Disease severity in subsequent pregnancies with RhD immunization: A nationwide cohort.

BACKGROUND AND OBJECTIVES: To evaluate the severity of haemolytic disease of the foetus and newborn (HDFN) in subsequent pregnancies with RhD immunization and to identify predictive factors for severe disease. MATERIALS AND METHODS: Nationwide prospective cohort study, including all pregnant women with RhD antibodies. All women with at least two pregnancies with RhD antibodies and RhD-positive foetuses were selected. The main outcome measure was the severity of HDFN in the first and subsequent pregnancy at risk. A subgroup analysis was performed for the group of women where RhD antibodies developed after giving birth to an RhD-positive child and thus after receiving anti-D at least twice (group A) or during the first pregnancy at risk for immunization (group B). RESULTS: Sixty-two RhD immunized women with a total of 150 RhD-positive children were included. The severity of HDFN increased for the whole group significantly in the subsequent pregnancy (p < 0.001), although it remained equal or even decreased in 44% of women. When antibodies were already detected at first trimester screening in the first immunized pregnancy, after giving birth to an RhD-positive child (group A), severe HDFN in the next pregnancy was uncommon (22%). Especially when no therapy or only non-intensive phototherapy was indicated during the first immunized pregnancy (6%) or if the antibody-dependent cell-mediated cytotoxicity result remained <10%. Contrarily, women with a negative first trimester screening and RhD antibodies detected later during the first pregnancy of an RhD-positive child (group B), often before they had ever received anti-D prophylaxis, were most prone for severe disease in a subsequent pregnancy (48%). CONCLUSION: RhD-mediated HDFN in a subsequent pregnancy is generally more severe than in the first pregnancy at risk and can be estimated using moment of antibody detection and severity in the first immunized pregnancy. Women developing antibodies in their first pregnancy of an RhD-positive child are at highest risk of severe disease in the next pregnancy.

Knowledge, attitude and practices of obstetric care providers towards maternal red-blood-cell immunization during pregnancy.

BACKGROUND AND OBJECTIVES: A successful routine RBC alloantibody screening programme should not lead to unnecessary emotional burden during pregnancy due to inadequate counselling on the risk of severe haemolytic disease of the foetus and the newborn (HDFN). Rareness of this disease may result in insufficient knowledge and subsequent inadequate information transfer to women, diagnosed with RBC antibodies. We investigated the current knowledge, views and experiences of Dutch obstetric care providers regarding RBC alloimmunization during pregnancy. MATERIALS AND METHODS: We performed a quantitative cross-sectional study, using a structured digital questionnaire to measure knowledge, attitude and practices (KAP) regarding maternal RBC alloimmunization among Dutch obstetric care providers in 2016. RESULTS: About 10% of obstetric care providers completed the questionnaire. A sufficient level of knowledge was found in 7% of all participants (N = 329). Knowledge about RhD immunisation and prophylaxis was sufficient in 60% of the responders. Knowledge gaps were found concerning the relevance of non-RhD RBC antibodies, the indications for giving extra RhD prophylaxis and the interpretation of laboratory test results. Healthcare providers estimated their own level of knowledge 'sufficient' (primary/secondary care) to 'good' (tertiary care), and all participants considered their professional role important within the screening programme. CONCLUSION: Dutch obstetric care providers showed a lack of knowledge regarding maternal RBC immunization. Awareness of the lack of knowledge is necessary to help obstetric care providers to be careful in giving information and even to decide to contact the expert centre before counselling the patient.

ABO incompatibility and RhIG immunoprophylaxis protect against non-D alloimmunization by pregnancy.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) is caused by maternal antibodies against fetal red blood cell antigens, most often anti-D, -K, or -c. ABO incompatibility between mother and child and anti-D immunoprophylaxis (RhIG) are known to reduce the risk of D immunization and subsequent HDFN. However, no immunoprophylaxis has been developed to prevent non-D immunizations. STUDY DESIGN AND METHODS: We evaluated whether ABO incompatibility has a preventive effect on formation of non-D alloantibodies, by performing a case-control study including pregnant women with newly detected non-D antibodies, identified within a nationwide data set, immunized during their first pregnancy and/or delivery. Subsequently, we assessed a possible protective effect of RhIG in a subgroup with non-Rh antibodies only. The proportions of previous ABO incompatibility and of RhIG administrations of these women were compared to the known rate of 19.4% ABO incompatibility and 9.9% RhIG administrations (D- women carrying a D+ child) in the general population of pregnant women. RESULTS: A total of 11.9% of the 232 included immunized women had a possible ABO incompatibility in their first pregnancy (vs. expected 19.4%; 95% confidence interval [CI], 7.3-18.8; p = 0.036). Furthermore, 1.0% women with non-Rh antibodies were D-, delivered a D+ child, and had therefore received RhIG, whereas 9.9% was expected (95% CI, 0.18-5.50; p = 0.003). CONCLUSION: We found that ABO incompatibility and RhIG reduce the risks not only for D, but also for non-Rh immunizations, suggesting that antibody-mediated immune suppression in this condition is not antigen specific.

Predicting anti-Kell-mediated hemolytic disease of the fetus and newborn: diagnostic accuracy of laboratory management.

BACKGROUND: There is controversy on critical cut-off values of laboratory testing to select pregnancies at increased risk for anti-Kell-mediated hemolytic disease of the fetus and newborn. Without early detection and treatment, anti-Kell-mediated hemolytic disease of the fetus and newborn may result in progressive fetal anemia, fetal hydrops, asphyxia, and perinatal death. OBJECTIVE: We aimed to determine the value of repeated anti-Kell titer determination and biological activity measurement using the antibody-dependent cellular cytotoxicity test determination in the management of pregnancies at risk for anti-Kell-mediated hemolytic disease of the fetus and newborn. STUDY DESIGN: This was a retrospective cohort study of pregnancies with anti-Kell and a Kell-positive fetus, identified from January 1999 through April 2015. Laboratory test results and clinical outcome were collected from the Dutch nationwide screening program and the national reference center for fetal therapy in The Netherlands, the Leiden University Medical Center. Diagnostic accuracy was measured (receiver operating characteristic curves, sensitivity, specificity, positive and negative predictive values) for anti-Kell titers and antibody-dependent cellular cytotoxicity test. The relationship between the titer and antibody-dependent cellular cytotoxicity measurements and the 2 foregoing measurements were computed with a Pearson product-moment correlation coefficient. RESULTS: In a 16-year unselected cohort, representing screening results of 3.2 million pregnancies resulting in live births in The Netherlands, we identified 1026 Kell-immunized pregnancies. In all, 93 pregnant women had anti-Kell and a Kell-positive child, without other red cell alloantibodies. In all, 49 children (53%) needed intrauterine or postnatal transfusion therapy. The first anti-Kell titer showed already a high diagnostic accuracy with an area under the curve of 91%. The optimal cut-off point for the titer was 4 (sensitivity 100%; 95% confidence interval, 91-100), specificity 27% (95% confidence interval, 15-43), and positive predictive value 60% (49-71%). The antibody-dependent cellular cytotoxicity test was not informative to select high-risk pregnancies. Linear regression showed no significant change during pregnancy, when antibody titer and antibody-dependent cellular cytotoxicity test results were compared with every 2 foregoing measurements (P < .0001). CONCLUSION: Early determination of the anti-Kell titer is sufficient to select pregnancies at increased risk for hemolytic disease of the fetus and newborn with need for transfusion therapy. If the Kell status of the fetus is known to be positive, a titer of ≥4 can be used to target intensive clinical monitoring.

Antigen specificity determines anti-red blood cell IgG-Fc alloantibody glycosylation and thereby severity of haemolytic disease of the fetus and newborn.

Haemolytic disease of the fetus and newborn (HDFN) is a severe disease in which fetal red blood cells (RBC) are destroyed by maternal anti-RBC IgG alloantibodies. HDFN is most often caused by anti-D but may also occur due to anti-K, -c- or -E. We recently found N-linked glycosylation of anti-D to be skewed towards low fucosylation, thereby increasing the affinity to IgG-Fc receptor IIIa and IIIb, which correlated with HDFN disease severity. Here, we analysed 230 pregnant women with anti-c, -E or -K alloantibodies from a prospective screening cohort and investigated the type of Fc-tail glycosylation of these antibodies in relation to the trigger of immunisation and pregnancy outcome. Anti-c, -E and -K show - independent of the event that had led to immunisation - a different kind of Fc-glycosylation compared to that of the total IgG fraction, but with less pronounced differences compared to anti-D. High Fc-galactosylation and sialylation of anti-c correlated with HDFN disease severity, while low anti-K Fc-fucosylation correlated with severe fetal anaemia. IgG-Fc glycosylation of anti-RBC antibodies is shaped depending on the antigen. These features influence their clinical potency and may therefore be used to predict severity and identify those needing treatment.

Glycosylation pattern of anti-platelet IgG is stable during pregnancy and predicts clinical outcome in alloimmune thrombocytopenia.

Fetal or neonatal alloimmune thrombocytopenia (FNAIT) is a potentially life-threatening disease where fetal platelets are destroyed by maternal anti-platelet IgG alloantibodies. The clinical outcome varies from asymptomatic, to petechiae or intracranial haemorrhage, but no marker has shown reliable correlation with severity, making screening for FNAIT impractical and highly inefficient. We recently found IgG Fc-glycosylation towards platelet and red blood cell antigens to be skewed towards decreased fucosylation, increased galactosylation and sialylation. The lowered core-fucosylation increases the affinity of the pathogenic antibodies to FcγRIIIa and FcγRIIIb, and hence platelet destruction. Here we analysed the N-linked glycans of human platelet antigen (HPA)-1a specific IgG1 with mass spectrometry in large series of FNAIT cases (n = 166) including longitudinal samples (n = 26). Besides a significant decrease in Fc-fucosylation after the first pregnancy (P = 0·0124), Fc-glycosylation levels remained stable during and after pregnancy and in subsequent pregnancies. Multiple logistic regression analysis identified anti-HPA-1a -fucosylation (P = 0·006) combined with galactosylation (P = 0·021) and antibody level (P = 0·038) correlated with bleeding severity, making these parameters a feasible marker in screening for severe cases of FNAIT.

Better perineal outcomes in sitting birthing position cannot be explained by changing from upright to supine position for performing an episiotomy.

BACKGROUND: women who give birth in supine position are more likely to have an episiotomy than women who give birth in sitting position. A confounding effect may be that women in upright positions in second stage of labour are asked to lie down if a professional needs to perform an episiotomy. This prospective cohort study aimed to determine whether this factor can explain the lower rate of episiotomy in sitting compared to supine position. METHODS: data from 1196 women who had a spontaneous, vaginal birth were analysed. Positions during second stage and at birth were carefully recorded. Three groups of birthing positions were compared in multivariable analyses: 1) horizontal during second stage and supine at birth (horizontal/supine), 2) horizontal and upright during second stage and supine at birth (various/supine), 3) sitting at birth regardless of the position in second stage. Logistic regression analysis was used to adjust for known risk factors for perineal damage. FINDINGS: women in sitting position at birth compared to those in the horizontal/supine group had a lower episiotomy rate (adjusted OR 0.28;95%-CI 0.14-0.56) and a non-significant higher intact perineum rate (adjusted OR 1.40, 95% CI 0.96-2.04). Women in the various/supine group compared to the horizontal/supine group had a similar episiotomy rate (adjusted OR 1.12;95%-CI 0.69-1.83). CONCLUSIONS: we did not confirm our hypothesis that more women in supine compared to sitting position have an episiotomy because women in upright position are asked to lie down if an episiotomy is necessary.

Assessing psychological health in midwifery practice: a validation study of the Four-Dimensional Symptom Questionnaire (4DSQ), a Dutch primary care instrument.

OBJECTIVE: the Four-Dimensional Symptom Questionnaire (4DSQ) is a validated self-report questionnaire, developed for general practice to assess the level of distress, somatization, depression and anxiety among patients. This study evaluated the validity of this instrument for midwifery practice by differential item functioning analysis. DESIGN: cross-sectional. SETTING AND PARTICIPANTS: the focal group consisted of clients of 15 primary care midwifery practices in The Netherlands (n=478). The reference group consisted of Dutch female primary care patients, matched for age (n=478). MEASUREMENTS AND FINDINGS: Differential item functioning (DIF) was assessed by ordinal regression and the Mantel Haenszel method. The impact of DIF was measured by linear regression. The depression scale was free of DIF. The somatization, distress and anxiety scale contained items with DIF. Because of DIF, pregnant and postpartum women had on average 1-2 points lower predicted scores on the somatization scale and 1 point lower scores on the anxiety scale. On the distress scale the midwifery group had 1-2 higher predicted scores. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the 4DSQ is a valid instrument for casefinding of psychological disease in midwifery practice, provided cut-off scores of the distress, anxiety and somatization scale be adapted.

One single dose of 200 microg of antenatal RhIG halves the risk of anti-D immunization and hemolytic disease of the fetus and newborn in the next pregnancy.

BACKGROUND: The objective was the evaluation of the effect of the Dutch national routine antenatal RhIG (anti-D) immunization prevention (RAADP) program comprising one single dose of 200 microg (1000 IU) of RhIG in the 30th week of pregnancy, restricted to women without a living child. STUDY DESIGN AND METHODS: A nationwide historic control study was performed. All newly detected anti-D-immunized para-1 in 1999, 2002, and 2004 were included and classified on the basis of received prophylaxis during the first pregnancy: antenatal and postnatal versus only postnatal RhIG. The numbers of D- parae-1 who delivered a D+ first child before the introduction (control group) or after the introduction (intervention group) of the RAADP were calculated from Vital Birth Statistics (8,700 and 12,000, respectively). RESULTS: Fifty-eight newly detected anti-D immunizations in the first trimester were observed in the control group and 39 in the intervention group, which resulted in a significant reduction of the prevalence of new anti-D immunizations from 0.67 percent (95% confidence interval [CI], 0.50%-0.84%) to 0.31 percent (95% CI, 0.21%-0.41%). No reduction was observed in anti-D immunizations newly detected at the 30th-week screening (0.25%). A nonsignificant risk reduction of the risk of severe hemolytic disease of the fetus and newborn (HDFN) was found (0.23% vs. 0.10%). The numbers needed to treat to prevent one anti-D-immunized pregnancy and one case of subsequent severe HDFN were 357 and 1255, respectively. CONCLUSIONS: RAADP of one single dose of 200 microg of RhIG in addition to postnatal RhIG (200 microg) halves the risk of anti-D immunization and subsequent severe HDFN.