Advertisement

Family history is a predictor of current preterm birth

  • Amanda Koire
    Affiliations
    Department of Quantitative and Computational Biology, Baylor College of Medicine, Houston, TX

    Medical Scientist Training Program, Baylor College of Medicine, Houston, TX
    Search for articles by this author
  • Derrick M. Chu
    Affiliations
    Medical Scientist Training Program, Baylor College of Medicine, Houston, TX

    Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX

    Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX
    Search for articles by this author
  • Kjersti Aagaard
    Correspondence
    Corresponding author: Kjersti Aagaard, MD, PhD.
    Affiliations
    Medical Scientist Training Program, Baylor College of Medicine, Houston, TX

    Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX

    Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
    Search for articles by this author
Open AccessPublished:November 11, 2020DOI:https://doi.org/10.1016/j.ajogmf.2020.100277

      Background

      Reliable prediction of spontaneous preterm birth remains limited, particularly for nulliparous and multiparous women without a personal history of preterm birth. Although previous preterm birth is a risk factor for recurrent preterm birth, most spontaneous preterm births occur in women with no previous history of preterm birth.

      Objective

      This study aimed to determine whether patients’ self-reported maternal family history of preterm births among siblings and across 3 generations was an independent risk factor for spontaneous preterm births after controlling for potential confounders.

      Study Design

      This was a retrospective analysis of a prospectively acquired cohort using a comprehensive single, academic center database of deliveries from August 2011 to July 2017. The objective of the current analysis was to evaluate the risk of preterm birth among women with and without a family history of preterm birth. All subjects in the database were directly queried regarding familial history across 3 generations, inclusive of obstetrical morbidities. Index subjects with probable indicated preterm birth (eg, concurrent diagnosis of preeclampsia; hemolysis, elevated liver enzymes, and low platelet count; or placenta previa or placenta accreta) were excluded, as were nonsingleton pregnancies. Univariate and multivariate analyses with logistic regression were used to determine significance and adjusted relative risk.

      Results

      In this study, 23,816 deliveries were included, with 2345 (9.9%) born prematurely (<37 weeks’ gestation). Across all subjects, preterm birth was significantly associated with a maternal family history of preterm birth by any definition (adjusted relative risk, 1.44; P<.001), and the fraction of preterm birth occurring in women with a positive family history increased with decreasing gestational age at which the index subjects of preterm birth occurred. For nulliparous women, a history in the subject’s sister posed the greatest risk (adjusted relative risk, 2.25; P=.003), whereas for multiparous women with no previous preterm birth, overall family history was most informative (P=.003). Interestingly, a personal history of the index subject herself being born preterm presented the greatest individual risk factor (adjusted relative risk, 1.94; P=.004).

      Conclusion

      Spontaneous preterm birth in the current pregnancy was significantly associated with a maternal family history of preterm birth among female relatives within 3 generations and notably sisters. The risk persisted among gravidae without a previous preterm birth, demonstrating the capacity for familial history to independently predict risk of spontaneous preterm birth even in the context of a negative personal history. This study provides evidence that self-reported maternal family history is relevant in a US population cohort and across more distant generations than has previously been reported.

      Key words

      Why was this study conducted?

      Reliable prediction of spontaneous preterm birth (PTB) is challenging, particularly for nulliparous or multiparous women without a previous PTB. This study sought to determine whether patients’ self-reported maternal family history of PTB was associated with a significant risk of her delivering a preterm neonate.

      Key findings

      We observed a significant association between a maternal family history of PTB and subsequent PTB. The association of maternal familial history was strongest for predicting risk of early PTB.

      What does this add to what is known?

      Our observation of risk estimates spanned 3 generations and provided potentially clinically useful risk estimates in a population-based cohort. The association was strongest among women who delivered earlier PTBs.

      Introduction

      Preterm birth (PTB) defined as birth before 37 weeks’ gestation occurs in approximately 10% of births in the United States
      • Martin J.A.
      • Hamilton B.E.
      • Osterman M.J.
      • Driscoll A.K.
      • Mathews T.J.
      Births: final data for 2015.
      and increases the risk of neonatal intensive care unit admission and respiratory, neurologic, intestinal, and retinal complications.
      • Saigal S.
      • Doyle L.W.
      An overview of mortality and sequelae of preterm birth from infancy to adulthood.
      ,
      • McIntire D.D.
      • Leveno K.J.
      Neonatal mortality and morbidity rates in late preterm births compared with births at term.
      Approximately 40% of PTBs are spontaneous rather than medically indicated,
      • Goldenberg R.L.
      • Culhane J.F.
      • Iams J.D.
      • Romero R.
      Epidemiology and causes of preterm birth.
      and the ability to predict which pregnancies will result in spontaneous PTB (sPTB) is limited. Although personal history of previous PTB is known to be a strong independent risk factor for a subsequent recurrent PTB,
      • Mercer B.M.
      • Goldenberg R.L.
      • Moawad A.H.
      • et al.
      The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      it is inherently unable to inform the likelihood of occurrence among nulliparous women. Although particularly valuable for assessing the likelihood of recurrent PTB, personal history is too often uninformative, because over a third of deliveries are to first-time mothers
      • Martin J.A.
      • Hamilton B.E.
      • Osterman M.J.
      • Driscoll A.K.
      • Mathews T.J.
      Births: final data for 2015.
      and additional factors are necessary to predict the outcome of more routine cases.
      Several family and genome-wide association studies have established an initial body of evidence supporting a genetic influence over the duration of gestation.
      • Wu W.
      • Witherspoon D.J.
      • Fraser A.
      • et al.
      The heritability of gestational age in a two-million member cohort: implications for spontaneous preterm birth.
      • Frey H.A.
      • Stout M.J.
      • Pearson L.N.
      • et al.
      Genetic variation associated with preterm birth in African-American women.
      • Huusko J.M.
      • Karjalainen M.K.
      • Graham B.E.
      • et al.
      Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.
      • Hallman M.
      • Haapalainen A.
      • Huusko J.M.
      • et al.
      Spontaneous premature birth as a target of genomic research.
      Several common single nucleotide polymorphisms have demonstrated a reproducible association with PTB,
      • Zhang G.
      • Feenstra B.
      • Bacelis J.
      • et al.
      Genetic associations with gestational duration and spontaneous preterm birth.
      and studies of monozygotic twin pairs have suggested up to 40% heritability for PTB.
      • Clausson B.
      • Lichtenstein P.
      • Cnattingius S.
      Genetic influence on birthweight and gestational length determined by studies in offspring of twins.
      Similarly, increased risk of PTB has been reported in women who were themselves born preterm,
      • Urquia M.L.
      • Wall-Wieler E.
      • Ruth C.A.
      • Liu X.
      • Roos L.L.
      Revisiting the association between maternal and offspring preterm birth using a sibling design.
      • Derakhshi B.
      • Esmailnasab N.
      • Ghaderi E.
      • Hemmatpour S.
      Risk factor of preterm labor in the west of Iran: a case-control study.
      • Porter T.F.
      • Fraser A.M.
      • Hunter C.Y.
      • Ward R.H.
      • Varner M.W.
      The risk of preterm birth across generations.
      • Boivin A.
      • Luo Z.C.
      • Audibert F.
      • et al.
      Risk for preterm and very preterm delivery in women who were born preterm.
      • Bhattacharya S.
      • Raja E.A.
      • Mirazo E.R.
      • et al.
      Inherited predisposition to spontaneous preterm delivery.
      • Sherf Y.
      • Sheiner E.
      • Vardi I.S.
      • Sergienko R.
      • Klein J.
      • Bilenko N.
      Recurrence of preterm delivery in women with a family history of preterm delivery.
      • Boyd H.A.
      • Poulsen G.
      • Wohlfahrt J.
      • Murray J.C.
      • Feenstra B.
      • Melbye M.
      Maternal contributions to preterm delivery.
      • Wilcox A.J.
      • Skjaerven R.
      • Lie R.T.
      Familial patterns of preterm delivery: maternal and fetal contributions.
      have a sister who was born preterm,
      • Urquia M.L.
      • Wall-Wieler E.
      • Ruth C.A.
      • Liu X.
      • Roos L.L.
      Revisiting the association between maternal and offspring preterm birth using a sibling design.
      ,
      • Bhattacharya S.
      • Raja E.A.
      • Mirazo E.R.
      • et al.
      Inherited predisposition to spontaneous preterm delivery.
      • Sherf Y.
      • Sheiner E.
      • Vardi I.S.
      • Sergienko R.
      • Klein J.
      • Bilenko N.
      Recurrence of preterm delivery in women with a family history of preterm delivery.
      • Boyd H.A.
      • Poulsen G.
      • Wohlfahrt J.
      • Murray J.C.
      • Feenstra B.
      • Melbye M.
      Maternal contributions to preterm delivery.
      ,
      • Plunkett J.
      • Borecki I.
      • Morgan T.
      • Stamilio D.
      • Muglia L.J.
      Population-based estimate of sibling risk for preterm birth, preterm premature rupture of membranes, placental abruption and pre-eclampsia.
      or have a sister who delivered a PTB.
      • Derakhshi B.
      • Esmailnasab N.
      • Ghaderi E.
      • Hemmatpour S.
      Risk factor of preterm labor in the west of Iran: a case-control study.
      ,
      • Boyd H.A.
      • Poulsen G.
      • Wohlfahrt J.
      • Murray J.C.
      • Feenstra B.
      • Melbye M.
      Maternal contributions to preterm delivery.
      ,
      • Winkvist A.
      • Mogren I.
      • Högberg U.
      Familial patterns in birth characteristics: impact on individual and population risks.
      In contrast, 1 previous study has suggested a limited contribution of paternal lineage on the occurrence of PTB in an index pregnancy, showing that risk of PTB is not affected by a gravida partner’s history nor his familial history.
      • Boyd H.A.
      • Poulsen G.
      • Wohlfahrt J.
      • Murray J.C.
      • Feenstra B.
      • Melbye M.
      Maternal contributions to preterm delivery.
      Numerous studies have documented the ethnic disparity in PTB rates in both US-born African Americans and African populations, further indicating a role of maternal genetics, although the multifactorial nature of PTB and the genetic heterogeneity associated with large ethnic classifications, such as “African American,” have made the identification of strong causal markers of PTB challenging.
      • Boyd H.A.
      • Poulsen G.
      • Wohlfahrt J.
      • Murray J.C.
      • Feenstra B.
      • Melbye M.
      Maternal contributions to preterm delivery.
      ,
      • Hao K.
      • Wang X.
      • Niu T.
      • et al.
      A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods.
      • Roberts A.K.
      • Monzon-Bordonaba F.
      • Van Deerlin P.G.
      • et al.
      Association of polymorphism within the promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of the fetal membranes.
      • Nansook P.
      • Naidoo R.N.
      • Muttoo S.
      • et al.
      IL-17A[G197G]-Association between NOx and gestational age in a South African birth cohort.
      • Aidoo M.
      • McElroy P.D.
      • Kolczak M.S.
      • et al.
      Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX.
      • Anum E.A.
      • Springel E.H.
      • Shriver M.D.
      • Strauss 3rd, J.F.
      Genetic contributions to disparities in preterm birth.
      Despite the evidence of a genetic contribution to PTB, its application into clinical practice remains limited. Previous studies have examined the risk of PTB association with personal or sibling history, but few have looked at previous generations or more distant female relatives, such as aunts or grandmothers. In addition, many of these studies used medical registries to identify PTB family history, which may not be easily used in clinical practice. Converting these observed associations between the maternal lineage and PTB risk into clinically actionable guidelines requires evidence that patients’ self-reported family history are reliable enough to detect differences in delivery outcomes. For these reasons, we sought to further clarify the role of the extended maternal family lineage in predicting sPTB in a large, ethnically diverse population and to determine whether the influence of maternal history can be detected using patient reports of family history. Specifically, we analyzed whether a maternal family history of PTB across 3 generations, including mothers, sisters, aunts, and grandmothers presented an independent risk factor for sPTB after controlling for potential confounders.

      Materials and Methods

      Study design

      This was a retrospective cohort study (2011–2017) designed to assess the relative risk (RR) of PTB among women with and without a family history of PTB. Data were gathered from a central, deidentified database, PeriBank,
      • Antony K.M.
      • Hemarajata P.
      • Chen J.
      • et al.
      Generation and validation of a universal perinatal database and biospecimen repository: PeriBank.
      of deliveries from 2 hospitals, the Ben Taub General Hospital and the Texas Children’s Pavilion for Women (Houston, TX). This database and all affiliated studies were approved by the Baylor College of Medicine Institutional Review Board (H-26364; H-33382). All subjects were consented and enrolled at the time of delivery. In addition to abstracted data from the electronic medical record, women were interviewed in their language of preference regarding their family obstetrical history. Subjects were queried for any history of PTB in any female relatives on their mother’s side of the family, including whether the patient herself was born preterm. Specifically, family members directly asked about were divided into 3 major categories: sisters, grandmothers or aunts, and maternal (subject herself was born preterm). A gestational age (GA) at delivery <37 weeks or >3 weeks before the due date was considered preterm.

      Study population

      Subjects included in the current study were enrolled between August 2011 and July 2017 (n=26,221). The exclusion criteria included multiple gestations and subjects with a documented comorbidity indicative of a probable indicated PTB (preeclampsia; hemolysis, elevated liver enzymes, and low platelet count; placenta previa or placenta accreta) (n=2405). In total, 23,816 women satisfied the aforementioned criteria and were included for subsequent analysis. For purposes of analysis, a family history of PTB and multiple gestations in the same family member was treated as equivalent to an absence of PTB history in that family member.

      Outcome measures and statistical analysis

      Statistical analysis was performed using R (version 3.4.0). The primary outcome considered was sPTB in the current (index) pregnancy, defined as GA of <37 weeks at delivery in the absence of comorbidities. Defined comorbidities were as previously described.
      • Antony K.M.
      • Hemarajata P.
      • Chen J.
      • et al.
      Generation and validation of a universal perinatal database and biospecimen repository: PeriBank.
      • Tolcher M.C.
      • Chu D.M.
      • Hollier L.M.
      • et al.
      Impact of USPSTF recommendations for aspirin for prevention of recurrent preeclampsia.
      • Kahr M.K.
      • Antony K.M.
      • DelBeccaro M.
      • Hu M.
      • Aagaard K.M.
      • Suter M.A.
      Increasing maternal obesity is associated with alterations in both maternal and neonatal thyroid hormone levels.
      • Chabarria K.C.
      • Racusin D.A.
      • Antony K.M.
      • et al.
      Marijuana use and its effects in pregnancy.
      • Kahr M.K.
      • Suter M.A.
      • Ballas J.
      • et al.
      Preterm birth and its associations with residence and ambient vehicular traffic exposure.
      Univariate analysis was performed using the chi-square analysis. Multivariate analysis was performed using logistic regression to evaluate the risk of delivering preterm given a family history of PTB. Analysis was further stratified by parity (nulliparous or multiparous with no previous PTB) and by which family member delivered preterm (mother, sister, or grandmother or aunt). Given the potential for confounding, models were adjusted for African American ethnicity, smoking, underweight or morbidly obese (defined as body mass index [BMI] of <20 or >40 kg/m2), and maternal age (defined as >40 or <18 years of age). RRs and adjusted RRs (aRRs) were calculated. A P value of <.05 was considered significant.

      Results

      Of the 23,816 deliveries that met the inclusion criteria between August 2011 and July 2017, 81.2% of gravidae identified as white, 14.1% as African or African American, and 4.6% as Asian (Table 1). Of the gravidae who identified as white, over 76% were of Hispanic ethnicity. The mean maternal BMI was 26.9, and the rates of reported prenatal substance use disorder, alcohol use, and smoking were 0.5%, 0.8%, and 1.0%, respectively. The mean maternal age was 29.8, and nearly 30% of the patients were nulliparous. Of those who were multiparous, 13.5% had experienced a PTB in a previous pregnancy.
      Table 1Maternal baseline characteristics
      Clinical characteristicsTotal
      Ethnicity
       Hispanic60.4
       Non-Hispanic39.6
      Race
       White78.7
       Black13.4
       Asian4.4
       Other or mixed0.5
       Unknown3.0
      Maternal age29.8±6.1
      Parity
       Nulliparous29.7
       Multiparous71.3
      Previous PTB
      Calculated for multiparous patients only.
      13.5
      BMI26.9±6.3
      Substance abuse0.5
      Alcohol use1.0
      Smoking0.8
      Family history of PTB
       Multiple family members172 (0.7)
       One family member996 (4.2)
       None22,657 (95.0)
      Data are presented as percentage, mean±standard deviation, or number (percentage).
      BMI, body mass index; PTB, preterm birth.
      Koire et al. Family history of spontaneous preterm birth across 3 generations. AJOG MFM 2021.
      a Calculated for multiparous patients only.
      A family history of PTB was present in 4.9% of the cohort, overall. Although in most of these cases, a single family member was reported (n=996), 14.7% (n=163) reported multiple family members with a PTB history, most often the subject’s own mother and an aunt or grandmother (n=139). Only 3 subjects reported a PTB history in all queried family members. Subjects with a positive family history of PTB were more likely to identify as African or African American (P<.001) to have a current or previous history of smoking (P<.001) and alcohol use (P=.026). Conversely, subjects with a positive family history of PTB were less likely to be Hispanic or Latino (P<.001), have had fewer previous pregnancies (gravida 2.5 vs 2.8; P<.001), and have fewer births (para 1.0 vs 1.5; P<.001). There was no significant difference in maternal age, previous subject PTB rate, and substance abuse rates between gravidae with a positive family history of PTB and those without (Table 2).
      Table 2Comparisons of baseline maternal characteristics with and without family history
      Clinical characteristicsTotalNo family historyFamily historyP value (chi-square or the Student t test)
      Number (n)23,81622,6571159
      Ethnicity
       Hispanic60.461.734.6<.001
      P<.05 is statistically significant.
       Non-Hispanic39.638.365.4
      Race
       White78.779.171.8<.001
      P<.05 is statistically significant.
       African American13.413.021.4
       Asian4.44.45.1
       Native American0.00.00.0
       Other or mixed0.40.40.3
       Unknown2.93.01.4
      Maternal age29.8±6.129.8±6.129.5±5.9.06
      Parity1.5±1.41.5±1.41.0±1.1<.001
      P<.05 is statistically significant.
      Gravida2.9±1.82.9±1.82.5±1.8<.001
      P<.05 is statistically significant.
      BMI26.9±6.326.9±6.326.8±6.8.5
      Previous PTB9.59.59.8.71
      Smoking
       Current0.80.81.2<.001
       Ever9.18.520.8
       Never89.890.477.9
      Substance abuse0.50.50.6.81
      Alcohol1.01.01.6.026a
      Data are presented as percentage or mean±standard deviation.
      BMI, body mass index; PTB, preterm birth.
      Koire et al. Family history of spontaneous preterm birth across 3 generations. AJOG MFM 2021.
      a P<.05 is statistically significant.
      We first assessed the influence of a maternal family history on the likelihood of a PTB in the current pregnancy after adjusting for smoking, BMI, maternal age, and ethnicity (Table 3). Across all subjects, those who reported a maternal family history of PTB by any definition were more likely to deliver preterm compared with those who denied a family history of PTB (aRR, 1.44; P<.001). Furthermore, All subcomponents of the family history were individually significant, including a history in more distant relatives, such as aunts or grandmothers. Of interest, a grandmaternal history (ie, subject herself was born preterm) demonstrated the greatest individual heritable risk factor (aRR, 1.85; P<.001). We next analyzed nulliparous and multiparous subjects with no personal PTB history separately in a stratified analysis in an effort to discern clinically useful information. For nulliparous women, having a sister who had given birth preterm was associated with the greatest risk; women positive for this particular subcomponent in their family history were more than twice as likely to have given birth preterm compared with those without a sororal PTB history (aRR, 2.25; P=.003). For multiparous women with no previous PTB, overall family history was significant (aRR, 1.52; P=.003), whereas a history in the subject’s mother was the greatest individual heritable risk factor (aRR if subject herself was born preterm, 1.94; P=.004).
      Table 3Risk of PTB with a positive family history
      Family history of PTBYes or noPretermTermP value (chi-square)RR (95% CI)Adjusted RR (95% CI)
      Adjusted for smoking, BMI (>40 or <20), maternal age (>40, <18), and ethnicity (African American).
      n%n%
      All subjects
      Any family historyYes15814.592885.5.001
      P<.05 is statistically significant
      1.51 (1.30–1.76)
      P<.05 is statistically significant
      1.44 (1.22–1.97)
      P<.05 is statistically significant
      No21879.620,54390.4
      SisterYes4917.423382.6.001
      P<.05 is statistically significant
      1.78 (1.38–2.30)
      P<.05 is statistically significant
      1.64 (1.22–1.83)
      P<.05 is statistically significant
      No22969.821,23890.2
      Mother (subject was delivered PT)Yes8516.343783.7.001
      P<.05 is statistically significant
      1.68 (1.38–2.05)
      P<.05 is statistically significant
      1.85 (1.43–2.36)
      P<.05 is statistically significant
      No22609.721,03490.3
      Grandmother or auntYes7013.445186.6.007
      P<.05 is statistically significant
      1.38 (1.10–1.72)
      P<.05 is statistically significant
      1.34 (1.01–1.74)
      P<.05 is statistically significant
      No22759.821,02090.2
      Nulliparous
      Any family historyYes5813.537386.5.013
      P<.05 is statistically significant
      1.52 (1.09–2.12)
      P<.05 is statistically significant
      1.45 (1.02–2.06)
      P<.05 is statistically significant
      No6389.6598590.4
      SisterYes1820.76979.3.001
      P<.05 is statistically significant
      2.81 (1.45–5.64)
      P<.05 is statistically significant
      2.25 (1.11–4.62)
      P<.05 is statistically significant
      No6789.7628990.3
      Mother (subject was delivered PT)Yes3114.418585.6.033
      P<.05 is statistically significant
      1.64 (1.41–2.58)
      P<.05 is statistically significant
      1.75 (1.09–2.80)
      P<.05 is statistically significant
      No6659.7617390.3
      Grandmother or auntYes2410.620389.4.801.90 (0.66–1.74)1.09 (0.65–1.76)
      No6729.8615590.2
      Multiparous, no previous PTB
      Any family historyYes6111.248588.8.002
      P<.05 is statistically significant
      1.60 (1.17–2.17)
      P<.05 is statistically significant
      1.52 (1.08–2.10)
      P<.05 is statistically significant
      No10497.612,83792.4
      SisterYes1911.514688.5.087
      P<.05 is statistically significant
      1.64 (0.94–2.79)1.70 (0.95–2.97)
      No10917.613,17692.4
      Mother (subject was delivered PT)Yes3212.721987.3.004
      P<.05 is statistically significant
      1.89 (1.22–2.89)
      P<.05 is statistically significant
      1.94 (1.22–3.06)
      P<.05 is statistically significant
      No10787.613,10392.4
      Grandmother or auntYes2811.821088.2.024
      P<.05 is statistically significant
      1.70 (1.07–2.64)
      P<.05 is statistically significant
      1.44 (0.86–2.32)
      No10827.613,11292.4
      CI, confidence interval; PT, preterm; PTB, preterm birth; RR, relative risk.
      Koire et al. Family history of spontaneous preterm birth across 3 generations. AJOG MFM 2021.
      a P<.05 is statistically significant
      b Adjusted for smoking, BMI (>40 or <20), maternal age (>40, <18), and ethnicity (African American).
      We further explored the relationship between maternal family history of PTB and GA at delivery by considering prematurity as a continuous rather than binary variable. For all subjects and stratified subgroups by nulliparity, an earlier GA in the current index pregnancy was associated with a higher likelihood that the subject reported a maternal family history by any definition (Figure 1, A). In other words, the greater the severity of the current PTB (as measured by GA in weeks), the more likely the subject herself was born preterm or have a positive family history. Specifically, although nulliparous women who reported a sister with a PTB history (sororal PTB) had an overall aRR of 2.25 (P=.003) when considering PTB as a binary outcome, nulliparous women who delivered at <28 weeks’ gestation were more likely to have reported a history of a sister with a PTB (4.9% vs 1.0% in term subjects; P=.03) (Figure 2, B). This difference was further pronounced in those who delivered closest to the limit of viability (<25 weeks’ gestation; 10.5% vs 1% in term subjects; P=.018) (Figure 1, B). Among multiparous subjects, PTBs at <28 weeks’ gestation were more likely to have a positive sororal history (6.6% vs 1.1%; P=.014) (Figure 1, C).
      Figure thumbnail gr1
      Figure 1Relationship between GA at delivery and maternal family history of PTB
      The cohort was first separated to reflect (A) all subjects, (B) nulliparous subjects, (C) multiparous subjects with no PTB history, and (D) multiparous subjects with a previous PTB. The fraction of PTBs with a reported family history is plotted for each upper limit for GA at delivery between 25 and 37 weeks, with maternal family history subdivided to reflect (a) any documented family history, (b) sister with a history of PTB, (c) mother with a history of PTB (specifically, current patient was delivered preterm), and (d) grandmother or aunt with a history of PTB. A family history of PTB was excluded if it was concurrent with a family history of multiple births. The dashed line represents the fraction of term deliveries with the same family history. The upper panels reflect the log(P value) for each point, with the dashed line representing .05 and the red line representing .01.
      GA, gestational age; PTB, preterm birth.
      Koire et al. Family history of spontaneous preterm birth across 3 generations. AJOG MFM 2021.
      Figure thumbnail gr2
      Figure 2PTB as a function of parity and maternal age
      A and B, Rate of PTB and mean maternal age of subjects with (red) and without (gray) a previous pregnancy delivered preterm (<37 weeks’ gestation) as a function of parity.
      PTB, preterm birth.
      Koire et al. Family history of spontaneous preterm birth across 3 generations. AJOG MFM 2021.
      Finally, we assessed whether a personal history of exclusively term pregnancies acts as a protective factor when predicting PTB risk in a future pregnancy. Comparing the rates of PTB for subjects with and without a previous pregnancy delivered preterm as a function of parity, we found that although any personal history of PTB increased the risk of PTB in the most recent pregnancy, a higher number of exclusively term deliveries in multiparous women demonstrated no association with a decreased PTB risk in the most recent pregnancy (Figure 2, A). The PTB risk in fact increased slightly with a higher number of term deliveries, although this association can be explained by a concurrent correlation between PTB risk and increasing mean maternal age (R2=0.91), which is a well-established PTB risk factor that also increases with parity (Figure 2, B).

      Comment

      Principal findings

      This study tested whether a subject-reported maternal family history of PTB across 3 generations, including the subject herself, her sisters, aunts, and her mother (the index pregnancy grandmother), presented an independent risk factor for sPTB. The principal findings of this study, which used a large patient cohort composed primarily of Hispanic and African American patients, were that a maternal family history of PTB was a valuable and independent indicator of increased risk of PTB. Specifically, across all subjects, those who reported a maternal family history of PTB by any definition were more likely to deliver preterm compared with those who denied a family history of PTB (aRR, 1.44; P<.001). Of interest, a grandmaternal history (ie, subject herself was born preterm) demonstrated the greatest individual heritable risk factor (aRR, 1.85; P<.001). For multiparous women with no previous PTB, overall family history was significant (aRR, 1.52; P=.003), whereas a history in the subject’s mother was the greatest individual heritable risk factor (aRR if subject herself was born preterm, 1.94; P=.004). When we alternately explored the relationship between maternal family history of PTB and GA at delivery by considering prematurity as a continuous rather than binary variable, although nulliparous women who reported a sister with a PTB history (sororal PTB) had an overall aRR of 2.25 (P=.003) when considering PTB as a binary outcome, nulliparous women who delivered at <28 weeks’ gestation were more likely to have reported a history of a sister with a PTB (4.9% vs 1.0% in term subjects; P=.03) (Figure 2, B). This difference was further pronounced in those who delivered closest to the limit of viability (<25 weeks’ gestation 10.5% vs 1% in term subjects; P=.018). Among multiparous subjects, PTBs at <28 weeks’ gestation were more likely to have a positive sororal history (6.6% vs 1.1%; P=.014). Finally, when we compared with the rates of PTB for subjects with and without a previous pregnancy delivered preterm as a function of parity, we found that although any personal history of PTB increased the risk of PTB in the most recent pregnancy, a higher number of exclusively term deliveries in multiparous women demonstrated no association with a decreased PTB risk in the most recent pregnancy. In fact, PTB risk increased slightly with a higher number of term deliveries, although this association can be explained by a concurrent correlation between PTB risk and increasing mean maternal age (R2=0.91), which is a well-established PTB risk factor that also increases with parity (Figure 2, B).

      Results in the context of what is known

      Our findings follow previous studies indicating that if the subject herself was born preterm
      • Urquia M.L.
      • Wall-Wieler E.
      • Ruth C.A.
      • Liu X.
      • Roos L.L.
      Revisiting the association between maternal and offspring preterm birth using a sibling design.
      • Derakhshi B.
      • Esmailnasab N.
      • Ghaderi E.
      • Hemmatpour S.
      Risk factor of preterm labor in the west of Iran: a case-control study.
      • Porter T.F.
      • Fraser A.M.
      • Hunter C.Y.
      • Ward R.H.
      • Varner M.W.
      The risk of preterm birth across generations.
      ,
      • Bhattacharya S.
      • Raja E.A.
      • Mirazo E.R.
      • et al.
      Inherited predisposition to spontaneous preterm delivery.
      ,
      • Sherf Y.
      • Sheiner E.
      • Vardi I.S.
      • Sergienko R.
      • Klein J.
      • Bilenko N.
      Recurrence of preterm delivery in women with a family history of preterm delivery.
      and if there is a family history of PTB in a sister sibling,
      • Derakhshi B.
      • Esmailnasab N.
      • Ghaderi E.
      • Hemmatpour S.
      Risk factor of preterm labor in the west of Iran: a case-control study.
      ,
      • Boyd H.A.
      • Poulsen G.
      • Wohlfahrt J.
      • Murray J.C.
      • Feenstra B.
      • Melbye M.
      Maternal contributions to preterm delivery.
      there is an association with an increased risk of PTB in the current pregnancy. We further demonstrate that a positive family history of PTB in more distant female relatives, such as a grandmother or aunt, may in addition confer greater risk of PTB. We have the advantage of having racial and ethnic diversities in our cohort.

      Clinical implications

      Our study provides clinically relevant information regarding PTB family history in relation to parity. This is particularly useful for assessing PTB risk in patients with no personal history of PTB (nulliparous and multiparous patients who have not had a previous PTB), as a first-time PTB in these patient subsets was significantly more likely to be associated with any maternal family history compared with a term delivery. The patient herself being born preterm was consistently significant as an individual risk factor in all patient subgroups and was the strongest association in multiparous women without a previous PTB, whereas for nulliparous women, their sister’s PTB history was most relevant. Although the most distant queried PTB history (in a grandmother or aunt) was consistently the weakest individual risk factor in the patient subsets, it was nonetheless significant when considered across all subjects. Given that a substantial proportion (>30%) of family history reports were exclusively in these relatives, inquiring about more distant family history still demonstrates value as a component of the overall patient risk assessment. In addition, the fraction of PTB associated with a family history increased as GA at delivery decreased, indicating that family history is most relevant for predicting risk of early PTB, which also has the highest neonatal morbidity and mortality. With this in mind, in Table 4, we provide a summary of clinical scenarios, and the observed aRRs were found to be significant as a concise summary of likely clinical utility.
      Table 4Relative risk summarized reference
      Clinical scenarioRelative risk
      If nulliparous and…
       …who herself was born preterm:1.75
       …with a sister who delivered preterm:2.25
       …with a grandmother or aunt who delivered preterm:No significant increase
      If multiparous and no previous preterm births and…
       …who herself was born preterm:1.84
       …with a sister who delivered preterm:No significant increase
       …with a grandmother or aunt who delivered preterm:No significant increase
      Koire et al. Family history of spontaneous preterm birth across 3 generations. AJOG MFM 2021.

      Research implications

      These findings provide avenues and hypotheses worth exploring in future research studies. Overall, our study indicates that a detailed maternal family history across more distant generations than has previously been reported may be clinically useful. Importantly, direct queries about the patient’s obstetrical history can produce self-reported family histories reliable enough to detect differences in delivery outcomes. This finding can potentially impact how PTB risk is currently managed in the clinical setting for women without a personal history of previous sPTB. For example, universal transvaginal ultrasound cervical length (CL) screening of singleton gestations without previous PTB is not current standard practice among all practitioners, because the prevalence of a potentially actionable CL in this population is quite low (1.5%–2.5% of those screened).
      Society for Maternal-Fetal Medicine Publications Committee, with assistance of Vincenzo Berghella
      Progesterone and preterm birth prevention: translating clinical trials data into clinical practice.
      However, when a short CL is identified through screening in this population, multiple studies have indicated that intervention with vaginal progesterone significantly decreases risk of extremely preterm and very preterm deliveries,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix.
      ,
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      although the optimal timing and dosage has not yet been fully explored. Based on our findings, we believe that a future trial designed to test whether this type of targeted rather than universal screening when combined with familial history might not only predict PTB but also could be an opportunity for intervention. In this scenario and others, future studies employing family history inquiries could present a practical, cost-effective, and noninvasive path to determine which patients would benefit most from additional screening that could lead to downstream clinical intervention.

      Strengths and limitations of our study

      The strengths of this study relate to the PeriBank database from which it was derived. The PeriBank is a large database of subjects continuously enrolled from 2 major hospital sites in our metropolitan area, capturing a large and diverse demographic group.
      • Antony K.M.
      • Hemarajata P.
      • Chen J.
      • et al.
      Generation and validation of a universal perinatal database and biospecimen repository: PeriBank.
      Metadata capture for each subject include medical record review and direct subject interview in their native language. In particular, subjects are directly queried to the best of their knowledge if any female relative on their mother’s side delivered or were delivered preterm. Our findings are of clinical relevance as it demonstrates that capturing family history through direct interview rather than medical record lookup can be demonstrably used to assess risk of PTB in the current pregnancy.
      However, we are limited in that direct query of family history may introduce responder recall bias. The data are reliant on the subjects’ knowledge of their personal family history of PTB, which may be more reliable in closer relatives, such as sisters, rather than aunts or grandmothers. It is likely that more of our subjects have a positive family history of PTB but cannot recall or do not know that information. In addition, it is possible that enrollment of patients at delivery rather than earlier prenatal visits could influence recall. However, complete and accurate family history would likely strengthen the risk associations identified.

      Conclusions

      The objective of the current analysis was to evaluate the risk of PTB among women with and without a family history of PTB following direct query at the time of delivery. Among 23,816 women included in this study, PTB was significantly associated with a maternal family history of PTB by any definition (aRR, 1.44; P<.001), and the fraction of PTB occurring in women with a positive family history increased with decreasing GA at which the index subjects’ PTB delivery occurred. For nulliparous women, a history in the subject’s sister posed the greatest risk (aRR, 2.25; P=.003), whereas for multiparous women with no previous PTB, overall family history was most informative (P=.003). Interestingly, a personal history of the index subject herself being born preterm presented the greatest individual risk factor (aRR, 1.94; P=.004). The risk persisted among gravidae without a previous PTB, demonstrating the capacity for familial history to independently predict risk of spontaneous PTB even in the context of a negative personal history. This study provides evidence that self-reported maternal family history is relevant in a US population cohort and across more distant generations than has previously been reported.

      References

        • Martin J.A.
        • Hamilton B.E.
        • Osterman M.J.
        • Driscoll A.K.
        • Mathews T.J.
        Births: final data for 2015.
        Natl Vital Stat Rep. 2017; 66: 1
        • Saigal S.
        • Doyle L.W.
        An overview of mortality and sequelae of preterm birth from infancy to adulthood.
        Lancet. 2008; 371: 261-269
        • McIntire D.D.
        • Leveno K.J.
        Neonatal mortality and morbidity rates in late preterm births compared with births at term.
        Obstet Gynecol. 2008; 111: 35-41
        • Goldenberg R.L.
        • Culhane J.F.
        • Iams J.D.
        • Romero R.
        Epidemiology and causes of preterm birth.
        Lancet. 2008; 371: 75-84
        • Mercer B.M.
        • Goldenberg R.L.
        • Moawad A.H.
        • et al.
        The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
        Am J Obstet Gynecol. 1999; 181: 1216-1221
        • Wu W.
        • Witherspoon D.J.
        • Fraser A.
        • et al.
        The heritability of gestational age in a two-million member cohort: implications for spontaneous preterm birth.
        Hum Genet. 2015; 134: 803-808
        • Frey H.A.
        • Stout M.J.
        • Pearson L.N.
        • et al.
        Genetic variation associated with preterm birth in African-American women.
        Am J Obstet Gynecol. 2016; 215: 235.e1-235.e8
        • Huusko J.M.
        • Karjalainen M.K.
        • Graham B.E.
        • et al.
        Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.
        PLoS Genet. 2018; 14e1007394
        • Hallman M.
        • Haapalainen A.
        • Huusko J.M.
        • et al.
        Spontaneous premature birth as a target of genomic research.
        Pediatr Res. 2019; 85: 422-431
        • Zhang G.
        • Feenstra B.
        • Bacelis J.
        • et al.
        Genetic associations with gestational duration and spontaneous preterm birth.
        N Engl J Med. 2017; 377: 1156-1167
        • Clausson B.
        • Lichtenstein P.
        • Cnattingius S.
        Genetic influence on birthweight and gestational length determined by studies in offspring of twins.
        BJOG. 2000; 107: 375-381
        • Urquia M.L.
        • Wall-Wieler E.
        • Ruth C.A.
        • Liu X.
        • Roos L.L.
        Revisiting the association between maternal and offspring preterm birth using a sibling design.
        BMC Pregnancy Childbirth. 2019; 19: 157
        • Derakhshi B.
        • Esmailnasab N.
        • Ghaderi E.
        • Hemmatpour S.
        Risk factor of preterm labor in the west of Iran: a case-control study.
        Iran J Public Health. 2014; 43: 499-506
        • Porter T.F.
        • Fraser A.M.
        • Hunter C.Y.
        • Ward R.H.
        • Varner M.W.
        The risk of preterm birth across generations.
        Obstet Gynecol. 1997; 90: 63-67
        • Boivin A.
        • Luo Z.C.
        • Audibert F.
        • et al.
        Risk for preterm and very preterm delivery in women who were born preterm.
        Obstet Gynecol. 2015; 125: 1177-1184
        • Bhattacharya S.
        • Raja E.A.
        • Mirazo E.R.
        • et al.
        Inherited predisposition to spontaneous preterm delivery.
        Obstet Gynecol. 2010; 115: 1125-1133
        • Sherf Y.
        • Sheiner E.
        • Vardi I.S.
        • Sergienko R.
        • Klein J.
        • Bilenko N.
        Recurrence of preterm delivery in women with a family history of preterm delivery.
        Am J Perinatol. 2017; 34: 397-402
        • Boyd H.A.
        • Poulsen G.
        • Wohlfahrt J.
        • Murray J.C.
        • Feenstra B.
        • Melbye M.
        Maternal contributions to preterm delivery.
        Am J Epidemiol. 2009; 170: 1358-1364
        • Wilcox A.J.
        • Skjaerven R.
        • Lie R.T.
        Familial patterns of preterm delivery: maternal and fetal contributions.
        Am J Epidemiol. 2008; 167: 474-479
        • Plunkett J.
        • Borecki I.
        • Morgan T.
        • Stamilio D.
        • Muglia L.J.
        Population-based estimate of sibling risk for preterm birth, preterm premature rupture of membranes, placental abruption and pre-eclampsia.
        BMC Genet. 2008; 9: 44
        • Winkvist A.
        • Mogren I.
        • Högberg U.
        Familial patterns in birth characteristics: impact on individual and population risks.
        Int J Epidemiol. 1998; 27: 248-254
        • Hao K.
        • Wang X.
        • Niu T.
        • et al.
        A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods.
        Hum Mol Genet. 2004; 13: 683-691
        • Roberts A.K.
        • Monzon-Bordonaba F.
        • Van Deerlin P.G.
        • et al.
        Association of polymorphism within the promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of the fetal membranes.
        Am J Obstet Gynecol. 1999; 180: 1297-1302
        • Nansook P.
        • Naidoo R.N.
        • Muttoo S.
        • et al.
        IL-17A[G197G]-Association between NOx and gestational age in a South African birth cohort.
        Int J Immunogenet. 2018; 45: 54-62
        • Aidoo M.
        • McElroy P.D.
        • Kolczak M.S.
        • et al.
        Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX.
        Genet Epidemiol. 2001; 21: 201-211
        • Anum E.A.
        • Springel E.H.
        • Shriver M.D.
        • Strauss 3rd, J.F.
        Genetic contributions to disparities in preterm birth.
        Pediatr Res. 2009; 65: 1-9
        • Antony K.M.
        • Hemarajata P.
        • Chen J.
        • et al.
        Generation and validation of a universal perinatal database and biospecimen repository: PeriBank.
        J Perinatol. 2016; 36: 921-929
        • Tolcher M.C.
        • Chu D.M.
        • Hollier L.M.
        • et al.
        Impact of USPSTF recommendations for aspirin for prevention of recurrent preeclampsia.
        Am J Obstet Gynecol. 2017; 217: 365.e1-365.e8
        • Kahr M.K.
        • Antony K.M.
        • DelBeccaro M.
        • Hu M.
        • Aagaard K.M.
        • Suter M.A.
        Increasing maternal obesity is associated with alterations in both maternal and neonatal thyroid hormone levels.
        Clin Endocrinol (Oxf). 2016; 84: 551-557
        • Chabarria K.C.
        • Racusin D.A.
        • Antony K.M.
        • et al.
        Marijuana use and its effects in pregnancy.
        Am J Obstet Gynecol. 2016; 215: 506.e1-506.e7
        • Kahr M.K.
        • Suter M.A.
        • Ballas J.
        • et al.
        Preterm birth and its associations with residence and ambient vehicular traffic exposure.
        Am J Obstet Gynecol. 2016; 215: 111.e1-111.e10
        • Society for Maternal-Fetal Medicine Publications Committee, with assistance of Vincenzo Berghella
        Progesterone and preterm birth prevention: translating clinical trials data into clinical practice.
        Am J Obstet Gynecol. 2012; 206: 376-386
        • Fonseca E.B.
        • Celik E.
        • Parra M.
        • Singh M.
        • Nicolaides K.H.
        Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix.
        N Engl J Med. 2007; 357: 462-469
        • Hassan S.S.
        • Romero R.
        • Vidyadhari D.
        • et al.
        Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
        Ultrasound Obstet Gynecol. 2011; 38: 18-31