OBJECTIVE: To clarify the obstetric consequences in a second pregnancy after a first singleton pregnancy complicated by spontaneous preterm delivery or preeclampsia and stratified by the variation in fetal growth.
METHODS: In a registry-based cohort study, we identified women having a first and second singleton delivery in Denmark from 1978 to 2007 (n=536,419). The exposures and endpoints were preterm delivery, preeclampsia, fetal growth, placental abruption, and stillbirth after 20 weeks of gestation. We used χ2 and t test to compare differences between incidences on first and second pregnancies.
RESULTS: Compared with a spontaneous first delivery at term, a delivery between 32 and 36 weeks of gestation increased the risk of preterm delivery in the second pregnancy from 2.7% to 14.7% (odds ratio [OR] 6.12, 95% confidence interval [CI] 5.84–6.42) and the risk of preeclampsia from 1.1% to 1.8% (OR 1.60, 95% CI 1.41–1.81); a delivery before 28 weeks increased the risk of a second preterm delivery to 26.0% (OR 13.1, 95% CI 10.8–15.9) and a second pregnancy with preeclampsia to 3.2% (OR 2.96, 95% CI 1.80–4.88). A first delivery in preeclamptic women between 32 and 36 weeks, compared with delivery after 37 weeks, increased the risk of preeclampsia in a second pregnancy from 14.1% to 25.3% (OR 2.08, 95% CI 1.87–2.31) and a small for gestational age infant from 3.1% to 9.6% (OR 2.82, 95% CI 2.38–3.35). Compared with the mean, fetal growth 2 to 3 standard deviations below mean in the first pregnancy increased the risk of preeclampsia from 1.1% to 1.8% (OR 1.62, 95% CI 1.34–1.96) in the second pregnancy.
CONCLUSION: Spontaneous preterm delivery, preeclampsia, and fetal growth deviation tend to recur and predispose to each other in a second pregnancy. Severe complications further increase these risks.
LEVEL OF EVIDENCE: II
Spontaneous preterm delivery, preeclampsia, and fetal growth deviation tend to recur and predispose to each other in a second pregnancy.
From the 1Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark; and 2Department of Obstetrics, Gynecology, and Reproductive Science, Yale Women and Children’s Center for Blood Disorders, Yale University School of Medicine, New Haven, Connecticut.
The authors thank Steen Rasmussen at the National Board of Health for assisting in the extraction of data.
Corresponding author: Jacob Alexander Lykke, MD, Department of Obstetrics, Rigshospitalet, Blegdamsvej 9, 2100 Kbh., Denmark; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
Preterm delivery, small for gestational age (SGA) offspring, preeclampsia, placental abruption, and stillbirth complicate up to 10–25% of first singleton pregnancies; the prevalence of these complications is lower in parous than in nulliparous women.1
These pregnancy complications are seemingly different in manifestation and are often regarded as separate disease entities. However, they frequently occur in the same pregnancy, and they seem to share much of their causation through a dysfunctional placenta.2–5 Also, a metabolic syndrome seems to be a pivotal component of these pregnancy complications6,7: Endothelial dysfunction,8,9 dyslipidemia,10,11 inflammation markers,12,13 and obesity14,15 have all been associated with these different pregnancy complications. On a genetic level, thrombophilia may also contribute to the pathophysiology of these.16 Thus, it seems plausible that each of these pregnancy complications could predispose to others in a subsequent pregnancy as well as a recurrence of the complication.
Previous studies have investigated the recurrence in a second pregnancy of preterm delivery,17–23 preeclampsia,24,25 SGA offspring,24 placental abruption,24,26 and stillbirth.24,27 Other studies have investigated the relation between one complication in the first pregnancy and the risk of developing a different complication in the subsequent consecutive pregnancy.24,28–31 However, none of these studies have investigated how the severity of these pregnancy complications affects the risk of recurrence or risk of other complications in a subsequent pregnancy.
We designed a registry-based study employing the Danish national registries to clarify the obstetric consequences in a second pregnancy after a first singleton pregnancy complicated by spontaneous preterm delivery, preeclampsia, and stratified by the variation in fetal growth. Specifically, we investigated 1) spontaneous preterm delivery at different gestational ages and the risk of subsequent preterm delivery, preeclampsia, SGA offspring, placental abruption, and stillbirth; 2) occurrence as well as severity of preeclampsia and the risk of subsequent preeclampsia, SGA offspring, placental abruption, and stillbirth; and 3) variation in fetal growth and the risk of subsequent SGA offspring, preeclampsia, placental abruption, stillbirth, and preterm delivery offspring in the second pregnancy.
MATERIALS AND METHODS
The National Patient Registry (NPR) collects information on all discharge diagnoses and all complications during pregnancy and delivery in Denmark since 1978.32 We extracted information on all singleton deliveries in Denmark from January 1, 1978, to October 1, 2007, which accrued 1,795,806 deliveries of 965,475 women. From this population, we defined a cohort consisting of women, who had a first delivery after the age of 15 years and a second delivery before the age of 50 years (n=550,805), excluding those with a cardiovascular diagnosis (n=11,969; 2.2%) or type 1 and 2 diabetes (n=2,179; 0.5%) preceding the second delivery, and women who died or emigrated within 3 months of the second delivery (n=46 and n=196). Thus, the cohort consisted of 536,419 women. The exposures and endpoints were preterm delivery, preeclampsia, fetal growth, placental abruption, and stillbirth after 20 weeks of gestation.
At delivery, gestational age is routinely recorded. Initially, gestational age was assessed by the last menstruation period; gradually, gestational age was determined by early second trimester ultrasonography from 1978 to 2007. We stratified preterm delivery into four groups by gestational age: 20 to 27 weeks, 28 to 31 weeks, 32 to 37 weeks; and deliveries after 37 weeks as the reference group. We defined a spontaneous delivery as a pregnancy without preeclampsia, SGA offspring, placental abruption, or stillbirth. Fetal growth was measured by the birth weight standardized for gender and gestational age33; SGA was defined as fetal growth 2 standard deviations (SDs) below the mean.
Implausible values of birth weight, gestational age, fetal growth, and the combination of these were reassigned as missing values; these were analyzed as separate groups. Missing values occurred more frequently in the earlier years.
Hypertensive pregnancy disorders, placental abruption, and stillbirth were assessed by the specific International Classification of Diseases, 8th and 10th Revision codes for these diagnoses (see the box, Diagnoses and International Classification of Diseases, 9th and 10th Revisions Codes). The hypertensive pregnancy disorders were stratified into gestational hypertension and preeclampsia (including eclampsia and hemolysis, elevated liver enzymes, low platelets syndrome). The definition of preeclampsia has changed criteria during the 30 study years,34 but the frequency of preeclampsia in the NPR has remained stable. The accuracy of the hypertensive diagnoses in the NPR has been manually validated several times, accruing specificities of more than 99% for all types, but sensitivities at 10% for gestational hypertension and 69% for preeclampsia.34
We used χ2 and t test to compare differences between incidences on first and second pregnancies. We used multivariate logistic models and included year of delivery, maternal age at first delivery, and years between first delivery and estimated time of conception in second pregnancy. After initial stratification, we included interaction links in a stepwise forward procedure using likelihood ratio statistics with an entry criterion of P<.05. All odds ratios (ORs) are presented with 95% confidence intervals (CIs). We used SPSS 16.0 for Macintosh (SPSS Inc., Chicago, IL) for all calculations. The study was approved by the Danish National Data Protection Agency.
The baseline characteristics are shown in Table 1. In general, the birth weight of the offspring was higher in the second pregnancy, and the prevalence of preterm delivery, SGA, hypertensive pregnancy disorders, placental abruption, and stillbirth were lower in the second pregnancy. Missing values were more frequent in the first pregnancy and in the earlier years.
Women with a spontaneous preterm delivery in their first pregnancy (Table 2) had increased risk of preterm delivery, preeclampsia, an SGA offspring, and placental abruption in the second pregnancy. These risks were inversely related to gestational age at their first delivery.
Compared with a delivery after 37 weeks, a first delivery between 32 and 36 weeks increased the risk of recurrence of preterm delivery in the second pregnancy from 2.7% to 14.7% (OR 6.12, 95% CI 5.84–6.42); a first delivery before 28 weeks increased this risk to 26.0% (OR 13.1, 95% CI 10.8–16.0). Decreasing gestational age in the first spontaneous preterm birth implied an increased risk of preeclampsia, SGA, and placental abruption in the second pregnancy, and the increases were of similar magnitude.
In women with preeclampsia in a first pregnancy, early gestational age at delivery increased the risk of recurrent preeclampsia, SGA offspring, placental abruption, and stillbirth in the second pregnancy (Table 3). Women with preeclampsia who delivered after 37 weeks of gestation had a 14.1% overall risk of developing preeclampsia in the second pregnancy; this risk increased to 37.9% in preeclamptic women who delivered before 28 weeks (OR 3.90, 95% CI 2.50–6.05).
Lower-than-average fetal growth in a first pregnancy not complicated by preterm delivery, hypertensive disorders, placental abruption, or stillbirth increased the risk of SGA offspring, preterm delivery, preeclampsia, placental abruption, and stillbirth in the second pregnancy (Table 4). Fetal growth 0.5 to 1 SD below the mean increased the risk of an SGA offspring in the second pregnancy from 1.5% to 3.6% (OR 2.40, 95% CI 2.27–2.53); fetal growth below 3 SD increased the risk to 22.2% (OR 19.3, 95% CI 15.9–23.4). Fetal growth between 1 and 1.5 SD below the mean increased the risk of preeclampsia in the second pregnancy from 1.1% to 1.3% (OR 1.18, 95% CI 1.07–1.30); fetal growth between 2 and 3 SD below the mean increased the risk to 1.8% (OR 1.62, 95% CI 1.34–1.96).
A higher than average fetal growth in the first pregnancy did not overall significantly increase the risk of preeclampsia or stillbirth in the second pregnancy (Table 4). However, a fetal growth up to 2 SD above the mean in the first pregnancy was associated with a lower-than-average risk of preterm delivery and placental abruption in the second pregnancy.
The present study illustrates the link between pregnancy complications across two pregnancies. A first spontaneous preterm delivery is a risk factor for the recurrence of preterm delivery as well as the development of preeclampsia, SGA offspring, and placental abruption in a second pregnancy. Previous studies have investigated the recurrence of preterm delivery, and our findings are in accordance with these.17–22 Furthermore, we have demonstrated the presence of a “dose–response relationship,” with increased risks after lower gestational age at a first delivery.
We did not find a significant increase in risk of stillbirth after a first spontaneous preterm delivery. Smith et al28 previously found a twofold increase after a first spontaneous preterm delivery. However, the authors did not control for placental abruption, and their definition of small for gestational age was below the 10th percentile; these differences could explain the discrepancy in the associations found. Surkan et al29 also found an adjusted twofold increase in risk of stillbirth after preterm delivery before 32 weeks of gestation.
Women with preeclampsia have increased risk of recurrence of the preeclampsia as compared with women with spontaneous deliveries. Preeclampsia in pregnancies associated with preterm delivery imposed an even higher risk of developing preeclampsia in the second pregnancy. This suggests that the severity of preeclampsia, reflected in the degree of associated prematurity, is an important clinical predictor for a subsequent pregnancy35; previous studies agree with these findings.24,25 Also, we found this severity of preeclampsia to be associated with the risk of developing SGA offspring, placental abruption, and stillbirth in the second pregnancy; these latter associations could be driven by their primary complications in the first preeclamptic pregnancies. However, we did not control for this because these complications are secondary events with respect to the preeclampsia and thus are markers of disease severity.
Even marginally low fetal growth (still categorized as appropriate for gestational age) increases the risk of SGA offspring as well as preeclampsia in the second pregnancy, thereby contributing to the hypothesis of a common cause,3 Rasmussen et al36 found the same relation in a Norwegian population. Additionally, we found increased risks of placental abruption, stillbirth, and preterm delivery in the second pregnancy; however, these risks could be driven by the increased risk of preeclampsia in the same pregnancy. Adjusting for preeclampsia in the second pregnancy attenuated these odds ratios only slightly (data not shown). In contrast, we found that fetal growth 1 to 2 SD above the mean in the first pregnancy had a protective effect on the risk of preterm delivery and placental abruption (although not significant) in the second pregnancy.
In summary, our data shows that spontaneous preterm delivery, preeclampsia, low fetal growth, placental abruption, and stillbirth in a first and second pregnancy are interrelated, which suggests that they all may be features of a common syndrome—a “placenta-associated syndrome”2: Each of these pregnancy complications in a first pregnancy predispose to the others in the second pregnancy. Still, each of them is more predictive of a recurrence of the same disorder; this illustrates that although we theorize the presence of a common syndrome, elusive factors may be playing different roles in each of the disorders.
Recently, the balance of angiogenic and antiangiogenic factors, ie, endoglin, soluble fms-like tyrosine kinase-1, vascular endothelial growth factor, and placental growth factor have been associated with different strengths with each of the complications.37–39 Further histologic evidence suggests that placentas from pregnancies complicated by preeclampsia, SGA, or abruption frequently show signs of ischemia in the form of lesions.40 In addition, maternal constitution, ie, high body mass index, predisposes more to preeclampsia than to spontaneous preterm delivery7,41; however, even spontaneous preterm delivery is related to a preexisting metabolic syndrome.10 Summarizing, a dysfunction of the endothelium, both the placental and the maternal, seems to be paramount in the development a placenta-associated syndrome; this is also reflected in the subsequent increased cardiovascular morbidity in women with pregnancy complications.42
The strengths and limitations of the present study are constituted in the registry-based design of the study. The data were collected in a prospective manner and thus recall bias is not present. The size of the population enabled us to investigate rare exposures and outcomes in a homogeneous, nonselected, and low-risk population and still have the statistical power to detect small dose–response effects.
The validity of the preeclampsia diagnosis in the NPR is acceptable: a sensitivity of 69% and specificity at 99%.34 The underreporting of gestational hypertension, ie, a sensitivity of 10%, may have an effect on the association between preterm delivery and low fetal growth in a first pregnancy and subsequent preeclampsia, abruption, and stillbirth in a second pregnancy: If the underreporting of gestational hypertension is biased to the nonpathologic first pregnancies, ie, there was more underreporting in pregnancies ending at term and with average fetal growth, this should bias our results toward null, and thus our results will be underestimated.
The operational definition of spontaneous preterm delivery—a pregnancy uncomplicated by SGA offspring, hypertensive disorders, placental abruption, and stillbirth—does not allow us to tell whether these women experienced true preterm labor, preterm premature rupture of membranes, undiagnosed abruption, or chorioamnionitis or whether they underwent induction of labor due to various complications; however, Ananth et al22 have in a U.S. population demonstrated that preeclampsia, SGA, and abruption constituted more than 54% of the diagnoses leading to medically indicated preterm birth. Also, we excluded implausible values of birth weight, gestational age, and fetal growth to prevent bias from misreporting in the NPR. Thus, we do not believe that major confounding is present. Possibly, cesarean delivery in a first pregnancy could be a confounder due to the scar of the uterus.
Unfortunately, we were not able to control for body mass index, gestational diabetes, smoking, socioeconomic status, race or ethnicity, change in partner, or other factors that were not registered in the NPR. Provided these factors are stable over the two pregnancies, the lack of control for these factors should have minimal effect on the association found: Smith et al28 did indeed find minimal confounding effect of these factors. Also, we were not able to control for any prophylactic interventions in the second pregnancy43; however, any efficient intervention should bias our estimates toward the null.
In conclusion, women delivering spontaneously preterm, having preeclampsia, or having SGA offspring are vulnerable from an obstetric point of view. They not only have increased risk of recurrence of the same pregnancy complication, but also are susceptible for other pregnancy complications in the next pregnancy; the more severe the complication as determined by gestational age or fetal growth deviation in the first pregnancy, the higher the risk of these complications in the second pregnancy. Based on the results of the present study, we may individualize the surveillance, prophylaxis or treatment in pregnant women with a previous pregnancy complication.
1.Bai J, Wong FW, Bauman A, Mohsin M. Parity and pregnancy outcomes. Am J Obstet Gynecol 2002;186:274–8.
2.Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99.
3.Ness RB, Sibai BM. Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia. Am J Obstet Gynecol 2006;195:40–9.
4.Villar J, Carroli G, Wojdyla D, Abalos E, Giordano D, Ba’aqeel H, et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet Gynecol 2006;194:921–31.
5.Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol 2006;108:1005–16.
6.Alberti KG, Zimmet P, Shaw J. Metabolic syndrome—a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 2006;23:469–80.
7.O’Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiology 2003;14:368–74.
8.Sankaralingam S, Arenas IA, Lalu MM, Davidge ST. Preeclampsia: current understanding of the molecular basis of vascular dysfunction. Expert Rev Mol Med 2006;8:1–20.
9.Powers RW, Catov JM, Bodnar LM, Gallaher MJ, Lain KY, Roberts JM. Evidence of endothelial dysfunction in preeclampsia and risk of adverse pregnancy outcome. Reprod Sci 2008;15:374–81.
10.Catov JM, Bodnar LM, Kip KE, Hubel C, Ness RB, Harger G, et al. Early pregnancy lipid concentrations and spontaneous preterm birth. Am J Obstet Gynecol 2007;197:610.e1–7.
11.Catov JM, Bodnar LM, Ness RB, Barron SJ, Roberts JM. Inflammation and dyslipidemia related to risk of spontaneous preterm birth. Am J Epidemiol 2007;166:1312–9.
12.Hauguel-de Mouzon S, Guerre-Millo M. The placenta cytokine network and inflammatory signals. Placenta 2006;27:794–8.
13.Romero R, Erez O, Espinoza J. Intrauterine infection, preterm labor, and cytokines. J Soc Gynecol Investig 2005;12:463–5.
14.Walsh SW. Obesity: a risk factor for preeclampsia. Trends Endocrinol Metab 2007;18:365–70.
15.Cnattingius S, Bergstrom R, Lipworth L, Kramer MS. Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 1998;338:147–52.
16.Pabinger I, Vormittag R. Thrombophilia and pregnancy outcomes. J Thromb Haemost 2005;3:1603–10.
17.Cnattingius S, Granath F, Petersson G, Harlow BL. The influence of gestational age and smoking habits on the risk of subsequent preterm deliveries. N Engl J Med 1999;341:943–8.
18.Adams MM, Elam-Evans LD, Wilson HG, Gilbertz DA. Rates of and factors associated with recurrence of preterm delivery. JAMA 2000;283:1591–6.
19.Kristensen J, Langhoff-Roos J, Kristensen FB. Implications of idiopathic preterm delivery for previous and subsequent pregnancies. Obstet Gynecol 1995;86:800–4.
20.Spong CY. Prediction and prevention of recurrent spontaneous preterm birth. Obstet Gynecol 2007;110:405–15.
21.Mazaki-Tovi S, Romero R, Kusanovic JP, Erez O, Pineles BL, Gotsch F, et al. Recurrent preterm birth. Semin Perinatol 2007;31:142–58.
22.Ananth CV, Getahun D, Peltier MR, Salihu HM, Vintzileos AM. Recurrence of spontaneous versus medically indicated preterm birth. Am J Obstet Gynecol 2006;195:643–50.
23.Esplin MS, O’Brien E, Fraser A, Kerber RA, Clark E, Simonsen SE, et al. Estimating recurrence of spontaneous preterm delivery. Obstet Gynecol 2008;112:516–23.
24.Ananth CV, Peltier MR, Chavez MR, Kirby RS, Getahun D, Vintzileos AM. Recurrence of ischemic placental disease. Obstet Gynecol 2007;110:128–33.
25.Barton JR, Sibai BM. Prediction and prevention of recurrent preeclampsia. Obstet Gynecol 2008;112:359–72.
26.Rasmussen S, Irgens LM, Albrechtsen S, Dalaker K. Women with a history of placental abruption: when in a subsequent pregnancy should special surveillance for a recurrent placental abruption be initiated? Acta Obstet Gynecol Scand 2001;80:708–12.
27.Black M, Shetty A, Bhattacharya S. Obstetric outcomes subsequent to intrauterine death in the first pregnancy. BJOG 2008;115:269–74.
28.Smith GC, Shah I, White IR, Pell JP, Dobbie R. Previous preeclampsia, preterm delivery, and delivery of a small for gestational age infant and the risk of unexplained stillbirth in the second pregnancy: a retrospective cohort study, Scotland, 1992–2001. Am J Epidemiol 2007;165:194–202.
29.Surkan PJ, Stephansson O, Dickman PW, Cnattingius S. Previous preterm and small-for-gestational-age births and the subsequent risk of stillbirth. N Engl J Med 2004;350:777–85.
30.Salihu HM, Mbah AK, Alio AP, Kirby RS. AGA-primed uteri compared with SGA-primed uteri and the success of subsequent in utero fetal programming. Obstet Gynecol 2008;111:935–43.
31.Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R. Preeclampsia and fetal growth. Obstet Gynecol 2000;96:950–5.
32.Andersen TF, Madsen M, Jørgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull 1999;46:263–8.
33.Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr 1996;85:843–8.
34.Klemmensen AK, Olsen SF, Osterdal ML, Tabor A. Validity of preeclampsia-related diagnoses recorded in a national hospital registry and in a postpartum interview of the women. Am J Epidemiol 2007;166:117–24.
35.Vatten LJ, Skjaerven R. Is pre-eclampsia more than one disease? BJOG 2004;111:298–302.
36.Rasmussen S, Irgens LM, Albrechtsen S, Dalaker K. Predicting preeclampsia in the second pregnancy from low birth weight in the first pregnancy. Obstet Gynecol 2000;96:696–700.
37.Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia [published erratum appears in N Engl J Med 2006;355:1840]. N Engl J Med 2006;355:992–1005.
38.Smith GC, Crossley JA, Aitken DA, Jenkins N, Lyall F, Cameron AD, et al. Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth. Obstet Gynecol 2007;109:1316–24.
39.Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med 2008;21:9–23.
40.Norwitz ER. Defective implantation and placentation: laying the blueprint for pregnancy complications. Reprod Biomed Online 2006;13:591–9.
41.Hendler I, Goldenberg RL, Mercer BM, Iams JD, Meis PJ, Moawad AH, et al. The Preterm Prediction Study: association between maternal body mass index and spontaneous and indicated preterm birth. Am J Obstet Gynecol 2005;192:882–6.
42.Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ 2002;325:157–60.
© 2009 by The American College of Obstetricians and Gynecologists.
43.Moore LE. Recurrent risk of adverse pregnancy outcome. Obstet Gynecol Clin North Am 2008;35:459–71.