We investigated the prevalence of maternal bleeding complications during pregnancy and delivery in women with RBC alloimmunization, compared to controls without RBC alloantibodies. Women with RBC alloimmunization had a higher overall prevalence of bleeding complications than controls. Higher rates of maternal hemorrhage in RBC alloimmunized cases, compared to controls, were independent of maternal age or previous obstetric history. Of note, bleedings that occurred within one week after an invasive procedure, such as amniocentesis or cordocentesis, were not counted for this study.
While the fetal risks and outcomes in RBC alloimmunization are well known [16], maternal complications in RBC alloimmunized women have not been studied so far. To the best of our knowledge, this investigation is the first to provide data on maternal bleeding complications in RBC alloimmunized women during pregnancy and delivery.
Despite substantial improvements in fetal medicine when implementing management according to Doppler assessment of middle cerebral artery as the threshold for fetal intervention [17] and gaining experience in IUTs over the last decades, adverse fetal or neonatal outcomes still exist. A large review of IUTs over 20 years in Sweden demonstrated a procedure-related complication rate of 4.9%, predominantly associated with technical difficulties in placing the needle into the right position. Ten patients from this review were delivered by emergency cesarean section resulting in live born children, but four mothers lost their children in conjunction with the IUTs [17]. Other studies report a fetal loss rate between 0.9 and 4.9% [18]. Fetal distress during or after the procedure is the most serious complication that may result in emergency delivery with the risk of prematurity, neonatal asphyxia or even infant death [18]. Procedure-related risks are increased when invasive, in utero transfusion is instituted prior to gestational weeks 22 to treat severe early-onset fetal anemia [19]. Data on the long-term outcome of children after antenatal transfusion demonstrated a normal neurodevelopmental outcome in more than 95%, with the highest risk for neurodevelopmental impairment in the presence of fetal hydrops [20]. In our study cohort, no severe complications after invasive procedures such as cordocentesis or IUT occurred. Thus, no additional patients had to be excluded due to procedure- related complications.
Even simple prenatal invasive procedures and every fetal intervention carry a specific risk of any kind of complications, typically bleeding or infection, to the mother, while not providing any direct medical benefits to the mother herself [21]. A recent review on maternal complications following open and fetoscopic fetal surgeries demonstrated a maternal complication rate of 6.2% for fetoscopic and 20.9% for open fetal surgeries [21]. The rate of serious maternal complications was 1.7% in fetoscopic and 4.5% in open procedures and included severe infection, sepsis, lung edema, complete heart block, hemorrhage, placental abruption, maternal cardiac arrest, uterine rupture and caesarean hysterectomy [21]. A retrospective investigation on 187 pregnancies after fetal surgery revealed a prevalence of premature, preterm rupture of membranes of 44.4%, chorio-amniotic membrane separation in 36%, chorioamnionitis in 4.5%, vaginal bleeding in 6.7% and placental abruption in 6.2% of patients [22]. Maternal complications of pregnancies after fetal surgery for spina bifida were chorio-amniotic membrane separation in 15% and maternal pulmonary embolism, chorioamnionitis, maternal heart block and uterine rupture in 2.1%, 1.4%, 0.7% and 0.7%, respectively [23].
The present study focused on maternal bleeding complications during pregnancy and delivery without considering procedure-related complications of fetal interventions. Our data demonstrate an about doubled rate of any bleeding complications in women with RBC (13.8%) alloimmunization, compared to women without RBC AB (6.2%). For the rarity of the disease, our study cohort was rather large, yet not large enough to allow for a detailed, statistically sound discrimination between groups for bleeding rates, according to the time frames of every single trimester or only for the delivery to postpartum period. While, for example, six women with RBC AB had bleeding complications during the third trimester (6/130, 4.6%), only one women of the control group without RBC AB experienced bleeding during this period (1/130, 0.8%; p = 0.12). Based on these proportions, sample size requirements to detect differences in bleeding complications for the third trimester separately, at a power of 80%, calculates the need for 284 women in each group included. Enrollment of such a large patient cohort, even when bleeding complications are not uncommon in the control and in the case groups, is unlikely to be successful for a relatively rare disease such as RBC alloimmunization.
Multiple factors can cause bleeding complications during pregnancy or delivery that can happen in the first, second, and third trimester of pregnancy [24]. Vaginal bleeding in the first trimester is usually defined as threatened abortion, eventually related to fetal genetic disorders or implantation difficulties. Bleeding that develops later than the beginning of the second trimester is often idiopathic, and the main risks associated with antepartum hemorrhage of unknown origin are preterm birth and low neonatal birth weight [25–28]. Severe postpartum hemorrhage is among the most common causes of severe, maternal life-threatening complications [29, 30]. In women with RBC AB, predisposition to ante- or peripartum bleedings may not only be considered a relatively frequent – maternal - pregnancy complication, but hypothetically also the origin of RBC alloimmunization, and boostering of the maternal immune response for subsequent pregnancies.
In a large Korean study, no difference was found between Rh positive and Rh negative primigravida women in terms of adverse pregnancy outcome, e.g. preeclampsia, placenta previa, placental abruption, postpartum hemorrhage and the need for uterine artery embolization [31]. That study, however, did not consider women with RBC AB and only first pregnancies were included. Interestingly, there are studies about a relationship of ABO blood groups and preeclampsia or pregnancy-induced hypertension. Recently published data of a large cohort study of 5.1 million unique persons provide evidence that pregnancy-induced hypertension was less common in blood groups A and AB, as compared to blood group 0 [32]. In contrary, other studies suggested that maternal A or AB blood types, but not B, were found at increased risk of preeclampsia compared with 0 type women [33] or that blood group 0 was significantly more common in early-onset and less common in late-onset preeclampsia [34]. However, data about the ABO blood groups and bleeding complications in pregnancy are lacking so far.