Pregnancy and delivery outcomes in individuals with <scp><i>RUNX1</i></scp>‐Familial Platelet Disorder

RUNX1-familial platelet disorder (FPD) is a dominantly inherited condition, caused by pathogenic variants in the RUNX1 gene. It is characterized by qualitative and quantitative platelet defects along with a 30%–50% lifetime risk of haematological malignancy.1, 2 Common symptoms include bruising susceptibility, abnormal bleeding, epistaxis and menorrhagia. While bleeding in this condition is well characterized, little has been reported about the pregnancy and delivery outcomes for individuals with RUNX1-FPD. Pregnancy complications have been reported for other inherited bleeding disorders.3-10 Those include antepartum bleeding, postpartum haemorrhage, need for blood transfusion, caesarean hysterectomy and maternal death. Intracranial haemorrhage is rare in affected infants, but cephalohematomas and subgaleal bleeds have been reported.8, 11 To better understand pregnancy and delivery outcomes in RUNX1-FPD, we retrospectively analysed data from 38 participants enrolled in the National Institutes of Health RUNX1 Natural History Study2 who had been pregnant (Table 1). None of the women had developed a haematological malignancy or had a haematopoietic stem cell transplant prior to their deliveries. Twenty-six women reported menorrhagia, which was generally controlled with hormonal contraceptives or progesterone intrauterine device. However, two women had been hospitalized and needed transfusions for menorrhagia. One woman received tranexamic acid (TXA) to control bleeding while trying to conceive. Four women ultimately elected for hysterectomies to control bleeding. In this cohort, there were 94 deliveries. The number of deliveries per woman ranged from 1 to 9, with a median of 2 and one set of twins. One delivery resulted in a stillbirth. There were an additional 13 reported miscarriages, the majority of which were first trimester. One miscarriage was at 3 months' gestation with excessive bleeding and required dilation and curettage (D&C). Thirty-two women did not know they had RUNX1-FPD during any of their pregnancies. Three were diagnosed before their first pregnancy and three additional learned after their first, but before subsequent pregnancies. The majority of pregnancies in this cohort were managed without awareness of the underlying diagnosis. Thrombocytopenia during pregnancy prompted RUNX1 testing in four women. One woman used in vitro fertilization with pre-implantation genetic testing (IFV-PGTM) for RUNX1. She did not have any prophylactic treatment nor did she experience adverse bleeding during egg retrieval or transfer. No women reported difficulty conceiving. Two women reported having amniocentesis, and neither had complications. Seven women reported spotting, to varying degrees of severity. Four were placed on bed rest due to bleeding, two in the second trimester and two in the third. One woman required cauterization for two pregnancies. Subchorionic haemorrhage occurred in five pregnancies, one of which required platelet transfusion. All of these resulted in live births. Two women had placenta previa; both delivered preterm (26 and 33 weeks) without requiring transfusions. Two women were diagnosed with preeclampsia and another with Haemolysis Elevated Liver Enzymes and Low Platelet (HELLP) Syndrome. Overall, two women had transfusions during pregnancy, but not during delivery. Placental abruption occurred in four pregnancies, three of which required emergent caesarean delivery and one—delivered prematurely at 33 weeks—required blood transfusion. Preterm delivery occurred in 10 pregnancies (11%). Thirty pregnancies were delivered via caesarean-section and 64 were delivered vaginally. Five were vaginal births after caesarean-sections (VBAC). Sixteen women had epidurals for 21 deliveries without complications. One had a platelet transfusion prior to her epidural. Seven women had transfusions for 10 deliveries. Seven were prophylactic platelet transfusions. Only one required intensive care unit admission for her third delivery. This was due to a life-threatening haemorrhage. Data on anti-HLA (human leukocyte antigen) antibodies were not available. Eleven women reported heavier postpartum bleeding, though most did not require intervention, and none required transfusion. One woman required D&C, but not transfusion. Three of the women who reported significant postpartum bleeding had received transfusions during delivery. While neonatal platelet testing is not standard, several parents reported that newborns who ultimately tested positive for RUNX1 variants were found to have very low platelet counts at birth (<50k). One newborn, who was delivered at 28 weeks with fetal growth restriction, received platelets for a small intraventricular haemorrhage. Otherwise, bleeding complications were not reported in newborns. Most pregnancies to individuals with RUNX1-FPD have good maternal and neonatal outcomes. While pregnancy and delivery complications are rare, referral to a maternal fetal medicine specialist may be considered. Decreases in platelet counts are commonly observed during pregnancy in the general population; therefore, monitoring of platelet levels is particularly critical in women with RUNX1-FPD throughout gestation. Marked thrombocytopenia in the third trimester may indicate increased bleeding risk delivery.11 Obstetricians should be aware of the diagnosis and should consult with haematology. Alerting the anaesthesia and neonatology teams at the time of delivery can also be beneficial, especially as neuraxial analgesia appears underutilized. Given the increased bleeding risk, blood products and haemostatic agents such as TXA and desmopressin acetate (DDAVP) should be available at delivery and can be given prophylactically. DDAVP has been safely used in pregnancy, with careful fluid and electrolyte monitoring. Uterotonics should be available in case of postpartum haemorrhage. Epidurals may be considered on a case-by-case basis. Clotting agents or blood products prior to regional anaesthesia administration may be helpful to reduce the risk of bleeding or to increase platelet counts, especially as proper neuraxial analgesia may reduce the risks of other complications.12 Postpartum treatment with TXA can be considered to reduce the risk of delayed postpartum haemorrhage. Since RUNX1-FPD is a dominant condition, if the genetic status of the newborn is unknown, a platelet count should be obtained at birth. The newborn should be examined closely for evidence of petechiae or easy bruising. While instrumental delivery was not reported in this cohort and there were no instances of cephalohematomas or subgaleal bleeds, inferring from other platelet disorders, it is recommended to avoid fetal scalp electrodes, vacuum or high forceps in delivery when possible.13 Although one preterm infant (28 weeks) had intraventricular haemorrhage, this was likely secondary to prematurity rather than RUNX1-FPD. Findings during pregnancy prompted RUNX1 testing in several women. RUNX1-FPD should be considered in pregnant individuals with thrombocytopenia, especially with antepartum or postpartum haemorrhage, and in newborns with thrombocytopenia. Genetic testing is particularly important in women with histories of abnormal bleeding or platelets prior to pregnancy and personal or family history of haematological malignancy. Placental abruption and postpartum haemorrhage rates appear to be increased in women with RUNX1-FPD compared to the background rate in low-risk pregnancies (<1% placental abruption and 1%–3% postpartum haemorrhage). However, miscarriages and other pregnancy complications do not appear to be elevated.14 In summary, pregnancy and delivery are generally safe for women with RUNX1-FPD; however, careful coordination between maternal fetal medicine, haematology, and anaesthesia is important to mitigate risks. Blood products and/or clotting agents should be available at delivery and may be used prophylactically to reduce bleeding risks and to allow for the use of neuraxial analgesia. Neonates should be monitored for possible adverse bleeding and thrombocytopenia, especially if prenatal genetic testing has not been completed. This study has limitations. Women had variable levels of information about their pregnancies, and medical record corroboration was not always possible. Average platelet counts during pregnancy were not available, but the average platelet count at the time of NIH visit (not during pregnancy) for participants was 110k × 109/L. Deliveries occurred at different hospitals and ranged in time from the 1970s to the present, so medical management was highly variable, and records were limited. Most participants in this cohort were White, non-Hispanic, and it does not account for the significant racial/ethnic disparities that are known to impact pregnancy outcomes.15 This analysis was also restricted to women who had RUNX1-FPD. However, this study does provide important insight as more individuals with RUNX1-FPD go through childbirth. NTD drafted the manuscript, analysed the data and collected the data. LH-C provided guidance on maternal fetal medicine and pregnancy guidelines and drafted the manuscript. AK, EB, KC, JD and SC collected the data and cared for patients. DJY and PL supervised the work and drafted the manuscript. All authors critically reviewed the manuscript for submission. We would like to thank the patients for their participation. These patients are part of the NIH RUNX1 Natural History Study, which has been approved by the NIH Institutional Review Board (NCT03854318). Informed consent was obtained from all enrolled participants, and all procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki, as revised in 2000. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and National Heart, Lung, and Blood Institute, National Institutes of Health. The authors declare no competing interests.