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Mothers with long QT syndrome are at increased risk for fetal death: findings from a multicenter international study

Published:September 11, 2019DOI:https://doi.org/10.1016/j.ajog.2019.09.004

      Background

      Most fetal deaths are unexplained. Long QT syndrome is a genetic disorder of cardiac ion channels. Affected individuals, including fetuses, are predisposed to sudden death. We sought to determine the risk of fetal death in familial long QT syndrome, in which the mother or father carries the long QT syndrome genotype. In addition, we assessed whether risk differed if the long QT syndrome genotype was inherited from the mother or father.

      Objective

      This was a retrospective review of pregnancies in families with the 3 most common heterozygous pathogenic long QT syndrome genotypes in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3), which occur in approximately 1 in 2000 individuals. The purpose of our study was to compare pregnancy and birth outcomes in familial long QT syndrome with the normal population and between maternal and paternal carriers of the long QT syndrome genotype. We hypothesized that fetal death before (miscarriage) and after (stillbirths) 20 weeks gestation would be increased in familial long QT syndrome compared with the normal population and that the parent of origin would not affect birth outcomes.

      Study Design

      Our study was a multicenter observational case series of 148 pregnancies from 103 families (80 mothers, 23 fathers) with familial long QT syndrome (60 with LQT1, 29 with LQT2, 14 with LQT3) who were recruited from 11 international centers with expertise in hereditary heart rhythm diseases, pediatric and/or adult electrophysiology, and high-risk pregnancies. Clinical databases from these sites were reviewed for long QT syndrome that occurred in men or women of childbearing age (18–40 years). Pregnancy outcomes (livebirth, stillbirth, and miscarriage), birthweights, and gestational age at delivery were compared among long QT syndrome genotypes and between maternal vs paternal long QT syndrome–affected status with the use of logistic regression analysis.

      Results

      Most offspring (80%; 118/148) were liveborn at term; 66% of offspring (73/110) had long QT syndrome. Newborn infants of mothers with long QT syndrome were delivered earlier and, when the data were controlled for gestational age, weighed less than newborn infants of long QT syndrome fathers. Fetal arrhythmias were observed rarely, but stillbirths (fetal death at >20 weeks gestation) were 8 times more frequent in long QT syndrome (4% vs approximately 0.5%); miscarriages (fetal death at ≤20 weeks gestation) were 2 times that of the general population (16% vs 8%). The likelihood of fetal death was significantly greater with maternal vs paternal long QT syndrome (24.4% vs 3.4%; P=.036). Only 10% of all fetal deaths underwent postmortem long QT syndrome testing; 2 of 3 cases were positive for the family long QT syndrome genotype.

      Conclusion

      This is the first report to demonstrate that mothers with long QT syndrome are at increased risk of fetal death and to uncover a previously unreported cause of stillbirth. Our results suggest that maternal effects of long QT syndrome channelopathy may cause placental or myometrial dysfunction that confers increased susceptibility to fetal death and growth restriction in newborn survivors, regardless of long QT syndrome status.

      Key words

      Cardiac channelopathies are disorders caused by mutation of cardiac ion channels, that result in alteration of cardiac electrical activity. Long QT syndrome (LQTS) is the most common channelopathy, and those who are affected are at increased risk of death because of life-threatening ventricular tachycardia.
      • Schwartz P.J.
      • Ackerman M.J.
      The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy.
      LQTS genotypes affect approximately 1 in 2000 individuals and can be inherited (approximately 90%) or occur de novo (10%).
      • Schwartz P.J.
      • Stramba-Badiale M.
      • Crotti L.
      • et al.
      Prevalence of the congenital long-QT syndrome.
      Three genetic subtypes of LQTS (LQT1, LQT2, LQT3) account for approximately 80% of all LQTS and at least 95% of genetically identifiable cases
      • Bohun M.D.
      • Peng G.
      • Terrensire C.
      • Iver V.
      • Sampson K.J.
      • Kass R.S.
      Molecular pathology of congenital long QT syndrome.
      (Supplemental Table 1). An LQTS genotype is a frequent finding in autopsy-negative sudden unexplained death in the young and in approximately 10% of sudden infant death syndrome cases and 8% of ostensibly normal stillbirths.
      • Schwartz P.J.
      • Priori S.G.
      • Dumaine R.
      • et al.
      A molecular link between the sudden infant death syndrome and the long-QT syndrome.
      • Ackerman M.J.
      • Siu B.L.
      • Sturner W.Q.
      • et al.
      Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.
      • Arnestad M.
      • Crotti L.
      • Rognum T.O.
      • et al.
      Prevalence of long-QT syndrome gene variants in sudden infant death syndrome.
      • Tester D.J.
      • Wong L.C.H.
      • Chanana P.
      • et al.
      Cardiac genetic predisposition in sudden infant death syndrome.
      • Schwartz P.J.
      • Kotta M.C.
      Sudden infant death syndrome and genetics: don't throw out the infant with the dirty water.
      • Crotti L.
      • Tester D.J.
      • White W.M.
      • et al.
      Long QT syndrome and intrauterine fetal death.
      • Crotti L.
      • Johnson C.N.
      • Graf E.
      • et al.
      Calmodulin mutations associated with recurrent cardiac arrest in infants.
      • Cuneo B.F.
      • Etheridge S.P.
      • Horigome H.
      • et al.
      Arrhythmia phenotype during fetal life suggests LQTS genotype: Risk stratification of perinatal long QT syndrome.
      • Murphy L.L.
      • Moon-Grady A.J.
      • Cuneo B.F.
      • et al.
      Developmentally regulated SCN5A splice variant potentiates dysfunction of a novel mutation associated with severe fetal arrhythmia.
      • Rashba E.J.
      • Wojciech Z.
      • Moss A.J.
      • et al.
      Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome.
      • Heradien M.J.
      • Goosen A.
      • Crotti L.
      • et al.
      Does pregnancy increase cardiac risk for LQT1 patients?.
      • Seth R.
      • Moss A.J.
      • McNitt S.
      • et al.
      Long QT syndrome and pregnancy.
      • Lee W.
      • Gemma L.W.
      • Ward G.W.
      • et al.
      Beta-blockers protect against dispersion of repolarization during exercise in congenital long-QT syndrome type 1.
      • Alders M.
      • Bikker H.
      • Christiaans I.
      Long QT syndrome.
      • Harris P.A.
      • Taylor R.
      • Thielk R.
      • Payne J.
      • Gonzales N.
      • Cone J.G.
      Research electronic data capture (REDCap): a data-driven methodology and workflow process for providing translational research informatics support.
      • Ventura S.J.
      • Curtin S.C.
      • Abma J.C.
      • Henshaw S.K.
      Estimated pregnancy rates, and rates of pregnancy outcomes for the United States, 1990-2008. Hyattsville, MD: National Center for Health Statistics; June 2012.
      There is a prevailing view that death in LQTS is due to the life-threatening signature arrhythmia, torsades de pointes, which is a form of polymorphic ventricular tachycardia.
      • Schwartz P.J.
      • Ackerman M.J.
      The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy.
      • Cuneo B.F.
      • Etheridge S.P.
      • Horigome H.
      • et al.
      Arrhythmia phenotype during fetal life suggests LQTS genotype: Risk stratification of perinatal long QT syndrome.
      • Murphy L.L.
      • Moon-Grady A.J.
      • Cuneo B.F.
      • et al.
      Developmentally regulated SCN5A splice variant potentiates dysfunction of a novel mutation associated with severe fetal arrhythmia.

      Why was this study conducted?

      The purpose of this study was to better understand pregnancy outcomes of familial long QT syndrome.

      Key findings

      The incidence of stillbirths (8 times) and miscarriages (2 times) were greater than in the general population. Not all stillbirths carried the family long QT syndrome genotype. The number of fetal deaths were higher and the infant birthweights were lower when the mother, but not the father, carried the long QT syndrome genotype.

      What does this add to what is known?

      Long QT syndrome pregnancies should be considered at increased risk for fetal death. Postmortem fetal genetic analysis should be performed after a fetal death in an long QT syndrome pregnancy. Mothers with long QT syndrome warrant increased surveillance for fetal well-being.
      Yet, little is known about the pregnancy outcomes of inherited LQTS, in which the father or mother carries a known LQTS genotype. Previous reports concentrated on pregnancy-related risk of maternal cardiac events, and fetal data were very limited with no mention of arrhythmia. The first report, which was retrospective and did not include LQTS genotype data, found that the percentage of stillbirths were not different between maternal LQTS probands and control subjects (1.2% of 322 vs 0.3% of 403).
      • Rashba E.J.
      • Wojciech Z.
      • Moss A.J.
      • et al.
      Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome.
      A second study of families with a specific LQT1 genotype (A341V) also found no difference in pregnancy outcomes between cases and control subjects.
      • Heradien M.J.
      • Goosen A.
      • Crotti L.
      • et al.
      Does pregnancy increase cardiac risk for LQT1 patients?.
      In both studies, and in a subsequent report of mothers with an LQT2 genotype,
      • Seth R.
      • Moss A.J.
      • McNitt S.
      • et al.
      Long QT syndrome and pregnancy.
      β-adrenergic blocking agents (β-blockers) were protective against maternal cardiac events by adrenergic blockade and shortening the QTc interval.
      • Lee W.
      • Gemma L.W.
      • Ward G.W.
      • et al.
      Beta-blockers protect against dispersion of repolarization during exercise in congenital long-QT syndrome type 1.
      These findings led to the recommendation that β-blockers be continued throughout pregnancy.
      To better understand the risk of fetal death in familial LQTS, we evaluated pregnancy outcomes in families in which a mother or father carried LQT1, LQT2, or LQT3. We sought to determine whether stillbirths (fetal death at ≥20 weeks gestation) and/or miscarriages (fetal death <20 weeks gestation) occurred more frequently in familial LQTS than in the normal population and whether the frequency was altered by parental origin of the LQTS genotype.

      Materials and Methods

      Participating centers and subject recruitment

      This was a retrospective study of past pregnancies in which either the mother or father carried a LQTS genotype. Subjects were recruited from 11 international centers (Supplemental Table 2). Centers were chosen to participate in the study if they had interest in genetic heart rhythm diseases and physicians who specialized in pediatric and/or adult electrophysiology, genetics, and high-risk pregnancies. The participating centers are known collectively as the Fetal LQTS Consortium. Each participating center reviewed their clinical patient databases for men and women with LQT1, LQT2, or LQT3 who were of childbearing age (18–40 years) at the time of enrollment. Subjects were informed of the study by a letter. In addition to the local site recruitment from participating centers (located in the United States, Canada, Italy, Norway, Sweden, Finland, The Netherlands, Japan, and Germany) subjects (men and women) were recruited through the Sudden Arrhythmic Death (SADS) Foundation, the International Long QT Syndrome Registry, and an internet site called “fetallqts.com.” Signed informed consent was obtained for each subject, and the institutional review boards or ethics committee at all centers approved the study (CORE site UC-Denver IRB# 13-1879). The study was registered on ClinicalTrials.gov (NCT02876380).

      Research cohort and pregnancy data

      Inclusion criteria were pregnancies in which the mother or father had a positive genetic test for LQT1, LQT2, or LQT3.
      • Alders M.
      • Bikker H.
      • Christiaans I.
      Long QT syndrome.
      The physician filled out a questionnaire that detailed the specific LQTS genotype and whether the mother or father was LQTS-positive, the outcome of any previous pregnancies, pregnancy complications, maternal treatment with β-blockers, and the occurrence of fetal arrhythmias. Cases were excluded from analysis if the offspring had a homozygous genetic mutation or positive genetic tests for multiple variants.

      Postnatal data

      For the offspring, we gathered the results of postnatal genetic testing, birthweight, gestational age at delivery, and mode of delivery. In the case of fetal death (either stillbirth or miscarriage), results of postmortem genetic testing performed on DNA that had been extracted from the fetus were obtained if available.
      Pre- and postnatal study data were collected and managed with REDCap electronic data capture tools that are hosted at the University of Colorado. REDCap is a secure, web-based application that was designed to support data capture for research studies.
      • Harris P.A.
      • Taylor R.
      • Thielk R.
      • Payne J.
      • Gonzales N.
      • Cone J.G.
      Research electronic data capture (REDCap): a data-driven methodology and workflow process for providing translational research informatics support.

      Statistics

      We analyzed pregnancy outcomes among pregnancies in families with LQTS. To determine the effects of β-blockers on gestational age at delivery and birthweight (controlled for gestational age), we used linear regression to compare pregnancies across 3 groups: untreated mothers with LQTS, treated mothers with LQTS, and fathers with LQTS (mothers were not treated). We also examined a subset of term births between the 3 groups of mothers. Live births and fetal deaths were compared among LQTS genotypes and between maternal vs paternal LQTS-affected status with the use of logistic regression analysis. Because some families had >1 child, generalized estimation equations that assumed an exchangeable working correlation structure were used to account for the correlation potentially introduced by the clustering effect of multiple pregnancies from the same family for all regression models. Comparisons among subgroups were tested by the Wald test. A probability value of <.05 was considered significant.

      Results

      Study cohort and pregnancy outcome

      Eleven participating centers enrolled 148 pregnancies from 103 families. Both maternal (80 families; 119 pregnancies) and paternal (23 families; 29 pregnancies) origin of LQTS were represented (Table 1; Figure 1). Among 119 pregnancies of 80 LQTS-positive women, LQT1 (65 pregnancies), LQT2 (41 pregnancies), and LQT3 (13 pregnancies) were present. Among 29 paternal LQTS pregnancies, LQT1 (20 pregnancies), LQT2 (4 pregnancies), and LQT3 (5 pregnancies) were present (Table 1; Figure 1).
      Table 1Maternal and paternal long QT syndrome status by family and pregnancy with row wise percentages
      GroupsTotal, n (%)LQT1, n (%)LQT2, n (%)LQT3, n (%)
      Families103 (100)60 (58)29 (28)14 (14)
       Maternal positive80 (100)45 (56)25 (31)10 (12)
       Paternal positive23 (100)15 (65)4 (17)4 (17)
      Pregnancies148 (100)85 (57)45 (30)18 (12)
       Maternal positive119 (100)65 (55)41 (34)13 (11)
       Paternal positive29 (100)20 (69)4 (14)5 (17)
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.
      Figure thumbnail gr1
      Figure 1Flow chart of the study population
      Outcome of long QT syndrome pregnancies (n=148) by maternal (n=119) or paternal (n=29) origin of long QT syndrome genotype.
      LB, livebirth; LQTS, long QT syndrome; MC, miscarriage; SB, stillbirth.
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.
      Live births occurred in 80% of the pregnancies (118/148; Table 2; Figure 1). There were 30 fetal deaths, including 16% miscarriages (24/148) and 4% stillbirths (6/148). The miscarriages occurred at 10.1±3.4 weeks gestation; the stillbirths occurred at 26.4±6.04 weeks gestation. All miscarriages occurred in families with maternal LQTS. This frequency of miscarriage was 2-fold that of the general population.
      • Ventura S.J.
      • Curtin S.C.
      • Abma J.C.
      • Henshaw S.K.
      Estimated pregnancy rates, and rates of pregnancy outcomes for the United States, 1990-2008. Hyattsville, MD: National Center for Health Statistics; June 2012.
      • MacDorman M.F.
      • Kirmeyer S.E.
      • Wilson E.C.
      Fetal and perinatal mortality, United States, 2006. Hyattsville, MD: National Center for Health Statistics; August 2012.
      • Hoyert D.L.
      • Gregory E.C.W.
      Cause of fetal death: data from the fetal death report, 2014.
      Euro-Peristat Project
      European Perinatal Health Report: Core indicators of the health and care of pregnant women and babies in Europe in 2015. Pages 93-95.
      Stillbirths occurred with a frequency approximately 8-fold greater than the general population.
      • Ventura S.J.
      • Curtin S.C.
      • Abma J.C.
      • Henshaw S.K.
      Estimated pregnancy rates, and rates of pregnancy outcomes for the United States, 1990-2008. Hyattsville, MD: National Center for Health Statistics; June 2012.
      • MacDorman M.F.
      • Kirmeyer S.E.
      • Wilson E.C.
      Fetal and perinatal mortality, United States, 2006. Hyattsville, MD: National Center for Health Statistics; August 2012.
      • Hoyert D.L.
      • Gregory E.C.W.
      Cause of fetal death: data from the fetal death report, 2014.
      Euro-Peristat Project
      European Perinatal Health Report: Core indicators of the health and care of pregnant women and babies in Europe in 2015. Pages 93-95.
      All but 1 stillbirth occurred in pregnancies with maternal LQTS.
      Table 2Outcomes of 148 pregnancies in 103 families with long QT syndrome
      Data are expressed as absolute (n) and relative (%) frequencies.
      OutcomeTotal (n=148), n (%)LQT1 (n=85), n (%)LQT2 (n=45), n (%)LQT3 (n=18), n (%)
      Liveborn118 (80)69 (81)34 (76)15 (83)
      All fetal deaths30 (20)16 (19)11 (24)3 (17)
       Miscarriage24 (16)12 (14)10 (22)2 (11)
       Stillbirth6 (4)4 (5)1 (2)1 (6)
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.
      a Data are expressed as absolute (n) and relative (%) frequencies.

      Pregnancy outcome based on LQTS genotype

      There were no statistically significant differences based on LQTS genotype for the proportion of pregnancies that ended in fetal death (Wald test P=.700; Table 2).

      Effect of parental origin of LQTS on pregnancy outcome

      The number of stillbirths was higher when the mother, not the father, carried the LQTS genotype (5.3% [5/95] vs 3.5% [1/29]; P=.694). However, and importantly, pregnancies were significantly more likely to end in fetal death with maternal rather than paternal LQTS (24.4% [29/119] vs 3.5% [1/29]; P=.036). This difference remained significant after adjustment for LQTS genotype (P=.039). The parent of LQTS origin and the LQT genotype in those pregnancies with fetal deaths are shown in Supplemental Table 3.

      Effect of β-blocker treatment on pregnancy outcome

      Of 80 LQTS-positive mothers, 71% (57/80) were treated with β-blockers: 78% (35/45) of LQT1, 84% (21/25) of LQT2, and 10% (1/10) of LQT3. Other antiarrhythmic agents that included mexiletine or flecainide were not prescribed to any mother. The 57 mothers with LQTS who were treated with β-blockers had 65 live births with several different β-blockers reported (with 1 mother reporting propranolol in 1 pregnancy and atenolol in a second pregnancy): metoprolol (34%; 22/65), nadolol (26%; 17/65), propranolol (22%; 14/65), atenolol (11%; 7/65), and bisoprolol (8%; 5/65).
      A total of 20 mothers with LQTS experienced ≥1 fetal death; 11 mothers had a history of β-blocker treatment during pregnancy. Two mothers were treated with metoprolol 3 with nadolol; 5 mothers were treated with propranolol, and 1 mother was treated with atenolol.

      Fetal arrhythmias

      Among the 118 live births, fetal arrhythmias were reported. The signature fetal LQTS arrhythmia of torsades de pointes ventricular tachycardia was observed in only 1.7% (2/118), both of whom were positive for the family mutation that was inherited from the mother: KCNH2 (p. Thr613Met) and SCN5A (p. Ala1330Thr). In 3.4% (4/118), intermittent or sustained AV block were reported (3 with LQT2 and 1 with LQT1). Benign fetal arrhythmias were reported in 5 infants: 2 had atrial ectopy; 2 had sinus bradycardia with heart rates <100 beats/min, and 1 had an unknown arrhythmia. Among stillborn fetuses, none had preceding fetal arrhythmias reported.

      Obstetrics outcome

      Delivery data were available for 98% of live births (115/118): 68 LQT1, 34 LQT2, and 13 LQT3 (Table 3). Most infants (66%; 76/115) were born by normal spontaneous vaginal delivery (Table 4). However, 34% of the infants (39/115) were delivered by cesarean delivery, including 14 (36% of cesarean deliveries and 12% of all deliveries) urgently delivered for fetal distress (bradycardia and/or poor fetal heart rate variability). All urgently delivered infants were positive for the family LQTS genotype.
      Table 3Linear regression models with generalized estimation equations
      Assuming an exchangeable working correlation structure for the outcome of infant birthweight adjusted for parental long QT syndrome and β-adrenergic blocker treatment status with and without gestational age for all births and restricted to full-term births (>38 weeks gestation).
      ModelEstimate (95% confidence interval)P value
      Without gestational age: all births
       Intercept2.76 (2.59–2.94)<.001
       Untreated mother with long QT syndrome vs treated mother with long QT syndrome0.30 (–0.09–0.68).135
       Father with long QT syndrome vs treated mother with long QT syndrome0.82 (0.55–1.09)<.001
      With gestational age: all births
       Intercept–4.41 (–5.16– –3.66)<.001
       Untreated mother with long QT syndrome vs treated mother with long QT syndrome0.32 (0.08–0.56).008
       Father with long QT syndrome vs treated mother with long QT syndrome0.52 (0.28–0.76)<.001
       Gestational age, wk0.19 (0.17–0.21)<.001
      With gestational age: full-term births only
       Intercept–3.45 (–8.06–1.16).142
       Untreated mother with long QT syndrome vs treated mother with long QT syndrome0.29 (–0.02–0.59).069
       Father with long QT syndrome vs treated mother with long QT syndrome0.47 (0.20–0.73)<.001
       Gestational age, wk0.16 (0.05–0.28).006
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.
      a Assuming an exchangeable working correlation structure for the outcome of infant birthweight adjusted for parental long QT syndrome and β-adrenergic blocker treatment status with and without gestational age for all births and restricted to full-term births (>38 weeks gestation).
      Table 4Method of delivery in 118 pregnancies with long QT syndrome by familial genotype
      Data are expressed as absolute (n) and relative frequencies (%)
      Delivery methodTotal (n=118), n (%)LQT1 (n=69), n (%)LQT2 (n=34), n (%)LQT3 (n=15), n (%)
      Normal spontaneous vaginal delivery76 (66)46 (68)20 (59)10 (77)
      Elective cesarean delivery19 (17)10 (15)8 (24)1 (8)
      Cesarean delivery for distress14 (12)10 (15)4 (12)0 (0)
      Cesarean delivery for obstetrics indications unrelated to fetal distress6 (5)2 (3)2 (6)2 (15)
      Unknown
      Not included in calculation of relative frequencies.
      3102
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.
      a Data are expressed as absolute (n) and relative frequencies (%)
      b Not included in calculation of relative frequencies.

      Maternal complications

      Among live births, 7 complications were described. There were 2 premature births (at 28 and 32 weeks gestation), and 1 mother each had premature rupture of membranes, pregnancy-induced hypertension, syncope at 35 weeks gestation (LQT1 mother on metoprolol), pericardial effusion and respiratory distress, manual placental extraction, and postpartum hemorrhage. A mother with LQT1 who received nadolol experienced a pulmonary embolism and died during a normal spontaneous vaginal delivery at 38 weeks gestation. The infant survived.

      Gestational age and birthweight

      Birthweight data were available in 94% pregnancies (111/118). The linear regression with generalized estimation equations uncovered a significant difference in gestational age at delivery in families with fathers with LQTS (39.4±1.2 weeks weeks) compared with families with mothers with LQTS. This difference was present, whether the mothers with LQTS were treated with β-blockers (38.1±2.8 weeks gestation; P=.001) or not treated (37.3±3.9 weeks gestation; P=.027). However, there was no significant difference in gestational age at delivery between treated and untreated mothers with LQTS (P=.776). Thus, mothers with LQTS delivered earlier, regardless of β-blocker treatment (Figure 2, A).
      Figure thumbnail gr2
      Figure 2Effect of β-blocker therapy during pregnancy on fetal outcomes
      A, Mean gestational age at delivery (weeks) with 2 standard error bar with the use of unadjusted probability values; B, mean birthweight (kilograms) with 1 standard error bar with the use of probability values that were adjusted for age at delivery.
      BB, β blocker; LQTS, long QT syndrome.
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.
      Infant birthweights were not statistically different in mothers with LQTS who were treated with β-blockers (2.8±0.7 kg; Table 5) and not treated (2.9±0.9 kg; Table 5; P=.135; Table 3) but were different when compared with infants born to fathers with LQTS (3.5±0.5 kg; Table 5; P<.001; Table 4). When we adjusted for gestational age at delivery, mothers with LQTS who were treated with β-blockers had significantly lower birthweights when compared with untreated mothers with LQTS (–0.32 kg; 95% confidence interval, –0.08 to –0.56; P=.008; Table 3) and families with LQTS-fathers (–0.52 kg; 95% confidence interval, –0.28 to –0.77; P<.001; Table 5). This difference was also seen when mothers who received atenolol, a class D pregnancy drug that has been implicated in growth restriction, were excluded from the analysis (data not shown). However, differences in infant birthweight between mothers with LQTS based on β-blocker treatment was not seen in the subgroup of term infants (P=.069; Table 3); infant birthweight of treated mothers was 3.03±0.55 kg vs 3.33±0.53 kg (Table 5). Not surprisingly, gestational age was significant in this subgroup of term infants (P=.006; Table 5); each completed week of gestation increased the average birthweight by 0.16 kg. Thus, β-blocker treatment was associated with lower birthweights in babies from mothers with LQTS when we adjusted for gestational age (Figure 2, B); however, this relationship was not statistically significant when we considered only full-term births.
      Table 5Average birthweight in kilograms at delivery by β-adrenergic blocking agent treatment and parental long QT syndrome status
      Data are presented as mean±standard deviation and [N].
      Long QT syndrome groupAll gestational ages, wkPreterm (<34 weeks gestation)Late preterm (34–37 weeks gestation)Term (>38 weeks gestation)
      Father3.53±0.51 [27]None3.57±0.34 [2]3.51±0.53 [25]
      Mother, no treatment2.91±0.92 [21]1.36±0.47 [4]3.05±0.57 [3]3.33±0.53 [14]
      Mother, treated2.79±0.73 [63]1.12±0.48 [4]2.32±0.47 [10]3.03±0.55 [49]
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.
      a Data are presented as mean±standard deviation and [N].
      The birthweight of 20% of newborn infants (22/111) was <10th percentile. Evaluating specific groups, 7.4% of births (2/27) to families of fathers with LQTS were <10th percentile compared with 23.8% of births (20/84) to mothers with LQTS, but the estimated odds of having an infant at <10th percentile for weight for maternal LQTS is 3.88 (95% confidence interval, 0.89–16.94) times the odds for paternal LQTS (P=.071). When the comparison was restricted to treated and untreated mothers with LQTS, the estimated odds of having an infant at <10th percentile for a treated LQTS mother was 4.49 times (95% confidence interval, 0.96–20.4) the odds for an untreated LQTS mother (P=.056).
      With regards to β-blocker treatment, 9.5% of the infants (2/21) were born to untreated mothers with LQTS, and 28.6% (18/63) were born to treated mothers with LQTS, but this difference was not statistically significant. Of interest, only 1 of the 22 infants who weighed <10th percentile was from an LQT3 family.

      Genetic testing in offspring

      Of the 118 live births, genetic testing results were available for 93% (110/118). The inherited LQTS genotype was found in 66% (73/110). Among all 30 fetal deaths (Supplementary Table 3), only 2 stillbirths (1 positive for LQTS genotype) and 1 miscarriage (positive for LQTS genotype) underwent postnatal genetic testing.

      Comment

      Principal findings

      This multicenter international study is the largest to deal with pregnancy outcomes in familial LQTS and includes data from families with the 3 most common LQTS genotypes. The major finding, that parental origin of the inherited LQTS genotype affected pregnancy outcome was unexpected, had not been reported previously and was pertinent to the clinical management of LQTS pregnancies and the epidemiology of fetal death. There were 3 other significant findings: (1) The majority (80%) of familial LQTS pregnancies culminate in term live births that are delivered vaginally. (2) Surprisingly, the percentage of stillbirths (4%) and miscarriages (16%) in inherited LQTS are considerably higher than in the general population (0.4% and 8%, respectively), and specify a cause for stillbirth that has not been suspected or reported previously. (3) In addition to an increased likelihood of fetal death (24.4% vs 3.4%; P=.036), mothers with LQTS delivered earlier (38.1±2.8 vs 39.4±1.2 weeks gestation; P=.001); when corrected for gestational age, infants weighed less than infants of fathers with LQTS.(2.8±0.7 vs 3.5±0.5 kg; P<.001). These observations, plus the genetic documentation of stillbirths in fetuses without the family mutation, raise the possibility of specific effects of the maternal channelopathy (placental, uterine, or otherwise) that confer increased susceptibility for fetal death and growth restriction.

      Maternal LQTS as a cause for stillbirth

      In the general population, stillbirths have occurred in approximately 0.5% of all pregnancies in the United States and Europe.
      • Ventura S.J.
      • Curtin S.C.
      • Abma J.C.
      • Henshaw S.K.
      Estimated pregnancy rates, and rates of pregnancy outcomes for the United States, 1990-2008. Hyattsville, MD: National Center for Health Statistics; June 2012.
      • MacDorman M.F.
      • Kirmeyer S.E.
      • Wilson E.C.
      Fetal and perinatal mortality, United States, 2006. Hyattsville, MD: National Center for Health Statistics; August 2012.
      • Hoyert D.L.
      • Gregory E.C.W.
      Cause of fetal death: data from the fetal death report, 2014.
      Euro-Peristat Project
      European Perinatal Health Report: Core indicators of the health and care of pregnant women and babies in Europe in 2015. Pages 93-95.
      Maternal, fetal, and pregnancy risk factors for stillbirth have been well-described,
      Stillbirth Collaborative Research Network Writing Group
      Causes of death among stillbirths.
      • Korteweg F.J.
      • Gordijn S.J.
      • Timmer A.
      • et al.
      The Tulip classification of perinatal mortality: introduction and multidisciplinary inter-rater agreement.
      yet even after detailed postmortem examination in tertiary care centers, the cause of stillbirth is unknown in 15–60% of cases.
      Stillbirth Collaborative Research Network Writing Group
      Causes of death among stillbirths.
      • Korteweg F.J.
      • Gordijn S.J.
      • Timmer A.
      • et al.
      The Tulip classification of perinatal mortality: introduction and multidisciplinary inter-rater agreement.
      • Wigglesworth J.S.
      Monitoring perinatal mortality: a pathophysiological approach.
      • Man J.
      • Hutchinson J.C.
      • Heazell A.E.
      • Ashworth M.
      • Levine S.
      • Sebire N.J.
      Stillbirth and intrauterine fetal death: factors affecting determination of cause of death at autopsy Ultrasound.
      • Manktelow B.N.
      • Smith L.K.
      • Evans T.A.
      • et al.
      MBRRACE-UK perinatal mortality surveillance report: UK perinatal death for births from January to December 2013. Supplementary report. UK Trusts and Health Boards. The Infant Mortality and Morbidity Studies Group.
      It has been reported that some stillbirths are preceded by abnormal umbilical artery Doppler studies that reflect placental dysfunction.
      • Ptacek I.
      • Sebire N.J.
      • Man J.A.
      • Brownbill P.
      • Heazell A.E.
      Systematic review of placental pathology reported in association with stillbirth.
      • Man J.
      • Hutchinson J.C.
      • Heazell A.E.
      • Ashworth M.
      • Jeffreys I.
      • Sebire N.J.
      Stillbirth and intrauterine fetal death: role of routine histopathological placental findings to determine cause of death.
      Although our sample size is too small to be conclusive, in our cohort, several observations suggest that increased stillbirths are due to a maternal factor rather than fetal factor. In LQTS, ventricular tachycardia is hypothesized to be the cause of fetal death in LQTS pregnancies. However, this seems unlikely in cases that we studied because ventricular tachycardia was detected in only 2 fetuses who survived. Further, the likelihood of fetal death is significantly lower if the LQTS genotype is of paternal origin. Although the likelihood is higher if the LQTS genotype is of maternal origin, we found that 2 of the 3 fetal deaths with LQTS did inherit the maternal LQTS genotype.

      Effects of maternal treatment with β-blockers

      Although fetal growth restriction has been a concern in pregnant women who receiving β-blockers, our findings were somewhat unexpected; infants of mothers with LQTS weighed <10th percentile if they delivered at <39 weeks gestation, regardless of treatment. β-blockers are the first-line therapy for arrhythmia prophylaxis in LQTS,
      • Priori S.G.
      • Wilde A.A.
      • Horie M.
      • et al.
      Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.
      and their use significantly reduces postpartum major cardiac event rates from 3.7% to 0.8%.
      • Heradien M.J.
      • Goosen A.
      • Crotti L.
      • et al.
      Does pregnancy increase cardiac risk for LQT1 patients?.
      • Seth R.
      • Moss A.J.
      • McNitt S.
      • et al.
      Long QT syndrome and pregnancy.
      There are abundant data to support the safety and efficacy of propranolol and nadolol (both are pregnancy risk category C),
      • Schwartz P.J.
      • Stramba-Badiale M.
      • Crotti L.
      • et al.
      Prevalence of the congenital long-QT syndrome.
      • Chow T.
      • Galvin J.
      • McGovern B.
      Antiarrhythmic drug therapy in pregnancy and lactation.
      but atenolol (pregnancy risk category D) is associated with significant intrauterine growth restriction,
      • Duan L.
      • Ng A.
      • Chen W.
      • Spencer H.T.
      • Lee M.-S.
      Beta-blocker subtypes and risk of low birth weight in newborns.
      and metoprolol is less effective in the prevention of arrhythmia recurrence.
      • Chockalingam P.
      • Crotti L.
      • Girardengo G.
      • et al.
      Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol.
      There is limited fetal/neonatal experience with nadolol, which is the preferred β-blocker for mothers with LQTS,
      • Ackerman M.J.
      • Priori S.G.
      • Dubin A.M.
      • et al.
      Beta-blocker therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: Are all beta-blockers equivalent?.
      compared with propranolol. These findings and our data suggest that β-blockers have a statistically, but not clinically, significant effect on birthweight support a favorable risk-benefit ratio for pregnant mothers with LQTS, while acknowledging the need for greater obstetric surveillance for markers of placental dysfunction during pregnancy.

      Clinical implications

      The findings that parental origin of the inherited LQTS genotype affected pregnancy outcome were unexpected and not previously reported. Maternal LQTS in other stillbirths has been noted previously.
      • Boule S.
      • Ovart L.
      • Marquie C.
      • et al.
      Pregnancy in women with an implantable cardioverter-defibrillator: Is it safe?.
      The recent findings that 2 of the 3 common LQTS genes are expressed in the placenta and the myometrium
      • Koppes E.
      • Himes K.P.
      • Chaillet R.J.
      Partial loss of genomic imprinting reveals important roles for Kcnq1 and Peg10 imprinted domains in placental development.
      • Winston NJ1
      • Johnson M.H.
      • McConnell J.M.
      • Cook D.I.
      • Day M.L.
      Expression and role of the ether-à-go-go-related (HERG1A) potassium-channel protein during preimplantation mouse development.
      leads us to speculate that ion channel mutations may affect placental and/or uterine function adversely, perhaps in similar ways to the changes in cardiac repolarization and arrhythmogenesis in rabbits that are exposed to high estrogen levels: increased action potential duration, QT interval, and susceptibility to triggered activity.
      • Odening K.E.
      • Koren G.
      How do sex hormones modify arrhythmogenesis in long-QT syndrome? Sex hormone effects on arrhythmogenic substrate and triggered activity.
      The cause of stillbirth in inherited LQTS appears to differ from the cause of stillbirth in de novo fetal LQTS. Signature LQTS fetal arrhythmias, 2-degree AV block, and/or ventricular tachycardia are the hallmark of de novo fetal LQTS genotypes.
      • Cuneo B.F.
      • Etheridge S.P.
      • Horigome H.
      • et al.
      Arrhythmia phenotype during fetal life suggests LQTS genotype: Risk stratification of perinatal long QT syndrome.
      • Murphy L.L.
      • Moon-Grady A.J.
      • Cuneo B.F.
      • et al.
      Developmentally regulated SCN5A splice variant potentiates dysfunction of a novel mutation associated with severe fetal arrhythmia.
      • Mitchell M.
      • Cuneo B.
      • Etheridge S.
      • Horigome H.
      • Weng H.Y.
      • Benson D.W.
      Fetal heart rate predictors of long QT syndrome.
      • Cuneo B.F.
      • Strasburger J.F.
      • Wakai R.T.
      In utero diagnosis of long QT syndrome by magnetocardiography.
      Previous reports of fetuses with these arrhythmias reported that >90% had a de novo LQTS mutation.
      • Ackerman M.J.
      • Siu B.L.
      • Sturner W.Q.
      • et al.
      Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.
      • Arnestad M.
      • Crotti L.
      • Rognum T.O.
      • et al.
      Prevalence of long-QT syndrome gene variants in sudden infant death syndrome.
      In contrast, despite known LQTS and increased pregnancy surveillance, signature LQTS fetal arrhythmias were observed rarely in our cohort. Finally, fetal deaths were not associated uniformly with LQTS genotype, although all losses that were tested were from pregnancies with maternal LQTS.

      Research implications

      Channel expression profiling in the placental vascular tissue of mother with an inherited channelopathy may provide clues to our findings. For example, potassium channel subfamilies including KV7.7 and KV11.1, the channels that are rendered abnormal in LQT1 and LQT2 genotypes (Supplemental Table 1), occur in the vascular smooth muscle and endothelium of the fetoplacental circulation and facilitate vasodilation.
      • Wareing M.
      • Greenwood S.L.
      Review: potassium channels in the human fetoplacental vasculature.
      To the best of our knowledge, placental potassium channel function has not been evaluated in LQTS and may be a relevant substudy in the National Institutes of Health–sponsored “Human Placenta Project.”
      • Guttmacher A.E.
      • Maddox Y.T.
      • Spong C.Y.
      The human placenta project: placental structure, development and function in real time.
      Routine examinations of fetal deaths do not include channelopathy-susceptibility genetic testing. Our results and the published data that implicate LQTS genotype in 8% of stillbirths
      • Schwartz P.J.
      • Kotta M.C.
      Sudden infant death syndrome and genetics: don't throw out the infant with the dirty water.
      may change the current practice.

      Study limitations

      This is a retrospective study with inherent limitations of recall bias and confounding factors. We were unable to compare fetal death results with specific control populations but were limited to general populations in Europe and the United States. Our control group for β-blocker treatment was an unequal number of fathers with LQTS. Data collection was not always complete because there is no standard protocol for pre- and postnatal assessment of pregnancies and offspring who are at risk for LQTS. Cases reported without a gestational age for live birth, miscarriage, or stillbirth had to be excluded to maintain robust data quality. We were not able to establish whether there is a genotype-specific effect on pregnancy outcome because of the small number of stillbirths in each LQTS genotype. Furthermore, we could not exclude the possibility of undetected torsades de pointes in the pregnancies that ended in stillbirth or miscarriage, because fetuses were not monitored continuously at home or at a young gestational age. Our results on the effects of β-blockers on fetal growth are complex and may be due to the small sample size. Last, although both men and women received information about the study, the finding of a predominance of stillbirths in families in which the mother was affected with LQTS may represent selection bias, because a mother may be more likely to be referred to a tertiary center for perinatal care if she has LQTS than if the father has LQTS.

      Conclusions

      Unlike fetal LQTS, because of de novo LQTS genotypes, the increased number of stillbirths and miscarriages in pregnancies in which 1 parent has autosomal-dominant LQTS cannot be explained by fetal ventricular arrhythmias. The association of stillbirth risk with maternal LQTS and documentation of stillbirths who did not inherit the maternal LQTS genotype implicate a potential maternal effect on fetal death, possibly because of altered functioning of placenta or myometrium. This speculation is supported by the number of newborn infants who weigh <10th percentile for gestational age at birth of LQTS-positive mothers, but not LQTS-positive fathers. Genetic testing should be offered in inherited LQTS pregnancies with fetal death to clarify the relationship between the fetal death and the LQTS genotype.
      Increased anxiety is present in all families with LQTS when a new pregnancy occurs. Our findings suggest that paternal families with LQTS are likely to have a good pregnancy outcome. At the same time, recognizing the increased risk in maternal families with LQTS may lead to increased maternal and fetal surveillance, with emphasis on placental function and fetal well-being to improve fetal and neonatal outcomes.

      Acknowledgment

      We thank Ms Halley Isberg, Research Institute, Children’s Hospital Colorado, for her help with data entry and study coordination; she was paid research funds from The Colorado Fetal Care Center , Department of Pediatrics , Children's Hospital Colorado .

      Appendix

      Supplemental Table 1Effect of long QT syndrome genotypes on depolarizing and repolarizing cardiac currents
      LQT subtypeGenotype (variant)Effect
      LQT1KCNQ1Loss of function in potassium repolaring current KCNQ1 (Kv7.1/IKs)
      LQT2KCNH2Loss of function in potassium repolarizing current hERG (Kv11.1/IKr)
      LQT3SCN5AGain of function in depolarizing current Nav 1.5/INa
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.
      Supplemental Table 2Families and pregnancies from participating sites
      SiteFamilies (N=103), n (%)Pregnancies (N=148), n (%)
      The Netherlands18 (17.5)31 (20.9)
      Helsinki, Finland20 (19.4)27 (18.2)
      Mayo Clinic, Rochester, MN17 (16.5)23 (15.5)
      Denver, CO11 (10.7)14 (9.5)
      Italy10 (9.7)11 (7.4)
      Salt Lake City, UT6 (5.8)10 (6.8)
      Vanderbilt University, Nashville, TN6 (5.8)9 (6.1)
      Bonn University, Bonn, Germany5 (4.9)7 (4.7)
      Japan3 (2.9)6 (4.1)
      Oslo University, Oslo, Norway4 (3.9)5 (3.4)
      Umea University, Umea, Sweden2 (1.9)4 (2.7)
      German Heart Center, Munich, Germany1 (1.0)1 (0.7)
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.
      Supplemental Table 3Parent of origin and his/her long QT syndrome genotype in fetal deaths
      Long QT syndromeGenotypeMiscarriage, nStillbirth, n
      ParentType
      MotherLQT1KCNQ1 p. Gly589Asp11
      MotherLQT1KCNQ1 p. Gly589Asp30
      FatherLQT1KCNQ1 p. Arg366Trp01
      MotherLQT1KCNQ1 p. Gly589Asp10
      MotherLQT3SCN5A p. Arg1958X10
      MotherLQT1KCNQ1 p. Tyr184Ser30
      MotherLQT3SCN5A p. Ile768Val01
      MotherLQT1KCNQ1 p. Arg192Cysfs*9101
      MotherLQT1KCNQ1 p. Try315Asn01
      MotherLQT2KCNH2 p. Glu788DAsp01
      MotherLQT1KCNQ1 p. Val254Met20
      MotherLQT2KCNH2 p. Ile19Phe10
      MotherLQT3SCN5A p. Ala1330Thr10
      MotherLQT2KCNH2 p. Lys610Asn30
      MotherLQT1KCNH2 p. IIe235Asn10
      MotherLQT2KCNH2 p. Thr613Met10
      MotherLQT1KCNQ1 p. Arg591Cys10
      MotherLQT2KCNQ1 p. Arg252Glyfs*10830
      MotherLQT2KCNH2 p. Asp609Asn10
      MotherLQT2KCNH2 p. Arg242fsx35910
      TOTAL246
      Cuneo et al. Fetal death and familial long QT syndrome. Am J Obstet Gynecol 2020.

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