w.) was given in the drinking water. The animals were killed after 12 or 16 weeks. Aorta and small arteries in the heart and in anterior tibial muscle were studied by light microscopy. Arterial lesions were frequently found in uraemic rats and were characterized by medial necrosis and calcifications. Following a 1-alpha-OH-D3 dose of 125 ng/100 g b.w. in uraemic rats both serum calcium and serum phosphate were increased and there was a high incidence of arterial calcifications both in the aorta and the small arteries. In uraemic rats receiving 10 ng/100 g b.w. of 1-alpha-OH-D3 serum calcium was only slightly elevated although the incidence of arterial calcifications (mainly in the aorta) was such higher than in uraemic rats without vitamin-D treatment. A dose of 3 ng/100 g b.w. of 1-alpha-OH-D3 given to uraemic rats did not result in any serum calcium increase, nor did it alter the incidence of arterial calcifications. Parathyroidectomy prevented arterial calcifications. Parathyroidectomy prevented arterial calcification in uraemic rats, but this effect was abolished by 1-alpha-OH-D3 in a dose of 10 ng/100 g b.w. which only raised the serum calcium to a subnormal value. In uraemia, treatment with 1-alpha-OH-D3 may increase the serum calcium X phosphate product, but this cannot fully explain the increased incidence of arterial calcifications. It is therefore suggested that vitamin D causes changes in the arterial wall which increase its susceptibility to the development of calcifications.

Tissue calcium in uraemia.

The content of calcium in the thoracic aorta, the heart and the kidney was determined in rats with moderate renal failure treated with 1.25-dihydroxycholecalciferol (1.25-DHCC) 100 ng/kg/day and Verapamil 20 mg/kg/day. In the aorta the content of calcium was significantly increased in uraemic rats and this increase was significantly augmented after administration of 1.25-DHCC. In the kidney no increase in calcium was seen in rats with uraemia, but treatment with 1.25-DHCC increased the calcium content significantly. This increase was not correlated to the serum calcium x phosphate product, which was almost normal. In the heart no changes in the content of calcium were observed. Verapamil did not influence the effect of 1.25-DHCC. It is concluded that administration of 1.25-DHCC per se may increase the content of calcium in the aorta and kidney in rats with moderate uraemia and possibly in this way sensitize the tissue to the development of tissue calcification.

Volvulus of the colon. A review of 93 cases and current aspects of treatment.

Ninety-three patients, comprising a consecutive, population-based series, were treated for volvulus of the colon between 1970 and 1985. The male:female ratio was 3.3:1 among the patients with volvulus of the sigmoid colon and 1:3.7 among those with caecal volvulus (p less than 0.001). Of the 60 patients with sigmoid volvulus, nine (15%) died. Elective surgery was performed in 13 of these 60 cases, without postoperative mortality. Previous volvulus attack(s) had occurred in 22 of the 60. Of the nine patients who underwent only detorsion at laparotomy, four had recurrence. Of the 33 patients with caecal volvulus, 31 underwent emergency laparotomy, and in seven of them the outcome was fatal. Of the nine patients who survived pexis operations, three had recurrence of volvulus. The results indicate that immediate laparotomy can be hazardous in patients with colonic volvulus. Semi-emergency resection after tube decompression, when the patient is in optimal condition and with preoperatively prepared bowel, is probably preferable.

Randomized comparison of straight and colonic J pouch anastomosis after low anterior resection.

OBJECTIVE: The authors compared clinical bowel function and complications of a low anterior resection with either a straight or colonic J pouch anastomosis. SUMMARY BACKGROUND DATA: Urgency and frequent bowel movements after rectal resection with a low anastomosis have been related to the loss of rectal reservoir function. Reconstruction with a colonic J pouch possibly can obviate some of this dysfunction. Earlier reports have been favorable, but they must be verified in randomized trials. METHOD: One hundred patients with rectal cancer in whom a sphincter-saving procedure was appropriate were randomized to reconstruction with either a straight or a colonic J pouch anastomosis. RESULTS: The incidence of symptomatic anastomotic leakage was lower in the pouch group (2% vs. 15%, p = 0.03). Eighty-nine patients could be evaluated after 1 year. The pouch patients had significantly fewer bowel movements per 24 hours, and less nocturnal evacuations, urgency, and incontinence. Overall well-being owing to the bowel function was rated significantly higher by the pouch patients. CONCLUSION: Reconstruction with a colonic J pouch was associated with a lower incidence of anastomotic leakage and better clinical bowel function when compared with the traditional straight anastomosis. Functional superiority was especially evident during the first 2 months.

A technique for segmental rectal and colonic perfusion in humans.

To enable a better characterization of pathophysiologic processes in colon and rectum, we have developed a perfusion technique for collection of soluble substances and cells from standardized intestinal segments. A tube with balloons attached to its outer wall was endoscopically introduced into the rectum and sigmoid colon, and its position ascertained fluoroscopically. The balloons delimited two segments, one in the sigmoid colon and one in the rectum. The segments were simultaneously perfused by a buffer at 37 degrees C. After a 30-min rinsing period, perfusate and cells were collected at 20-min intervals. Of 51 attempted perfusions, 45 were successfully completed. Recovered volumes equaled those infused. Leakage from the proximal intestine to the segments was negligible. In 18 healthy volunteers, the mean perfusate concentration from the rectal segment was 57.5 (27.5-120.2) mg/L for albumin, 1.3 (1.0-1.7) micrograms/L for eosinophil cationic protein, 5.1 (2.8-9.5) ng/L for prostaglandin E2, and 61.7 (41.7-89.1) micrograms/L for hyaluronan, and all values were lower in the sigmoid segment. Steady state conditions were achieved from the second perfusion period. The perfusate contained 4-80 x 10(4) cells, more than 95% of which were epithelial cells. The technique is safe, has a good subject compliance, and seems to be a valuable tool in investigations on quantitative release of soluble substances and cells in, e.g., colorectal inflammation.

Delorme's operation for rectal prolapse in elderly or unfit patients.

OBJECTIVE: To evaluate the results after Delorme's operation for rectal prolapse in elderly and unfit patients. DESIGN: Retrospective analysis and telephone interview. SETTING: Akademiska sjukhuset, Uppsala, Sweden. SUBJECTS: A consecutive series of 14 women (median age 82, range 32-92) operated on for rectal prolapse 1987-1992 and followed up after a median of 18 months. RESULTS: There were no serious postoperative complications. Continence was improved in 6/11 incontinent patients. The recurrence rate was 3/14 (21%). CONCLUSION: Delorme's operation is an attractive alternative in elderly or unfit patients, but is not recommended for younger and low risk patients because of the recurrence rate.