Materials and Methods
Data sources
Data were obtained from 3 nationwide Swedish population-based registers. Record linkage between registers is made possible by use of an individually unique national registration number assigned to all Swedish residents at birth or first permanent residency.
The Swedish Medical Birth Register
The Swedish Medical Birth Register (MBR) was established in 1973 and contains more than 98% of all births in Sweden and records information on maternal characteristics, reproductive history, and complications during pregnancy, delivery, and the neonatal period. For the purpose of the present study, all births in Sweden between 1973 and 2009 were identified in the MBR.
The Swedish Cancer Register
The Swedish Cancer Register (SCR) was established in 1958 to monitor the cancer burden in the Swedish population. Reporting of all newly diagnosed cancer cases and some premalignant conditions, including HM, is mandatory. Reports are made separately by both a clinician and a pathologist or cytologist. No treatment data are available in the SCR. Earlier studies have shown an underreporting of approximately 20% of all cases of HM to the SCR. The SCR does not differentiate between complete and partial hydatidiform mole, and cases of postmolar GTN are not registered. The SCR was used to identify women diagnosed with HM.
The Multi-Generation Register
The Multi-Generation Register (MGR) encompasses all individuals in Sweden born in 1932 or later, who resided in Sweden at some point after 1961. It allows the identification of family structures, including information on reproductive history. Information from the MGR allowed the identification of births before 1973, not encompassed in the MBR ( Figure ).
Study population
A total of 3,730,789 births were identified in the MBR between 1973 and 2009. From these, we excluded multiple births (n = 90,128), children with missing data on maternal country of origin (n = 169), and children born to a woman with a childbirth and a diagnosis of HM registered the same date (suggesting a twin molar pregnancy or a third-trimester partial molar pregnancy) (n = 17, referring to 7 unique women). To be able to perform a complete case analysis, children with missing data on small for gestational age (SGA) or large for gestational age (LGA) were also excluded (n = 18,063). In this way, the analyses encompassed 3,622,412 children and 1,878,917 mothers.
Exposure variable
Our exposure variable was maternal history of HM prior to childbirth. Information on exposure was extracted from the SCR, using the International Classification of Diseases (ICD)-7: 173 and pathoanatomical diagnosis: 801 codes to identify all recorded cases of HM. In this way, a total of 4940 cases of HM were identified in the SCR since 1958, 20 of which were identified as a repeat mole.
By means of record linkage between the MBR and the SCR, we found 3709 unique women with a first diagnosis of HM during the period that was included in the analysis. Of these, 3071 women had a diagnosis of HM prior to at least 1 of their childbirths, with a total of 5186 exposed births. The study population was further stratified into a maternal history of HM prior to the index pregnancy, defined as no birth between the HM and the index pregnancy (n = 2867), and a maternal history of HM and at least 1 birth between the HM and the index pregnancy (n = 2319). Information on births occurring prior to 1973 was retrieved from the MGR.
Outcome variables
Outcomes of interest included adverse maternal pregnancy outcomes (maternal preeclampsia [PE]; ICD-8: 63703, 63704, 63709, 63799; ICD-9: 642E, 642F, 642H; ICD-10: O11, O14; maternal hypertension; ICD-8: 63701; ICD-9: 642D, 642X; ICD-10: O13, O16; placental abruption; ICD-8: 6514; ICD-9: 641C; ICD-10: O45 and premature rupture of membranes [PROM]; ICD-8: 6610; ICD-9: 658B, 658C; ICD-10: O42; and adverse offspring outcomes [congenital malformations; ICD-9: 740-759; ICD-10: Q30-Q99, preterm birth (delivery <37 gestational weeks), stillbirth, neonatal mortality (child died <28 days’ postpartum), SGA, and LGA]).
Statistical analysis
An unconditional logistic regression analysis was used to estimate the association between maternal history of HM and different adverse maternal and offspring outcomes. Exposure to HM was included in the regression models using a dichotomous categorization (ie, never exposed to HM vs exposed to HM prior to index delivery) as well as a 3-level categorization (ie, never exposed to HM, HM prior to index delivery, HM followed by at least 1 childbirth prior to index delivery). Births with no maternal history of HM were used as the reference group irrespective of categorization of HM exposure.
Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and robust SEs were used in the logistic regression analysis to account for the dependency structure in the data (ie, that the same woman could contribute with >1 delivery). The strength of the association between potential confounding variables (maternal age at index birth, country of origin, education, smoking at first visit to antenatal care, and body mass index [BMI]) and HM exposure prior to the index birth was assessed using multinomial regression in which the 3-level representation of HM was included as the outcome variable ( Table 1 ). The unconditional logistic regression models were adjusted for maternal age at delivery (<20 years, 20-29 years, 30-39 years, and ≥40 years old) and region of birth (Europe, Africa, Asia, and America) ( Tables 2 and 3 ). P values from Wald tests were calculated in all regression models and a 5% significance level was used.
| Characteristic | Deliveries | HM prior to index delivery a | HM and at least 1 childbirth prior to index delivery a |
|---|---|---|---|
| Age at birth, y | |||
| <20 | 118,838 | 39 | 5 |
| 20-29 | 2,043,266 | 1440 | 872 |
| 30-39 | 1,387,749 | 1288 | 1336 |
| ≥40 | 72,559 | 100 | 106 |
| P < .001 | |||
| Maternal country of origin | |||
| Europe (including Russia) | 3,402,706 | 2685 | 2189 |
| Africa | 44,663 | 25 | 23 |
| Asia (including Oceania) | 137,946 | 124 | 83 |
| United States | 37,097 | 33 | 24 |
| P = .1950 | |||
| Maternal education, y | |||
| 10 | 512,207 | 383 | 394 |
| 10-13 | 1,738,707 | 1357 | 1114 |
| More than13 | 1,306,811 | 1099 | 797 |
| Missing | 64,687 | 28 | 14 |
| P < .001 | |||
| Maternal smoking | |||
| No | 2,088,502 | 1747 | 1425 |
| 1-9 cigarettes/day | 295,828 | 232 | 197 |
| ≥10 cigarettes/day | 164,775 | 117 | 106 |
| Missing | 1,073,307 | 771 | 591 |
| P = .4592 | |||
| Maternal BMI, kg/m 2 | |||
| <19 | 134,012 | 104 | 56 |
| 19-24 | 1,321,924 | 1118 | 878 |
| 25-29 | 418,273 | 351 | 307 |
| ≥30 | 156,182 | 114 | 112 |
| Missing | 1,592,021 | 1180 | 966 |
| P = .0155 | |||
| Total | 3,622,412 | 2867 | 2319 |
a Note these numbers refer to deliveries, not unique women. Hence, women who have more than 1 exposed index delivery contribute more than once to this table. The number of unique women with HM in this cohort was 3709. Of these, 3071 were exposed to HM prior to at least 1 of their childbirths.
| Outcome | Model 1 a | Model 2 a | ||
|---|---|---|---|---|
| No history of HM | Previous history of HM (ever) | HM prior to index delivery | HM and at least 1 childbirth prior to index delivery | |
| Preeclampsia | ||||
| OR (95% CI) | 1.00 (reference) | 0.75 (0.59–0.96) | 0.79 (0.58–1.06) | 0.71 (0.50–1.02) |
| P value | .023 | .074 | ||
| Number of events | 69,262 | 77 | 44 | 33 |
| Pregnancy hypertension | ||||
| OR (95% CI) | 1.00 (reference) | 1.01 (0.74–1.38) | 1.05 (0.70–1.57) | 0.96 (0.61–1.52) |
| P value | .947 | .957 | ||
| Number of events | 27,577 | 43 | 24 | 19 |
| Placental abruption | ||||
| OR (95% CI) | 1.00 (reference) | 1.10 (0.75–1.63) | 1.05 (0.62–1.77) | 1.17 (0.68–2.02) |
| P value | .617 | .841 | ||
| Number of events | 16,553 | 27 | 14 | 13 |
| PROM | ||||
| OR (95% CI) | 1.00 (reference) | 0.88 (0.71–1.09) | 0.99 (0.76–1.30) | 0.74 (0.52–1.05) |
| P value | .247 | .251 | ||
| Number of events | 67,825 | 87 | 54 | 33 |
| Number of pregnancies | 3,617,226 | 5186 | 2867 | 2319 |
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