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Rinnakkaistallenteet Terveystieteiden tiedekunta
2019
Maternal use of drugs and preeclampsia
Sahlman, H
Wiley
Tieteelliset aikakauslehtiartikkelit
© The British Pharmacological Society All rights reserved
http://dx.doi.org/10.1111/bcp.14117
https://erepo.uef.fi/handle/123456789/7954
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This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi:
10.1111/bcp.14117
Sahlman H (Orcid ID: 0000-0003-1737-6066)
Maternal use of drugs and preeclampsia
Running title: Maternal use of drugs and preeclampsia
Sahlman H1, Koponen M1, El-Nezami H2,3, Vahakangas K1, Keski-Nisula L4,5
1 School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
2 Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
3 School of Biological Sciences, University of Hong Kong,Pok Fu Lam Road, Hong Kong SAR, China
4 Department of Obstetrics and Gynecology, Kuopio University Hospital, Puijonlaaksontie 2, 70210 Kuopio, Finland,
5 Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
Corresponding author: Sahlman Heidi, PhD, post-doctoral researcher, School of Pharmacy/Toxicology, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland, heidi.sahlman@uef.fi
Koponen Marjaana, PhD,post-doctoral researcher,School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
El-Nezami Hani, Professor,School of Biological Sciences, University of Hong Kong, Pok Fu Lam Road, Hong Kong SAR, China
Vähäkangas Kirsi, Professor emerita, School of Pharmacy/Toxicology, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
Keski-Nisula Leea, Professor, Department of Obstetrics and Gynecology, Kuopio University Hospital, Puijonlaaksontie 2, 70210 Kuopio, Finland
The authors confirm that the PI for this paper is Prof. Leea Keski-Nisula and that she had direct clinical responsibility for the patients.
Keywords: pregnancy, maternal use of drugs, preeclampsia
Word count: 2594
Number of tables: 3 tables Abstract
Aims: The aim was to compare and describe maternal use of drugs between women with preeclampsia and controls and to estimate the possible association with preeclampsia.
Methods: The study cohort was collected from the Kuopio University Hospital Birth Register, which includes information about all women who gave birth in Kuopio University Hospital during the years 2002−2016, including information from approximately 36,000 parturients of whom 1,252 had preeclampsia. Maternal use of 16 groups of drugs during pregnancy was analyzed from all women with preeclampsia and 1,256 controls.
Results: Every second woman had used at least one drug during pregnancy butthose with preeclampsia had used significantly more than the controls (cases 59.5% vs. controls 35.5%;
p<0.001). In both study groups, the most commonly used drugs were antibiotics (cases 19.5%, controls 17.0%), antihypertensives (cases 29.0%, controls 7.6%) and paracetamol (cases 13.1%, controls 5.9%). Women with preeclampsia had used significantly more benzodiazepines, paracetamol, antihypertensives and acid-suppressive drugs than the women in the control group (p<0.05).
Conclusions: Women with preeclampsia were more likely to use medicines during pregnancy.
While the association between benzodiazepines, antihypertensives and acid-suppressive drugs and preeclampsia may be explained by reverse causation, the association of paracetamol with preeclampsia remains to be clarified. Because paracetamol is a frequently used drug, more information about its safety during pregnancy including its role in preeclampsia is urgently needed.
Statement1: What is already known about this subject?
Preeclampsia poses a risk to both the mother and the unborn child.
The use of some drugs during pregnancy might be associated with the increased risk of preeclampsia.
Results about the role of maternal use of drugs in the development of preeclampsia are controversial and the data is very limited.
Statement 2: What this study adds
Women with preeclampsia had used a greater variety of drugs during pregnancy.
The use of benzodiazepines, paracetamol, antihypertensives and acid-suppressive drugs was associated with preeclampsia.Introduction
The use of drugs during pregnancy is very common; it is estimated that every second pregnant Finnish woman uses at least one prescription drug during her pregnancy[1,2] and in some other Western countries, the proportions are reported to be even higher, e.g. up to 59% in Canada and almost 100% in France[3-5]. The most commonly used drugs during pregnancy are antibiotics, accounting for more than 25% of all drugs used [2,3]. Other commonly used drug groups are paracetamol, NSAIDs, anti-emetics, acid-suppressive drugs, antidepressants, antiasthmatics[2,3,6] and according to a Canadian study[3] also hormones such as oral contraceptives.
During pregnancy, certain drugs may be necessary to ensure maternal and sometimes also fetal health. However, since the fetus is very sensitive to the effects of chemicals[7], the use and choice of drugs to be taken during pregnancy should always be considered carefully.
There are only a few drugs, which have been proven safe during pregnancy. On the other hand, considering the high number of drugs commonly used, only a small proportion have been confirmed to be clearly teratogenic[2,8]. However, teratogenicity is not the only possible harmful effect during pregnancy, for example, maternal use of some drugs has been linked to other harmful effects such as an increased risk of preeclampsia.
Preeclampsia, occurring globally in 3−8% of pregnancies, is a serious, etiologically heterogeneous complication which affects both the mother and the unborn child[9]. In the most severe cases, preeclampsia may cause serious organ damage and fetal growth restriction and commonly, preterm birth and the associated risks of neonatal morbidity and mortality. In addition to the risks during pregnancy, preeclampsia has been associated with a higher risk for the later development of chronic hypertension, diabetes and renal disease in the mother. It has been speculated that preeclampsia poses significant long-term risks to the offspring, for example an increased risk of stroke[10] and the development of diabetes[11].
The cause of preeclampsia is not fully understood. It is believed to be a multifactorial disease;
maternal and fetal genetic factors as well as environmental factors contribute to its development[12]. The use of some drugs during pregnancy may be associated with an increased risk for the development of preeclampsia. For example, the use of some antidepressants during pregnancy (especially during the first or the second trimester of pregnancy)[13-16],antiretrovirals used in the treatment of HIV patients[17-19], triptans for the treatment of migraine[20], the asthma medication, montelukast[21] and metamphetamine abuse[22,23], has been linked to the increased risk of preeclampsia. However, results between studies have been controversial or there is limited data on which one can draw conclusions.
Thus, there is a need to gather more information about maternal use of drugs and the risk of preeclampsia.
The aim of this study was to compare and describe the maternal use of drugs between women with preeclampsia and control women and to estimate the possible association with preeclampsia and to clarify the need of further studies.
Materials and methods Study cohort
The study cohort was collected from the Kuopio University Hospital (KUH) Birth Register which includes information about all mothers who gave birth in Kuopio University Hospital during the years 2002−2016, i.e. information from approximately 36,000 parturients. The data was used to evaluate whether there were differences in the use of drugs during pregnancy between mothers with mild and severe preeclampsia and control mothers without preeclampsia.
The KUH Birth Register contains demographic and clinical information about the woman and her ongoing pregnancy (maternal age, weight and height, parity, gravidity, smoking), maternal diseases, and the delivery (mode and gestational age at delivery, birth weight, Apgar scores, fetal sex and number of fetuses). It contains information about maternal care during pregnancy, including medical examinations and drugs administered in the hospital. The birth
register also contains a section for self-reporting in which the women themselves can report drug use, unless they are hospitalized. As well as information about their use of over-the- counter and prescription drugs, this section contains information about their smoking and dietary habits during pregnancy.
Of all the mothers giving birth during the follow-up period, 1,252 were diagnosed with preeclampsia during ongoing index pregnancy, delivery or early puerperium. Cases were identified according to the International Statistical Classification of Diseases and Related Health Problems 10th revision (ICD-10) codes; mild to moderate preeclampsia (O13 and O14.0), severe preeclampsia (O14.1) or unspecified preeclampsia (O14.9) or eclamptic seizures (O15.0, O15.1, O15.2 and O15.9). The control group contained 1,256 controls, who were selected by gestational age at delivery (+/- week) such that it corresponded to the cases with preeclampsia. Gestational age at delivery was selected as a controlled factor, since women with preeclampsia had significantly more often a preterm delivery and a longer duration of pregnancy is associated with a higher possibility to use drugs. All included women had delivery at or after 22 gestational weeks (GWs). A delivery with less than 37 GWs was classified as preterm (less than 32 GWs as very preterm, and 32 ̶ 36 GWs as moderately preterm) and a delivery at 37 or more GWs as term.
In the analyses, used drugs were grouped based on Anatomical Therapeutic Chemical Classification System (ATC) codes, which are listed in Table 1. Analgesics, antibiotics and benzodiazepines that were explicitly used during delivery or immediately postpartum period or was used for the treatment of preeclampsia symptoms were excluded from the analysis.
Low-dose acetylsalicylic acid (ASA), used for the prophylaxis of preeclampsia, was also excluded from the analysis. Here, maternal smoking was divided into four groups: 1) non- smoker, 2) smoking only before pregnancy but not during pregnancy, 3) smoking at some time of pregnancy and 4) smoking throughout the pregnancy. The latter two groups have likely also smoked before pregnancy. Age was divided into three age groups (<20, 20–40, >40 years) and three BMI groups were formed (<25, 25 ̶ 30, >30 kg/m2).
The study was approved by Central Finland Health Care District ethical committee (18U/2011, 6.10.2016).
Statistical analysis
Numbers and percentages of cases and controls as well as the means and SDs were analyzed using descriptive statistics or crosstabs analysis. Binary logistic regression or multinomial logistic regression was used to analyze the relationships between preeclampsia and the use of medicines or smoking during pregnancy and to compute odds ratio (OR)/adjusted odds ratio (aOR) and confidence interval 95% (CI 95%). Maternal age (<20, 20-40, >40 years), BMI (<25, 25-30, >30 kg/m2), parity, type of delivery, smoking, diagnosed hypertension (ICD- 10 codes O10.0, O10.1, O10.2, O10.3, O10.4, O10.9, O11 and O16) and diagnosed diabetes (O24.0, O24.1 and O24.9) or gestational diabetes (GDM) (O24.4) was used for adjusting in the analyses. A p-value 0.05 was considered statistically significant. The database was analyzed using both SPSS (version 23) and SAS 9.4 programs. SAS 9.4 program was used to group the use of drugs. Statistical analysis was carried out using the SPSS program.
Results
The KUH Birth Register contained 1,252 women with preeclampsia, which is approximately 3.5% of all women giving birth in KUH during the years 2002−2016. Women with preeclampsia had higher BMI, and they had hypertension (cases 15.5%, controls 2.4%) and diabetes or GDM (cases 20.3%, controls 9.2%) more often than control women (Table 2). Women with preeclampsia were more often nulliparous than the controls. In addition, they smoked less throughout pregnancy (cases 5.3%, controls 9.3%) and their babies weighed significantly less at birth than the babies born to controls. Overall, 26.1% of women had preterm delivery (cases 29.5% and controls 22.7%) even though we tried to control prematurity with control selection and 9.8% had extremely and 16.3% moderately preterm deliveries. In the total study population, the mean gestational age at the time of delivery was 37.1 weeks (SD 3.6 weeks;
range 23−42 GWs). In total, 69.1% of women had a vaginal delivery, significantly fewer cases (61.5%) than in controls (76.7%).
In total, 47.5% of women had used at least one drug during pregnancy and the cases were more likely to use drugs than the controls (cases 59.5%, controls 35.5%; p<0.001) (Table 3).
In both groups, the most commonly used drugs were antibiotics (cases 19.5%, controls 17.0%), antihypertensives (cases 29%, controls 7.6%) and paracetamol (cases 13.1%, controls 5.9%). There were some other commonly used drugs i.e. antithrombotics, thyroxine, benzodiazepines, NSAIDs as well as antidiabetic drugs. All 16 types of drugs were more commonly used among women with preeclampsia, but eight groups (benzodiazepines, opioids, NSAID, paracetamol, thyroxine, antihypertensives, antidiabetic drugs and acid- suppressive drugs) were significantly more commonly used among women with preeclampsia.
After adjustment (maternal age, parity, type of delivery, BMI, smoking, diagnosed hypertension and diabetes or GDM), women with preeclampsia were found to be using significantly more often benzodiazepines, paracetamol, antihypertensives and acid- suppressive drugs than controls (Table 2). The use of paracetamol, acid-suppressive drugs, and antihypertensives was associated with both mild and severe preeclampsia as compared to controls. The use of benzodiazepines was associated with severe preeclampsia whereas that of opioids was associated with mild preeclampsia. The use of antithrombotics was inversely associated with mild preeclampsia.
Discussion
We accessed the KUH Birth Register to analyze drug use in pregnant women suffering from preeclampsia to clarify the connection between the use of drugs and preeclampsia. This is the first study that has evaluated as many as 16 groups of drugs during pregnancy and describing differences in drug use between women with preeclampsia and their control women.
Our analysis revealed that approximately 50% of the women had used at least one drug during their pregnancy. Women with preeclampsia used a wide variety of drugs more frequently than the controls and were using as many as eight different drug groups significantly more.
When the data was adjusted for many specific confounders such as maternal age, BMI and prepregnancy comorbidities such as diabetes and hypertension, the maternal use of four different groups of drugs still differed significantly between the groups. Since the published literature about drug use in women with preeclampsia is scanty, our study provides a significant addition to the formerly published data.
The use of paracetamol was associated with preeclampsia i.e. women with preeclampsia were nearly twice more likely to have used paracetamol than the control women. Our study supports earlier findings[24,25]for a review see[26] but the role of paracetamol in the development of preeclampsia will need to be clarified in further studies. Rebordosa and coworkers[25]
reported that paracetamol was associated with an increased risk of preeclampsia and thromboembolic complications due to the reduced production of prostacyclin. It is possible that this association might be explained by reverse causation: women with preeclampsia have more pain (e.g. headache) because of the preeclampsia itself [26]. However, preeclampsia is not the only adverse effect linked to the use of paracetamol during pregnancy. There is accumulating evidence that the use of paracetamol during pregnancy is not as safe as has been thought earlier, e.g. in some studies, it has been linked to an increased risk of autism, ADHD and lower IQ in the developing fetus[27-29]. Because paracetamol is a frequently used drug, more information is urgently needed about the consumption of paracetamol during pregnancy, especially its role in preeclampsia.
Our analysis showed that the use of NSAIDs, especially ibuprofen, was more common among women with preeclampsia. With respect to opioids, only a few women reported their use during pregnancy, with their use being more common among women suffering from mild preeclampsia. According to the literature, the abuse of the illicit stimulant, metamphetamine, has been linked to an increased risk for preeclampsia[23]. Furthermore, an association between the use of codeine and preeclampsia has also been reported[30]. According to Nezvalová-Henriksen et al.[30] and also in our database, it seemed that the combined use of paracetamol and codeine was a common combination in opioid users. Thus, the association of opioids with preeclampsia may be linked to the use of paracetamol or be due to the treatment of preeclampsia related symptoms (e.g. headache).
Benzodiazepines are commonly used to treat anxiety disorders, anxiety symptoms of other psychiatric disorders, seizures and insomnia, but are also used to prevent and treat symptoms of preeclampsia [31]. We excluded benzodiazepines that were used for the treatment of preeclampsia symptoms from this analysis (accounting for 25.3% of benzodiazepine use).
Nonetheless, even with this omission, the use of benzodiazepines was associated with severe preeclampsia. As the indication for drug use was rarely reported, our exclusions were not
comprehensive. Thus, it is possible that reverse causation explains this association, i.e.
women with severe preeclampsia were prescribed benzodiazepines to treat the preclinical symptoms of preeclampsia.
Symptoms of reflux are typical during pregnancy and according to a recent Dutch study[6] acid- suppressive drugs are one of the most commonly used drugs during pregnancy. In our study, women with preeclampsia had used significantly more often acid-suppressive drugs (4.5%) as compared with the controls (1.7%). The use of calcium-based antacids during pregnancy for providing relief from gastro-oesophageal reflux has been suggested to be beneficial because it may reduce the risk of hypertension and preeclampsia[32,33]. Additionally, women with confirmed or suspected preeclampsia who have used proton pump inhibitors (PPIs) have had lower serum sFlt-1 levels, perhaps indicative of their possible protective effect in preeclampsia[34]. Thus, this association might be due to reverse causation if these drugs are used more because of preeclampsia related symptoms such as epigastric pain or heartburn.
The association between some drugs and preeclampsia could be attributable to the symptoms of preeclampsia and their treatment, or risk factors contributing to the risk of preeclampsia. For example, diabetes is one of the known risk factor for preeclampsia[35] and antihypertensives are a part of its recommended treatment to control the disease-related blood pressure[36]. Additionally, subclinical hypothyroidism is likely to be associated with a higher risk of preeclampsia and thus it may explain why thyroxine is more commonly used by women with preeclampsia[37-42].
The prevalence of preeclampsia (3.5% of the 36,000 parturients) in Kuopio University Hospital and its birth register is in line with the general prevalence estimates of preeclampsia[9]. An important strength of this study is the relatively high number of cases with preeclampsia (n=1,252) which enabled us to evaluate the use of several different groups of drugs and to analyze their use according to the severity of disease. The KUH Birth Register included information on self-reported use of drugs during pregnancy which covered also the use of over-the-counter drugs. In addition, we had data on self-reported smoking habits during pregnancy. One major limitation is that we are unaware of the exact timing of the drug use in relation to the development of preeclampsia. Therefore, the associations found might be due to reverse causation i.e. the treatment of symptoms of preeclampsia. Another limitation is that the indication for drug use was seldom reported. However, we excluded analgesics,
antibiotics and benzodiazepines that were explicitly used during delivery or in the immediately postpartum period or for the treatment of preeclampsia, as well as low-dose ASA which could be prescribed for the prophylaxis of preeclampsia.
As a conclusion, women with preeclampsia used more drugs than the control women. The most significant differences were seen in the use of paracetamol, benzodiazepines, antihypertensives and acid-suppressive drugs. While the association between benzodiazepines, antihypertensives and acid-suppressive drugs with preeclampsia may be explained by reverse causation, the association of paracetamol with preeclampsia remains to be confirmed. Because paracetamol is a frequently used drug, more information about paracetamol during pregnancy including its role in preeclampsia is urgently needed. Further studies with these drugs should focus on clarifying whether there is a difference in the risk depending on the time and/or dose of exposure, or are there other underlying factors which would reveal the potential role of drugs in the development of preeclampsia.
References
1. Artama M, Gissler M, Malm H, Ritvanen A, Drugs and Pregnancy Study Group. Nationwide register-based surveillance system on drugs and pregnancy in Finland 1996-2006.
Pharmacoepidemiol Drug Saf. 2011;20(7):729-738.
2. Lahesmaa-Korpinen A. Raskaudenaikainen lääkkeiden käyttö suomessa. SIC Lääketietoa Fimeasta.
2013;1:48-49,50,51,52.
3. Berard A, Sheehy O. The quebec pregnancy cohort--prevalence of medication use during gestation and pregnancy outcomes. PLoS One. 2014;9(4):e93870.
4. Lacroix I, Hurault C, Sarramon MF, et al. Prescription of drugs during pregnancy: A study using EFEMERIS, the new french database. Eur J Clin Pharmacol. 2009;65(8):839-846.
5. Demailly R, Escolano S, Quantin C, Tubert-Bitter P, Ahmed I. Prescription drug use during pregnancy in france: A study from the national health insurance permanent sample.
Pharmacoepidemiol Drug Saf. 2017;26(9):1126-1134.
6. Mulder B, Bijlsma MJ, Schuiling-Veninga CC, et al. Risks versus benefits of medication use during pregnancy: What do women perceive? Patient Prefer Adherence. 2017;12:1-8.
7. Tilson HA. The concern for developmental neurotoxicology: Is it justified and what is being done about it? Environ Health Perspect. 1995;103 Suppl 6:147-151.
8. van Gelder MM, de Jong-van den Berg LT, Roeleveld N. Drugs associated with teratogenic mechanisms. part II: A literature review of the evidence on human risks. Hum Reprod.
2014;29(1):168-183.
9. Hod T, Cerdeira AS, Karumanchi SA. Molecular mechanisms of preeclampsia. Cold Spring Harb Perspect Med. 2015;5(10):10.1101/cshperspect.a023473.
10. Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJ. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: The helsinki birth cohort study. Stroke.
2009;40(4):1176-1180.
11. Kajantie E, Osmond C, Eriksson JG. Gestational hypertension is associated with increased risk of type 2 diabetes in adult offspring: The helsinki birth cohort study. Am J Obstet Gynecol.
2017;216(3):281.e1-281.e7.
12. English FA, Kenny LC, McCarthy FP. Risk factors and effective management of preeclampsia.
Integr Blood Press Control. 2015;8:7-12.
13. Avalos LA, Chen H, Li DK. Antidepressant medication use, depression, and the risk of preeclampsia. CNS Spectr. 2015;20(1):39-47.
14. De Vera MA, Berard A. Antidepressant use during pregnancy and the risk of pregnancy-induced hypertension. Br J Clin Pharmacol. 2012;74(2):362-369.
15. Palmsten K, Huybrechts KF, Michels KB, et al. Antidepressant use and risk for preeclampsia.
Epidemiology. 2013;24(5):682-691.
16. Uguz F. Is there any association between use of antidepressants and preeclampsia or gestational hypertension?: A systematic review of current studies. J Clin Psychopharmacol. 2017;37(1):72-77.
17. Suy A, Martinez E, Coll O, et al. Increased risk of pre-eclampsia and fetal death in HIV-infected pregnant women receiving highly active antiretroviral therapy. AIDS. 2006;20(1):59-66.
18. Tooke L, Riemer L, Matjila M, Harrison M. Antiretrovirals causing severe pre-eclampsia.
Pregnancy Hypertens. 2016;6(4):266-268.
19. Wimalasundera RC, Larbalestier N, Smith JH, et al. Pre-eclampsia, antiretroviral therapy, and immune reconstitution. Lancet. 2002;360(9340):1152-1154.
20. Kallen B, Nilsson E, Otterblad Olausson P. Delivery outcome after maternal use of drugs for migraine: A register study in sweden. Drug Saf. 2011;34(8):691-703.
21. Cavero-Carbonell C, Vinkel-Hansen A, Rabanque-Hernandez MJ, Martos C, Garne E. Fetal exposure to montelukast and congenital anomalies: A population based study in denmark. Birth Defects Res. 2017;109(6):452-459.
22. Cohen JM, Hernandez-Diaz S, Bateman BT, et al. Placental complications associated with psychostimulant use in pregnancy. Obstet Gynecol. 2017;130(6):1192-1201.
23. Gorman MC, Orme KS, Nguyen NT, Kent EJ,3rd, Caughey AB. Outcomes in pregnancies complicated by methamphetamine use. Am J Obstet Gynecol. 2014;211(4):429.e1-429.e7.
24. Blue NR, Murray-Krezan C, Drake-Lavelle S, et al. Effect of ibuprofen vs acetaminophen on postpartum hypertension in preeclampsia with severe features: A double-masked, randomized controlled trial. Am J Obstet Gynecol. 2018;218(6):616.e1-616.e8.
25. Rebordosa C, Zelop CM, Kogevinas M, Sorensen HT, Olsen J. Use of acetaminophen during pregnancy and risk of preeclampsia, hypertensive and vascular disorders: A birth cohort study. J Matern Fetal Neonatal Med. 2010;23(5):371-378.
26. Scialli AR, Ang R, Breitmeyer J, Royal MA. A review of the literature on the effects of acetaminophen on pregnancy outcome. Reprod Toxicol. 2010;30(4):495-507.
27. Andrade C. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention- deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016;77(3):e312-4.
28. Andrade C. Use of acetaminophen (paracetamol) during pregnancy and the risk of autism spectrum disorder in the offspring. J Clin Psychiatry. 2016;77(2):e152-4.
29. Bauer AZ, Kriebel D, Herbert MR, Bornehag CG, Swan SH. Prenatal paracetamol exposure and child neurodevelopment: A review. Horm Behav. 2018;101:125-147.
30. Nezvalova-Henriksen K, Spigset O, Nordeng H. Effects of codeine on pregnancy outcome: Results from a large population-based cohort study. Eur J Clin Pharmacol. 2011;67(12):1253-1261.
31. Freeman MP, Goez-Mogollon L, McInerney KA, et al. Obstetrical and neonatal outcomes after benzodiazepine exposure during pregnancy: Results from a prospective registry of women with psychiatric disorders. Gen Hosp Psychiatry. 2018;53:73-79.
32. Dagli U, Kalkan IH. Treatment of reflux disease during pregnancy and lactation. Turk J Gastroenterol. 2017;28(Suppl 1):S53-S56.
33. Tytgat GN, Heading RC, Muller-Lissner S, et al. Contemporary understanding and management of reflux and constipation in the general population and pregnancy: A consensus meeting. Aliment Pharmacol Ther. 2003;18(3):291-301.
34. Saleh L, Samantar R, Garrelds IM, van den Meiracker AH, Visser W, Danser AHJ. Low soluble fms- like tyrosine kinase-1, endoglin, and endothelin-1 levels in women with confirmed or suspected preeclampsia using proton pump inhibitors. Hypertension. 2017;70(3):594-600.
35. Weissgerber TL, Mudd LM. Preeclampsia and diabetes. Curr Diab Rep. 2015;15(3):9-015-0579-4.
36. Berzan E, Doyle R, Brown CM. Treatment of preeclampsia: Current approach and future perspectives. Curr Hypertens Rep. 2014;16(9):473-014-0473-5.
37. Akram FH, Johansson B, Mollerstrom G, Landgren BM, Stavreus-Evers A, Skjoldebrand-Sparre L.
Incidence of subclinical hypothyroidism and hypothyroidism in early pregnancy. J Womens Health (Larchmt). 2017;26(11):1231-1235.
38. Krassas G, Karras SN, Pontikides N. Thyroid diseases during pregnancy: A number of important issues. Hormones (Athens). 2015;14(1):59-69.
39. Korevaar TI, Steegers EA, Chaker L, et al. The risk of preeclampsia according to high thyroid function in pregnancy differs by hCG concentration. J Clin Endocrinol Metab. 2016;101(12):5037- 5043.
40. Negro R, Stagnaro-Green A. Diagnosis and management of subclinical hypothyroidism in pregnancy. BMJ. 2014;349:g4929.
41. Barisic T, Mandic V, Vasilj A, Tiric D. Higher levels of thyrotropin in pregnancy and adverse pregnancy outcomes. J Matern Fetal Neonatal Med. 2018:1-6.
42. Zhang Y, Dai X, Yang S, et al. Maternal low thyroxin levels are associated with adverse pregnancy outcomes in a chinese population. PLoS One. 2017;12(5):e0178100.
Table 1. Definition of different drug groups based on ATC codes.
Drug group ATC code Drugs used in the cohort
Antidepressants N06A
amitriptyline, doxepin, fluoxetine, citalopram, paroxetine, sertraline, escitalopram,
mirtazapine, venlafaxine, duloxetine
Antipsychotics N05A
perphenazine, haloperidol, clozapine, olanzapine, quetiapine, lithium, risperidone
Antiepileptic drugs N03A
phenytoin, fosphenytoin clonazepam, carbamazepine oxcarbazepine, valproic acid,
lamotrigine, levetiracetam, pregabalin
Benzodiazepines and related drugs
Benzodiazepine derivatives
N05BA, N05CD
diazepam, oxazepam, alprazolam, temazepam, midazolam
Benzodiazepine
related drugs N05CF zopiclone, zolpidem Nonsteroidal anti-
inflammatory drugs (NSAIDs)
M01A, except
M01AX05 ibuprofen, naproxen, ketoprofen,
Opioids N02A codeine, oxycodone, buprenorphine, tramadol
Paracetamol N02BE01 paracetamol
Thyroxin H03A levothyroxine
Antidiabetic drugs
Insulin A10A insulin
Other antidiabetic
agents A10B metformin
Antiasthmatics
Adrenergics,
inhalants R03A
salbutamol, terbutaline, formoterol,
salmeterol/fluticasone, budesonide/formoterol Other drugs for
obstructive airway
diseases, inhalants R03B
beclomethasone, budenoside, fluticasone, ciclesonide, ipratropium bromide, sodium cromoglycate
Adrenergics for
systemic use R03C terbutaline
Antihistamines
Antihistamines for
systemic use R06A
meclozine, cetirizine, levocetirizine, loratadine, desloratadine, ebastine, fexofenadine
Nasal
decongestants for
systemic use R01B acrivastine/pseudoephedrine
Antibiotics J01
doxycycline, lymecycline, tetracycline, amoxicillin, pivmecillinam, phenoxymethylpenicillin, cefalexin, methenamine
cefadroxil, cefuroxime, trimethoprim, erythromycin, roxithromycin, clarithromycin, azithromycin,
nitrofurantoin Acid-suppressive medication A02
aluminum hydroxide, magnesium subcarbonate, calcium carbonate, ranitidine
Antitrombotic agents,
heparin group B01AB dalteparin, enoxaparin Antihypertensives
Diuretics C03 hydrochloride thiazide, furosemide Beta blocking
agents C07
propranolol, sotalol, metoprolol, bisoprolol, labetalol, carvedilol
Calcium channel
blockers C08 amlodipine, isradipine, nifedipine
Agents acting on the renin-
angiotensin system C09 enalapril, candesartan Intestinal anti-inflammatory
agents A07E budesonide, salazopyrine, mesalazine
Table 2. Demographic and clinical characteristics of women with preeclampsia (n=1,252) and control women (n=1,256).
Maternal or perinatal characteristics Preeclampsia cases Controls Unadjusted OR (Cl 95 %) p value
Maternal age, years 29.19±5.95 28.98 ±5.38 1.01 (0.99̶ ̶ 1.02) 0.358
<20 50 (4.0%) 37 (2.9%) 1.40 (0.91 ̶ 2.15) 0.130
20-40 1161 (92.7%) 1200 (95.5%) 1.00
>40 41 (3.3%) 19 (1.5%) 2.23 (1.29 ̶ 3.87) 0.004
Weight, kg 71.53±17.32 65.27±13.53 1.03 (1.02 ̶ 1.03) <0.001
Height, cm 164.59±5.84 164.83±5.77 0.99 (0.98 ̶ 1.01) 0.317
BMI kg/m2 26.37±0.17 24.01±0.13 1.09 (1.07 ̶ 1.11) <0.001
<25 661 (52.8%) 911 (72.5%) 1.00
25-30 313 (25.0%) 213 (17.0%) 2.03 (1.66 ̶ 2.48) <0.001
>30 278 (22.2%) 132 (10.5%) 2.90 (2.31 ̶ 3.65) <0.001
Parity
Nulliparous 818 (65.3%) 466 (37.1%) 1.00
Primi- or multiparous 434 (34.7%) 790 (62.9%) 0.31 (0.26 ̶ 0.37) <0.001
Gestational weeks at delivery 37.02±3.56 37.17±3.62 0.99 (0.97 ̶ 1.01) 0.289
Term ≥ 37 882 (70.4%) 971 (77.3%) 1.00
Moderately preterm, 32−36 242 (19.3%) 166 (13.2%) 1.61 (1.29 ̶ 2.00) <0.001
Extremely preterm, ≤ 31 128 (10.2%) 119 (9.5%) 1.18 (0.91 ̶ 1.55) 0.212
Mode of delivery
Vaginal delivery 770 (61.5%) 963 (76.7%) 1.00
Cesarean delivery 482 (38.5%) 293 (23.3%) 2.06 (1.73 ̶ 2.45) <0.001
Smokinga)
Before pregnancy 75 (6.0%) 70 (5.6%) 1.10 (0.78 ̶ 1.54) 0.583
At some time during pregnancy 195 (15.6%) 129 (10.3%) 1.55 (1.22 ̶ 1.97) <0.001
Throughout pregnancy 66 (5.3%) 117 (9.3%) 0.58 (0.42 ̶ 0.79) 0.001
Comorbid medical information
Hypertension 194 (15.5%) 30 (2.4 %) 7.49 (5.06 -11.10) <0.001
Diabetes or GDM 254 (20.3 %) 116 (9.2 %) 2.50 (1.98 - 3.17) <0.001
Birth weight, g 2927.57±901.86 3093.69±844.47 1.00 (1.00 ̶ 1.00) <0.001
Apgar scores (5 min) >8 scores 1106 (88.3%) 1124 (89.5%) 0.89 (0.69 ̶ 1.14) 0.890
Sex of the baby, male 619 (49.4%) 618 (49.2%) 1.00
Sex of the baby, female 633 (50.6%) 638 (50.8%) 0.99 (0.85 ̶ 1.16) 0.905
a) compared to nonsmoking. GDM = gestational diabetes.
Table 3. Use of drugs during ongoing pregnancy and severity of preeclampsia in cases (n=1,252) and controls (n=1,256).
Drug group Preeclampsia cases n (%) Controls n (%) Unadjusted OR (95% CI) p value Adjusted OR* (95% CI) p value
Antidepressants 47 (3.8%) 33 (2.6%) 1.45 (0.92 ̶ 2.27) 0.110 1.02 (0.61 -1.70) 0.953
26 (3.6%) mild 1.37 (0.81 ̶ 2.30) 0.241 1.00 (0.56 -1.79) 0.991
21 (4%) severe 1.56 (0.89 ̶ 2.72) 0.119 1.06 (0.56 -1.98) 0.869
Antipsychotics 21 (1.7%) 10 (0.8%) 2.13 (1.00 ̶ 4.53) 0.051 1.40 (0.60 -3.28) 0.434
9 (1.2%) mild 1.55 (0.63 ̶ 3.84) 0.340 1.02 (0.38 -2.75) 0.968
12 (2.3%) severe 2.94 (1.26 ̶ 6.84) 0.012 2.02 (0.78 -5.24) 0.146
Antiepileptic drugs 10 (0.8%) 6 (0.5%) 1.68 (0.61 ̶ 4.63) 0.318 1.29 (0.41 -4.09) 0.668
5 (0.7%) mild 1.44 (0.44 ̶ 4.72) 0.552 1.27 (0.35 -4.59) 0.720
5 (1.0%) severe 2.02 (0.61 ̶ 6.64) 0.248 1.35 (0.34 -5.32 0.671
Benzodiazepines 83 (6.6%) 25 (2.0%) 3.50 (2.22 ̶ 5.51) <0.001 2.76 (1.69 -4.53) <0.001
24 (3.3%) mild 1.67 (0.95 ̶ 2.95) 0.076 1.61 (0.88 -2.93) 0.122
59 (11.3%) severe 6.29 (3.89 ̶ 10.16) <0.001 4.18 (2.46 -7.11) <0.001
Opioids 24 (1.9%) 8 (0.6%) 3.05 (1.36 ̶ 6.81) 0.007 2.03 (0.85 -4.86) 0.110
18 (2.5%) mild 3.94 (1.70 ̶ 9.10) 0.001 2.94 (1.66 -2.98) 0.020
6 (1.2%) severe 1.82 (0.63 ̶ 5.26) 0.271 0.99 (0.32 -3.10) 0.987
NSAIDs 77 (6.2%) 44 (3.5%) 1.81 (1.24-2.64) 0.002 1.21 (0.79 -1.85) 0.380
32 (4.4%) mild 1.26 (0.79 ̶ 2.01) 0.328 1.18 (0.71 -1.96) 0.526
45 (8.6%) severe 2.60 (1.70 ̶ 4.00) <0.001 1.21 (0.75 -1.96) 0.425
Paracetamol 164 (13.1%) 74 (5.9%) 2.41 (1.81 ̶ 3.21) <0.001 1.98 (1.44 -2.73) <0.001
82 (11.2%) mild 2.02 (1.45 ̶ 2.80) <0.001 2.04 (1.42 -2.92) <0.001
82 (15.7%) severe 2.98 (2.14 ̶ 4.16) <0.001 1.89 (1.31 -2.75) 0.001
Thyroxine 88 (7.0%) 61 (4.9%) 1.48 (1.06 ̶ 2.07) 0.022 0.92 (0.63 -1.35) 0.672
51 (7.0%) mild 1.47 (1.00 ̶ 2.16) 0.049 0.93 (0.61 -1.42) 0.721
37 (7.1%) severe 1.50 (0.98 ̶ 2.28) 0.061 0.92 (0.57 -1.48) 0.729
Antidiabetic drugs 70 (5.6%) 32 (2.5%) 2.27 (1.48 ̶ 3.47) <0.001 1.23 (0.74 -2.03) 0.428
40 (5.5%) mild 2.21 (1.38 ̶ 3.56) 0.001 1.32 (0.75 -2.32) 0.329
30 (5.8%) severe 2.34 (1.41 ̶ 3.89) 0.001 1.18 (0.65 -2.15) 0.589
Antiasthmatics 54 (4.3%) 45 (3.6%) 1.21 (0.81 ̶ 1.82) 0.358 0.96 (0.61 -1.51) 0.856
31 (4.2%) mild 1.19 (0.75 ̶ 1.90) 0.461 0.94 (0.57 -1.57) 0.826
23 (4.4%) severe 1.24 (0.74 ̶ 2.08) 0.406 0.99 (0.56 -1.75) 0.963
Antihistamines 30 (2.4%) 17 (1.4%) 1.79 (0.98 ̶ 3.26) 0.057 1.08 (0.55 -2.12) 0.824
16 (2.2%) mild 1.63 (0.82 ̶ 3.25) 0.164 0.97 (0.46 -2.06) 0.937
14 (2.7%) severe 2.01 (0.99 ̶ 4.11) 0.055 1.31 (0.58 -2.95) 0.515
Antibiotics 244 (19.5%) 214 (17.0%) 1.18 (0.96 ̶ 1.44) 0.112 1.10 (0.87 - 1.38) 0.421
151 (20.7%) mild 1.27 (1.01 ̶ 1.60) 0.045 1.24 (0.96 - 1.60) 0.095
93 (17.9%) severe 1.06 (0.81 ̶ 1.38) 0.680 0.91 (0.68 - 1.23) 0.546
Acid-suppressive
medication 56 (4.5%) 21 (1.7%) 2.75 (1.66 ̶ 4.58) <0.001 2.60 (1.48 -4.53) 0.001
36 (4.9%) mild 3.05 (1.76 ̶ 5.26) <0.001 3.06 (1.70 -5.55) <0.001
20 (3.8%) severe 2.35 (1.26 ̶ 4.37) 0.007 1.99 (1.01 -3.94) 0.048
Antithrombotics 98 (7.8%) 80 (6.4%) 1.25 (0.92 ̶ 1.70) 0.156 0.70 (0.49 -1.00) 0.052
34 (4.7%) mild 0.72 (0.48 ̶ 1.08) 0.114 0.53 (0.34 -0.84) 0.007
64 (12.3%) severe 2.06 (1.46 ̶ 2.91) <0.001 0.86 (0.58 -1.28) 0.457
Antihypertensives 363 (29.0%) 95 (7.6%) 4.99 (3.92 ̶ 6.36) <0.001 3.66 (2.78 -4.83) <0.001
153 (20.9%) mild 3.24 (2.46 ̶ 4.26) <0.001 2.69 (1.97 -3.69) <0.001
210 (40.3%) severe 8.25 (6.28 ̶ 10.84) <0.001 5.13 (3.75 -7.02) <0.001 Intestinal anti-
inflammatory agents 16 (1.3%) 10 (0.8%) 1.61 (0.73 ̶ 3.57) 0.238 1.65 (0.66 - 4.09) 0.284
9 (1.2%) mild 1.55 (0.63 ̶ 3.84) 0.340 1.78 (0.66 - 4.77) 0.254
7 (1.3%) severe 1.70 (0.64 ̶ 4.48) 0.286 1.45 (0.47 - 4.45) 0.513
Total 1 252 (100) 1 256 (100)
*adjusted for maternal age, parity, type of delivery, BMI, smoking, diagnosed hypertension and diabetes or GDM
Data Availability Statement: Research data are not shared.
