Objective
We hypothesized that preeclampsia partly shares pathophysiology with stillbirth, placental abruption, spontaneous preterm birth, and giving birth to a small-for-gestational-age infant, and that women who develop preeclampsia in the first pregnancy may have increased risks of the other outcomes in the second pregnancy, even in the absence of preeclampsia.
Study Design
In a nationwide Swedish cohort (n = 354,676) we estimated risks of adverse outcomes in the second pregnancy related to preterm (<37 weeks) and term (≥37 weeks) preeclampsia in the first pregnancy, using women without preeclampsia in the first pregnancy as reference.
Results
Women with prior preterm preeclampsia had, in second pregnancy, more than doubled risks of stillbirth, placental abruption, and preterm births, and an even greater risk of giving birth to a small-for-gestational-age infant.
Conclusion
Women with previous preterm preeclampsia have increased risks of adverse pregnancy outcomes in a second pregnancy despite the absence of preeclampsia.
Preeclampsia occurs in 2.5-3.0% of all pregnancies and is a major contributor to maternal and fetal morbidity and mortality worldwide. Preeclampsia has a recurrence rate of about 15% in second pregnancy and even higher recurrence rates are seen in women with a previous preterm preeclampsia. The etiology of preeclampsia is elusive, but there is an association with abnormal placentation, especially for preeclampsia with an early onset.
Stillbirth, placental abruption, spontaneous preterm birth, and intrauterine growth restriction are associated with both abnormal placentation and preeclampsia. Each complication has a recurrence risk, and there are recent reports that the complications may predispose to each other. This may be because abnormal placentation tends to recur in subsequent pregnancies. We hypothesized that women with a history of preeclampsia, especially preterm preeclampsia, have increased risks of pregnancy complications associated with abnormal placentation in the second pregnancy, even in the absence of preeclampsia.
In the present nationwide Swedish study, we included >350,000 women with first and second births from 1992 through 2006. Among women without preeclampsia in the second pregnancy, we estimated associations between preterm and term preeclampsia in the first pregnancy and risks of stillbirth, placental abruption, spontaneous preterm birth, and small-for-gestational-age (SGA) birth in the second pregnancy.
Materials and Methods
The Swedish Medical Birth Register contains data on >99% of all births in Sweden, including demographic data, information on reproductive history and complications during pregnancy, delivery, and the neonatal period. Complications during pregnancy and delivery are classified according to the International Classification of Diseases, Ninth Revision ( ICD-9 ) and International Statistical Classification of Diseases, 10th Revision ( ICD-10 ) and are noted by the responsible doctor at discharge from hospital. By means of each individual’s unique national registration number, the birth register can be linked with other Swedish data sources.
Study population
During the years 1992 through 2006, there were approximately 1.5 million births recorded in the birth register. During the period, there were 371,086 women with their first and second consecutive singleton pregnancies resulting in birth of an infant at ≥22 weeks of gestation. Body mass index (BMI) is associated with both exposure and outcomes of the study and has been reported to the register since 1992. We therefore chose to include women from 1992 onward. We excluded 8325 women with chronic diseases (chronic hypertension, prepregnancy diabetes mellitus, chronic renal disease, and systemic lupus erythematosus), as noted in first or second pregnancy. These women were identified at the first antenatal visit (using check-boxes) and/or at hospital discharge after delivery ( ICD-9 and ICD-10 codes 642A-C, 642H, O10, O11, 250, 648A, O240, O241, O243, 581, 582, N03, N04, 710A, and M32). We also excluded 5620 women with preeclampsia in the second pregnancy ( ICD-9 and ICD-10 codes 642E-G, O14, and O15), 637 women with missing information on gestational age in the first pregnancy, and 1828 women with missing information on birthweight and/or gestational age in the second pregnancy. Clinically, preeclampsia was defined as a blood pressure >140/90 mm Hg combined with proteinuria (≥0.3 g/24 hours) occurring >20 weeks of gestation. Thus, the final study population included 354,676 women with 2 successive single births, who did not have predisposing chronic diseases and did not have preeclampsia in their second pregnancy.
Exposures
As we lacked information about time of onset of disease, preeclampsia in the first pregnancy was categorized into preterm (gestational age <37 weeks at birth) and term (≥37 weeks at birth) preeclampsia. Preeclampsia was defined as a blood pressure >140/90 mm Hg combined with proteinuria (≥0.3 g/24 hours) occurring >20 weeks of gestation and was identified by corresponding ICD-9 and ICD-10 codes. In Sweden, gestational age is assessed by ultrasound scans in 95% of women, usually around the 17th week of gestation. If no early second-trimester ultrasound scan was available, the last menstrual period was used to calculate gestational age at delivery. The quality of the diagnosis of preeclampsia has been validated previously: of 148 pregnancies coded as preeclampsia in the birth register, 137 (93%) had the disease according to the individual records.
In Sweden, information about maternal characteristics is recorded in a standardized manner during a woman’s first visit for antenatal care, which occurs <15th week of gestation in >95% of the pregnancies. From the second pregnancy, we calculated BMI as the weight in kilograms divided by the square of height in meters. We also used information about family situation (living or not living with the infant’s father) and smoking habits. Information about maternal age was collected when the woman was discharged from the delivery hospital. Information on mother’s education and country of birth was obtained by linkage with the education register as of Dec. 31, 2005, and the register of total population, respectively, both held by Statistics Sweden. We calculated the interpregnancy interval as the number of completed years between birth of the first child and the estimated date of conception of the second child. Variables were categorized according to Table 1 .
| Stillbirth | Placental abruption | Spontaneous preterm birth a | Small for gestational age a , b | ||
|---|---|---|---|---|---|
| Maternal characteristics | Total no. | Rate, % | Rate, % | Rate, % | Rate (%) |
| Preeclampsia first pregnancy | |||||
| Yes | 12,376 | 0.31 | 0.57 | 2.97 | 2.13 |
| No | 342,300 | 0.22 | 0.32 | 2.56 | 1.17 |
| Maternal age second delivery, y | |||||
| ≤24 | 43,893 | 0.19 | 0.38 | 3.30 | 1.63 |
| 25-29 | 126,453 | 0.22 | 0.31 | 2.39 | 1.15 |
| 30-34 | 133,207 | 0.21 | 0.31 | 2.37 | 1.07 |
| ≥35 | 51,123 | 0.26 | 0.40 | 2.91 | 1.30 |
| BMI second pregnancy, kg/m 2 | |||||
| ≤19 | 31,863 | 0.18 | 0.33 | 3.36 | 2.06 |
| 20-24 | 169,896 | 0.20 | 0.32 | 2.36 | 1.14 |
| 25-29 | 75,319 | 0.26 | 0.30 | 2.29 | 1.06 |
| ≥30 | 28,351 | 0.38 | 0.31 | 2.67 | 0.95 |
| Missing | 49,247 | 0.16 | 0.42 | 3.15 | 1.24 |
| Partnership second pregnancy | |||||
| Yes | 326,601 | 0.22 | 0.32 | 2.46 | 1.17 |
| No | 7886 | 0.34 | 0.46 | 3.61 | 2.51 |
| Missing | 20,189 | 0.10 | 0.38 | 3.93 | 1.26 |
| Smoking habits second pregnancy | |||||
| Nonsmoker | 302,491 | 0.21 | 0.29 | 2.37 | 1.01 |
| 1-9 cigarettes/d | 21,593 | 0.32 | 0.55 | 3.42 | 2.88 |
| ≥10 cigarettes/d | 8664 | 0.50 | 0.73 | 4.06 | 3.60 |
| Missing | 21,928 | 0.11 | 0.47 | 3.91 | 1.28 |
| Education, y | |||||
| ≤12 | 179,742 | 0.23 | 0.37 | 2.74 | 1.32 |
| ≥13 | 141,752 | 0.19 | 0.28 | 2.27 | 0.86 |
| Missing | 33,182 | 0.30 | 0.36 | 2.96 | 2.04 |
| Ethnicity | |||||
| Nordic | 310,365 | 0.21 | 0.33 | 2.49 | 1.08 |
| Non-Nordic | 41,262 | 0.28 | 0.33 | 3.09 | 2.06 |
| Missing | 3049 | 0.30 | 0.56 | 3.20 | 2.34 |
| Interpregnancy interval, y | |||||
| ≤1.0 | 64,877 | 0.21 | 0.40 | 2.94 | 1.18 |
| 1.0-3.9 | 247,409 | 0.20 | 0.29 | 2.38 | 1.12 |
| 4.0-6.9 | 32,658 | 0.34 | 0.43 | 2.96 | 1.60 |
| ≥7.0 | 9613 | 0.35 | 0.58 | 3.57 | 1.97 |
| Missing | 119 | 1.68 | 1.68 | 9.65 | 6.84 |
| Year of second birth | |||||
| 1992-1996 | 70,180 | 0.22 | 0.34 | 2.54 | 1.29 |
| 1997-2001 | 130,303 | 0.23 | 0.33 | 2.52 | 1.29 |
| 2002-2006 | 154,193 | 0.21 | 0.32 | 2.63 | 1.09 |
| Total no. | 354,676 | 781 | 1169 | 8975 | 4253 |
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