Subfecundity as a Correlate of Preeclampsia: A Study within the Danish National Birth Cohort

Olga Basso1,2,, Clarice R. Weinberg3, Donna D. Baird2, Allen J. Wilcox2 and Jørn Olsen1

1 Danish Epidemiology Science Centre, Aarhus University, Aarhus, Denmark.
2 Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC.
3 Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Received for publication May 21, 2002; accepted for publication August 28, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A long interpregnancy interval is associated with preeclampsia. If some women experiencing a long interval between births had difficulty conceiving, subfecundity and preeclampsia may share a common etiology. Therefore, the authors examined the association between subfecundity and preeclampsia. By using interview data collected during the second trimester of pregnancy (1998–2001) from women participating in the Danish National Birth Cohort, they identified 20,034 and 24,698 singleton livebirths to primiparous and multiparous women, respectively, for whom preeclampsia information was available from hospital birth records. Among women with no known hypertension, the authors estimated a higher risk of preeclampsia in those with longer times to pregnancy (TTPs), after adjustment for maternal age, prepregnancy body mass index, and smoking. Compared with primiparas who became pregnant right away (referent category), the risk of preeclampsia increased with TTP and then stabilized for women taking 6 months or longer to conceive, whose risk of preeclampsia increased by 50%. Multiparas also had an increased risk, but only those reporting a TTP longer than 12 months (odds ratio = 2.47, 95% confidence interval: 1.30, 4.69). The authors found that a long TTP was associated with preeclampsia, supporting the hypothesis that some factors delaying clinically recognized conception may also be in a causal pathway for preeclampsia.

cohort studies; infertility; longitudinal studies; pre-eclampsia; pregnancy complications

Abbreviations: Abbreviations: BMI, body mass index; TTP, time to pregnancy.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The etiology of preeclampsia remains elusive despite extensive studies. In Denmark, as well as in many developed countries, its incidence is estimated to be about 3 percent. Preeclampsia is more frequent in first pregnancies and in multifetal pregnancies (1).

What is generally termed preeclampsia is probably the common final syndrome resulting from heterogeneous causes. Preeclampsia may be placental in origin and may also be influenced by maternal factors, such as obesity, diabetes, and preexisting hypertension (2). Shallow trophoblastic invasion, a hallmark of preeclampsia, is also seen in normotensive pregnancies with fetal growth retardation as well as in a fraction of pregnancies without either condition, and it is not always present in preeclamptic pregnancies (3).

Preeclampsia appears to have a genetic component acting through the father as well as the mother (4, 5). Immune maladaptation has also been put forward as a causal mechanism (6, 7), although recent studies have questioned its role (1, 8).

If the first pregnancy modifies the maternal spiral arteries so that trophoblastic invasion occurs more smoothly thereafter, this factor might explain the lower incidence of preeclampsia among multiparas (9). Recently, however, there have been reports that a long interpregnancy interval is an independent predictor of preeclampsia in women with no preeclampsia in the previous pregnancy (1, 8). This finding suggests that the protective effect of past pregnancies may decline over time or that another factor correlating with time may also contribute to the increased risk with long interpregnancy intervals. We speculated that some couples with a long interpregnancy interval may be subfecund. The same underlying problem might cause both subfecundity and preeclampsia. Conception and early trophoblastic invasion involve complex hormonal and immune regulation that may well play a role in the development of preeclampsia (10–12).

Time to pregnancy (TTP) is a marker of fecundity, expressed as the number of cycles required for a couple to conceive from the start of unprotected intercourse. Only sparse evidence is available that preeclampsia may be more frequent among infertile women (13, 14). Therefore, we investigated TTP as a predictor of preeclampsia in a large cohort of Danish women.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The Danish National Birth Cohort is an ongoing project in which pregnant women are recruited and information is collected about a number of exposures. The women enrolled in the cohort are interviewed four times, twice during pregnancy and twice after the child is born. Approximately 60 percent of all eligible pregnant women in Denmark are contacted (based on whether the general practitioners and midwives collaborate), and 60 percent of these women agree to enter the study (15).

Women in the cohort are periodically linked to the Danish Population Registry, which is independent of the Danish Hospital Registry, to check whether they have delivered their infants. Of the 50,773 women participating in the first interview, 5.6 percent delivered a live baby, but no record of the birth could be found in the Hospital Registry. Reasons for this omission can be 1) errors in the mother’s personal identification number, 2) home delivery (11 percent of those women missing had stated their intention to deliver at home), 3) delivery outside Denmark, or 4) delay of the county offices in reporting to the National Board of Health. For a further 2.8 percent of the women, there was no record of a livebirth, and we considered these likely fetal losses or stillbirths (although a small fraction of the women may have emigrated).

Of the 45,610 women for whom there was a retrievable record of a singleton birth from week 24 of gestation, we excluded 103 for whom the medical records reported preexisting diabetes and 775 for whom values for the main covariates (parity, smoking, body mass index (BMI)) were missing. Thus, 44,732 births were available for analysis. This study used exposure information collected at the first interview for women who later gave birth to a live child whose birth record was available in the Danish Hospital Registry at the National Board of Health. Median time of the first interview was the 16th week, and 95 percent of first interviews were completed by the 24th week of gestation. The interviews in the present analysis were administered between April 3, 1998, and February 7, 2001. Baseline information was collected during this interview.

Preeclampsia and other information concerning the birth was ascertained through the Danish Hospital Registry at the National Board of Health. The International Classification of Diseases, Tenth Revision, codes were used for preeclampsia (gestational hypertension with significant proteinuria: O140, O141, O149) and eclampsia (O150, O151, O152, O159).

The questions concerning pregnancy planning and TTP were phrased as follows: "Was this pregnancy planned?" (possible answers were "planned," "partly planned," "not planned," "don’t know," "do not wish to answer"). If the woman responded that the pregnancy was planned or partly planned, she was then asked, "How long did you try to become pregnant before you succeeded?" (possible answers were "did not try to become pregnant," "became pregnant right away," "1–2 months," "3–5 months," "6–12 months," "more than 12 months," "don’t know," "do not wish to answer"). Nonplanners and those who reported they had not tried to become pregnant were asked whether they had conceived despite contraception.

Of the women who responded that they had partly planned this pregnancy, 75 percent reported a TTP. However, since we were not sure what "partly planning" implied as far as the ability to reconstruct TTP, we considered all these women in one group (without taking into consideration their TTP); only in an additional analysis did we check how our estimates were affected when women who reported that they had partly planned their pregnancy were included, together with the planners, in their respective category of TTP. Of the 33,691 women who reported having planned their pregnancy, 332 did not report a TTP, and we categorized them as "part planners."

We included in the logistic regression models maternal age at delivery (<=25, 26–30, 31–35, and >=35 years), prepregnancy BMI (<21, 21–24.9, 25–29.9, >=30 kg/m2), and smoking during pregnancy (never, quit before interview, smoking reported at interview) based on an a priori decision. Information on smoking, prepregnancy weight, and height was reported at the first interview. We explored whether a history of spontaneous abortion, as reported by the women, confounded our estimates of the association between TTP and preeclampsia. A history of abortion was associated with longer TTP but not with preeclampsia. Restricting the definition of abortion to one occurring in the second trimester or later did not change the estimated association. Therefore, we omitted history of spontaneous abortion in the final models.

Information on some menstrual cycle characteristics (age at menarche, cycle length and regularity) was also included in this interview. Menarche and cycle length were not associated with preeclampsia, but we included irregular cycles in the final model.

We performed all analyses separately according to parity (nulliparous vs. parous). Unfortunately, we did not have information on the interpregnancy interval, although it was an issue for multiparas only.

The interview included a question on whether the woman had ever had hypertension. The possible answers were "no," "yes," "only in pregnancy" (without specifying which pregnancy), or "don’t know." Women reporting hypertension were at a much higher risk of preeclampsia (presumably due to different causal mechanisms), and, since the information on hypertension was ambiguous, we produced separate estimates for women without prior hypertension and for women with prior hypertension (including pregnancy hypertension).

We checked whether an interaction existed in the relation with preeclampsia between TTP and BMI, TTP and maternal age, and TTP and smoking. All variables were categorized as shown in the regression models in this paper. We found no interactions among women without hypertension. The numbers were too sparse to interpret the results for women with hypertension, who were not the main focus of this study, however.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 1 shows some characteristics of the women grouped by parity and by whether they reported ever having hypertension. Women reporting hypertension had a higher BMI and a much higher risk of preeclampsia. Compared with primiparas without hypertension, multiparas without hypertension conceived faster, had a lower incidence of preeclampsia, and recurred less frequently to infertility treatment.


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TABLE 1. Characteristics of the women according to parity and known hypertension (analysis sample from the Danish National Birth Cohort, 1998–2001)
 
Table 2 reports the incidence of preeclampsia and the crude odds ratios according to planning/TTP. Among primiparas, the proportion with preeclampsia increased with a waiting TTP longer than 2 months. Among multiparas, only those women waiting more than 12 months appeared to have an increased risk.


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TABLE 2. Prevalence of preeclampsia and unadjusted odds ratios according to TTP*/planning (analysis sample from the Danish National Birth Cohort, 1998–2001)
 
Table 3 shows the adjusted estimates of the associations between several predictors and preeclampsia in primiparas. Among women not reporting hypertension, the risk of preeclampsia was similar to the unadjusted odds ratios. Women who had not planned their pregnancy had the same estimated risk as the planners who conceived right away. As in the crude analysis, we did not find an association between TTP and preeclampsia for primiparous women who reported hypertension.


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TABLE 3. Adjusted odds ratios of preeclampsia for primiparas (analysis sample from the Danish National Birth Cohort, 1998–2001)*
 
Among multiparas (table 4), a TTP longer than 12 months was a relatively strong predictor of preeclampsia for women with no hypertension, although the estimate was lower than the unadjusted one. No association with TTP was found for multiparas reporting hypertension. Having irregular cycles was associated with a modest increase in risk for multiparas with and without hypertension.


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TABLE 4. Adjusted odds ratios of preeclampsia for multiparas (analysis sample from the Danish National Birth Cohort, 1998–2001)*
 
Having irregular cycles may have interfered with a woman’s reporting of TTP, so we estimated the association between TTP and preeclampsia for only those women with regular cycles. Changes in the estimates were negligible.

When the TTP reported by part planners was included in the model, the estimates were only slightly lower than those obtained when the part planners were considered one category regardless of their TTP. Still no association was found for either primiparas or multiparas who had reported hypertension. In our analysis, we examined preeclampsia as a dichotomous outcome, although it was coded moderate, severe, eclampsia, or unknown in the hospital record. We then distinguished moderate and unknown preeclampsia from severe preeclampsia and eclampsia. The estimates associated with a TTP longer than 3 months were slightly elevated for primiparas when we limited the analysis to cases of moderate (and unknown) preeclampsia, which were 75 percent of all cases. There appeared to be no association between a long TTP and severe preeclampsia, although there were only 122 cases. In multiparas, a TTP longer than 12 months was associated with moderate preeclampsia as it was in the main analysis and, possibly, also with severe preeclampsia (odds ratio = 4.42, 95 percent confidence interval: 0.79, 24.7). However, only 23 cases of severe preeclampsia occurred in multiparas, and the highest frequency was among women whose pregnancies were unplanned, who had no TTP.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We found that a long TTP was associated with preeclampsia in women with no history of hypertension. In primiparas, we found an increase of approximately 50 percent in the risk of preeclampsia for women reporting a TTP longer than 2 months. In multiparas only, a TTP longer than 12 months was associated with preeclampsia. We did not have the information to assess the extent to which subfecundity might account for the previously observed increase in risk associated with long interpregnancy intervals, but subfecundity is likely to explain at least some of it (1, 8).

Women who have hypertension are known to be at elevated risk of preeclampsia, and subfecundity did not appear to be a risk factor in this group. Identification of subfecundity as a risk factor may be clinically useful in low-risk women and in primiparas. However, our information on prior hypertension was ambiguous because some women reporting that they had gestational hypertension may have been referring to the current pregnancy rather than a previous one. This possibility is suggested by the fact that 58 of the 14,707 women without prior pregnancies reported having gestational hypertension, and six of the 58 were diagnosed with preeclampsia by the end of their pregnancy. Thus, a small fraction of women who had early signs of preeclampsia during the current pregnancy are probably mixed with women who had preeclampsia or hypertension in a prior pregnancy, which makes interpretation of the findings in this subgroup problematic.

The major weakness of this study concerns the diagnosis of preeclampsia, which was derived from the Danish Hospital Registry. Although we were not able to assess the quality of the data, BMI and smoking were associated with preeclampsia in the expected direction and magnitude (16, 17). Our estimates of the incidence of preeclampsia are similar to—or higher than—those reported by some authors (18–21) but lower than the estimates reported by others (8, 16, 22, 23).

Our reported incidence of preeclampsia was also slightly lower than that found in a Danish sample of women giving birth between 1990 and 1994 (1), suggesting that the women in the cohort may differ from the general population in some respects. Our estimates of the association between TTP and preeclampsia would be biased away from the null if women who conceived quickly and then developed preeclampsia were selectively underrepresented in the cohort (or were selectively missed by the hospital diagnoses). Such a mechanism, while theoretically possible, seems unlikely.

The rate of participation in the Danish National Birth Cohort is relatively low, but we do not think that this fact biased our analyses. TTP was reported earlier in pregnancy than preeclampsia is normally diagnosed. Moreover, we do not expect subfecundity to induce differential surveillance because it is not a known risk factor for preeclampsia. For 96.1 percent of the women in the cohort, we had information on how many prenatal visits with a midwife they had made during pregnancy. The average number varied between 5.8 and 6.1 (with a standard deviation of 1.62–1.79) and did not appear to be a function of TTP, previous or existing hypertension, BMI, or parity. This finding suggests that women in the cohort were generally given the same level of prenatal care, which in Denmark is free of charge. The cohort included few women in extreme age groups; 97 percent of primiparas and 98 percent of multiparas delivered between the ages of 21 and 39 years. This age distribution would be expected to contribute to a relatively low risk of preeclampsia.

We used TTP as reported in the interview, which was not categorized further than "more than 12 months." More detailed information would have been of interest, especially for multiparas, among whom we saw an increased risk of preeclampsia only in pregnancies conceived after a TTP longer than 12 months, but the increased risk may have been limited to women whose waiting time was longer.

Stillbirths were not included in our data, so we could analyze only those pregnancies ending in a livebirth. If the relative risk of late fetal loss in relation to preeclampsia is the same across categories of TTP, this exclusion would not have biased our results, but fertility problems are possibly associated with fetal and perinatal death (24, 25). Therefore, any bias produced by omitting stillbirths would likely be the result of differentially omitting more preeclampsia cases from the subfecund categories, resulting in possible bias toward the null. The 1,401 women in our study who had most likely had a fetal loss had longer TTPs, but this difference might be explained by the fact that they were older, more often nulliparous, and had a higher BMI. We explored the characteristics of the women for whom we could not find a record in the Danish Hospital Registry, and the data do not suggest that their absence would have introduced bias in our estimates.

Subfecundity has previously been reported to be associated with spontaneous abortions (26, 27), preterm delivery (28, 29), and perhaps low birth weight (28, 30). To our knowledge, however, only two reports exist of an increased incidence of preeclampsia in subfertile women (13, 14), and none has considered TTP.

A long TTP may reflect difficulties in conception or implantation, or it can be a marker of very early fetal loss. These conditions may in turn be associated with preeclampsia through a common causal mechanism, such as abnormal implantation (12), hormonal disorders (11, 12), antiphospholipid antibodies (10), polycystic ovarian syndrome (31), or endometrial bacteria (32). Exposure to organic solvents, a reproductive toxicant, has been associated with both subfecundity (33) and preeclampsia (34), but mechanisms of action have not been determined.

We examined menstrual characteristics to see whether these factors could provide any insight into the relation between TTP and preeclampsia. We found that age at menarche and cycle length were not related to risk. Having irregular cycles was independently associated with preeclampsia in multiparas.

Previous studies have reported that the risk of preeclampsia is inversely correlated with length of exposure to a woman’s partner’s sperm (6, 7, 35), although the hypothesis regarding immune maladaptation has been questioned (1, 8). Since a long TTP presumably involves a longer exposure to the partner’s sperm, the effect of TTP that we reported here may have been underestimated.

The level of information available did not enable us to propose a biologic mechanism to explain the association between subfecundity and preeclampsia. Although TTP is widely used as an indicator of subfecundity, it is a rather poor proxy for female reproductive dysfunction and, because it is a measure for the couple, may reflect a variety of underlying conditions involving either the male or the female. The fact that we could detect an association between subfecundity and preeclampsia despite the biologic heterogeneity among the subfecund couples suggests that, if this association is corroborated by other studies, it may be possible to identify a more homogenous group of subfecund women who could provide new clues about the etiology of preeclampsia.


    ACKNOWLEDGMENTS
 
Dr. Basso is supported by a grant from the Danish Medical Research Council (no. 22-00-0008).

The Danish National Research Foundation has established the Danish Epidemiology Science Centre, which initiated and created the Danish National Birth Cohort. Furthermore, the cohort is a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort was obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, and the Augustinus Foundation.


    NOTES
 
Correspondence to Dr. Olga Basso, Danish Epidemiology Science Centre, Aarhus University, Building 260, Vennelyst Boulevard 6, DK 8000 Aarhus C, Denmark (e-mail: ob{at}soci.au.dk). Back


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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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