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Department of Quantitative and Computational Biology, Baylor College of Medicine, Houston, TXMedical Scientist Training Program, Baylor College of Medicine, Houston, TX
Medical Scientist Training Program, Baylor College of Medicine, Houston, TXInterdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TXDivision of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX
Medical Scientist Training Program, Baylor College of Medicine, Houston, TXInterdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TXDivision of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children’s Hospital, Houston, TXDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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.
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
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,
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
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.
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.
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.
Association of polymorphism within the promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of the fetal membranes.
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.
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,
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.
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.
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
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).
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 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 MFM2021.
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 MFM2021.
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
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 scenario
Relative 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 MFM2021.
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,
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.
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.
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.
Association of polymorphism within the promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of the fetal membranes.
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.
Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
A.K. and D.M.C. contributed equally to this work as joint first authors.
The authors report no conflict of interest.
This work was funded by the March of Dimes Preterm Birth Research Initiative and the National Institutes of Health (NIH). The authors gratefully acknowledge the support of the NIH Director’s New Innovator Award (K.A.; DP2 DP21DP2OD001500), the NIH and National Institute of Nursing Research (K.A.; NR014792-01), the Burroughs Welcome Fund Preterm Birth Initiative (K.A.), the March of Dimes Preterm Birth Research Initiative (K.A.), the Baylor College of Medicine Medical Scientist Training Program (A.K., D.M.C., and K.A.; National Institute of General Medical Sciences [NIGMS] T32 GM007330), the NIGMS (D.M.C., T32GM088129), the Baylor Research Advocates for Student Scientists (A.K. and D.M.C.), the Robert and Janice McNair Foundation and McNair Medical Institute (A.K.), and the Baylor College of Medicine Comprehensive Cancer Training Program (A.K.; Cancer Prevention and Research Institute of Texas [grant number RP160283]).
Cite this article as: Koire A, Chu DM, Aagaard K. Family history is a predictor of current preterm birth. Am J Obstet Gynecol MFM 2021;3:100277.
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