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 1252 had preeclampsia. Maternal use of 16 groups of drugs during pregnancy was analysed from all women with preeclampsia and 1256 controls.
Results
Every second woman had used at least 1 drug during pregnancy but those 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.
Keywords: maternal use of drugs, preeclampsia, pregnancy
What is already known on the 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 are very limited.
What this paper 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.
1. INTRODUCTION
The use of drugs during pregnancy is very common; it is estimated that every second pregnant Finnish woman uses at least 1 prescription drug during her pregnancy1, 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, 4, 5 The most commonly used drugs during pregnancy are antibiotics, accounting for > 25% of all drugs used.2, 3 Other commonly used drug groups are paracetamol, nonsteroidal anti‐inflammatory drugs (NSAIDs), antiemetics, acid‐suppressive drugs, antidepressants, antiasthmatics2, 3, 6 and according to a Canadian study3 also hormones such as oral contraceptives.
During pregnancy, certain drugs may be necessary to ensure maternal and sometimes also foetal health. However, since the foetus 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. By contrast, 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, aetiologically heterogeneous complication which affects both the mother and the unborn child.9 In the most severe cases, preeclampsia may cause serious organ damage and foetal 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 stroke10 and the development of diabetes.11
The cause of preeclampsia is not fully understood. It is believed to be a multifactorial disease; maternal and foetal 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, 14, 15, 16 antiretrovirals used in the treatment of human immunodeficiency virus patients,17, 18, 19 triptans for the treatment of migraine,20 the asthma medication montelukast21 and methamphetamine abuse,22, 23 has been linked to increased risk of preeclampsia. However, results between studies have been controversial or there are 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.
2. METHODS
2.1. 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 were 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, foetal sex, and number of foetuses). 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, 1252 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 1256 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 (GW). A delivery with <37 GWs was classified as preterm (<32 GW as very preterm, and 32–36 GW as moderately preterm) and delivery at 37 or more GWs as term.
In the analyses, used drugs were grouped based on Anatomical Therapeutic Chemical Classification System 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, used for the prophylaxis of preeclampsia, was also excluded from the analysis. Here, maternal smoking was divided into 4 groups: (i) nonsmoker; (ii) smoking only before pregnancy but not during pregnancy; (iii) smoking at some time of pregnancy; and (iv) smoking throughout the pregnancy. The latter 2 groups have likely also smoked before pregnancy. Age was divided into 3 groups (<20, 20–40, >40 y) and 3 BMI groups were formed (<25, 25–30, >30 kg/m2).
Table 1.
Definition of different drug groups based on Anatomical Therapeutic Chemical Classification System (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 | Aluminium hydroxide, magnesium subcarbonate, calcium carbonate, ranitidine |
| Antithrombotic 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 |
The study was approved by Central Finland Health Care District ethical committee (18 U/2011, 6.10.2016).
2.2. Statistical analysis
Numbers and percentages of cases and controls as well as the means and SDs were analysed using descriptive statistics or crosstabs analysis. Binary logistic regression or multinomial logistic regression was used to analyse the relationships between preeclampsia and the use of medicines or smoking during pregnancy and to compute odds ratio/adjusted odds ratio and confidence interval 95% (CI 95%). Maternal age (<20, 20–40, >40 y), 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 <.05 was considered statistically significant. The database was analysed 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.
3. RESULTS
The KUH Birth Register contained 1252 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%).
Table 2.
Demographic and clinical characteristics of women with preeclampsia (n = 1252) and control women (n = 1256)
| Maternal or perinatal characteristics | Preeclampsia cases | Controls | Unadjusted OR (95%CI) | P value |
|---|---|---|---|---|
| Maternal age (y) | 29.19 ± 5.95 | 28.98 ± 5.38 | 1.01 (0.99–1.02) | .358 |
| <20 | 50 (4.0%) | 37 (2.9%) | 1.40 (0.91–2.15) | .130 |
| 20–40 | 1161 (92.7%) | 1200 (95.5%) | 1.00 | |
| >40 | 41 (3.3%) | 19 (1.5%) | 2.23 (1.29–3.87) | .004 |
| Weight (kg) | 71.53 ± 17.32 | 65.27 ± 13.53 | 1.03 (1.02–1.03) | <.001 |
| Height (cm) | 164.59 ± 5.84 | 164.83 ± 5.77 | 0.99 (0.98–1.01) | .317 |
| BMI (kg/m2) | 26.37 ± 0.17 | 24.01 ± 0.13 | 1.09 (1.07–1.11) | <.001 |
| <25 | 661 (52.8%) | 911 (72.5%) | 1.00 | |
| 25–30 | 313 (25.0%) | 213 (17.0%) | 2.03 (1.66–2.48) | <.001 |
| >30 | 278 (22.2%) | 132 (10.5%) | 2.90 (2.31–3.65) | <.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) | <.001 |
| Gestational weeks at delivery | 37.02 ± 3.56 | 37.17 ± 3.62 | 0.99 (0.97–1.01) | .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) | <.001 |
| Extremely preterm, ≤31 | 128 (10.2%) | 119 (9.5%) | 1.18 (0.91–1.55) | .212 |
| Mode of delivery | ||||
| Vaginal delivery | 770 (61.5%) | 963 (76.7%) | 1.00 | |
| Caesarean delivery | 482 (38.5%) | 293 (23.3%) | 2.06 (1.73–2.45) | <.001 |
| Smokinga | ||||
| Before pregnancy | 75 (6.0%) | 70 (5.6%) | 1.10 (0.78–1.54) | .583 |
| At some time during pregnancy | 195 (15.6%) | 129 (10.3%) | 1.55 (1.22–1.97) | <.001 |
| Throughout pregnancy | 66 (5.3%) | 117 (9.3%) | 0.58 (0.42–0.79) | .001 |
| Comorbid medical information | ||||
| Hypertension | 194 (15.5%) | 30 (2.4%) | 7.49 (5.06–11.10) | <.001 |
| Diabetes or GDM | 254 (20.3%) | 116 (9.2%) | 2.50 (1.98–3.17) | <.001 |
| Birth weight (g) | 2927.57 ± 901.86 | 3093.69 ± 844.47 | 1.00 (1.00–1.00) | <.001 |
| Apgar scores (5 min) >8 scores | 1106 (88.3%) | 1124 (89.5%) | 0.89 (0.69–1.14) | .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) | .905 |
compared to nonsmoking. BMI = body mass index; GDM = gestational diabetes.
In total, 47.5% of women had used at least 1 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.
Table 3.
Use of drugs during ongoing pregnancy and severity of preeclampsia in cases (n = 1252) and controls (n = 1256)
| 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) | .110 | 1.02 (0.61–1.70) | .953 |
| 26 (3.6%) mild | 1.37 (0.81–2.30) | .241 | 1.00 (0.56–1.79) | .991 | ||
| 21 (4%) severe | 1.56 (0.89–2.72) | .119 | 1.06 (0.56–1.98) | .869 | ||
| Antipsychotics | 21 (1.7%) | 10 (0.8%) | 2.13 (1.00–4.53) | .051 | 1.40 (0.60–3.28) | .434 |
| 9 (1.2%) mild | 1.55 (0.63–3.84) | .340 | 1.02 (0.38–2.75) | .968 | ||
| 12 (2.3%) severe | 2.94 (1.26–6.84) | .012 | 2.02 (0.78–5.24) | .146 | ||
| Antiepileptic drugs | 10 (0.8%) | 6 (0.5%) | 1.68 (0.61–4.63) | .318 | 1.29 (0.41–4.09) | .668 |
| 5 (0.7%) mild | 1.44 (0.44–4.72) | .552 | 1.27 (0.35–4.59) | .720 | ||
| 5 (1.0%) severe | 2.02 (0.61–6.64) | .248 | 1.35 (0.34–5.32 | .671 | ||
| Benzodiazepines | 83 (6.6%) | 25 (2.0%) | 3.50 (2.22–5.51) | <.001 | 2.76 (1.69–4.53) | <.001 |
| 24 (3.3%) mild | 1.67 (0.95–2.95) | .076 | 1.61 (0.88–2.93) | .122 | ||
| 59 (11.3%) severe | 6.29 (3.89–10.16) | <.001 | 4.18 (2.46–7.11) | <.001 | ||
| Opioids | 24 (1.9%) | 8 (0.6%) | 3.05 (1.36–6.81) | .007 | 2.03 (0.85–4.86) | .110 |
| 18 (2.5%) mild | 3.94 (1.70–9.10) | .001 | 2.94 (1.66–2.98) | .020 | ||
| 6 (1.2%) severe | 1.82 (0.63–5.26) | .271 | 0.99 (0.32–3.10) | .987 | ||
| NSAIDs | 77 (6.2%) | 44 (3.5%) | 1.81 (1.24–2.64) | .002 | 1.21 (0.79–1.85) | .380 |
| 32 (4.4%) mild | 1.26 (0.79–2.01) | .328 | 1.18 (0.71–1.96) | .526 | ||
| 45 (8.6%) severe | 2.60 (1.70–4.00) | <.001 | 1.21 (0.75–1.96) | .425 | ||
| Paracetamol | 164 (13.1%) | 74 (5.9%) | 2.41 (1.81–3.21) | <.001 | 1.98 (1.44–2.73) | <.001 |
| 82 (11.2%) mild | 2.02 (1.45–2.80) | <.001 | 2.04 (1.42–2.92) | <.001 | ||
| 82 (15.7%) severe | 2.98 (2.14–4.16) | <.001 | 1.89 (1.31–2.75) | .001 | ||
| Thyroxine | 88 (7.0%) | 61 (4.9%) | 1.48 (1.06–2.07) | .022 | 0.92 (0.63–1.35) | .672 |
| 51 (7.0%) mild | 1.47 (1.00–2.16) | .049 | 0.93 (0.61–1.42) | .721 | ||
| 37 (7.1%) severe | 1.50 (0.98–2.28) | .061 | 0.92 (0.57–1.48) | .729 | ||
| Antidiabetic drugs | 70 (5.6%) | 32 (2.5%) | 2.27 (1.48–3.47) | <.001 | 1.23 (0.74–2.03) | .428 |
| 40 (5.5%) mild | 2.21 (1.38–3.56) | .001 | 1.32 (0.75–2.32) | .329 | ||
| 30 (5.8%) severe | 2.34 (1.41–3.89) | .001 | 1.18 (0.65–2.15) | .589 | ||
| Antiasthmatics | 54 (4.3%) | 45 (3.6%) | 1.21 (0.81–1.82) | .358 | 0.96 (0.61–1.51) | .856 |
| 31 (4.2%) mild | 1.19 (0.75–1.90) | .461 | 0.94 (0.57–1.57) | .826 | ||
| 23 (4.4%) severe | 1.24 (0.74–2.08) | .406 | 0.99 (0.56–1.75) | .963 | ||
| Antihistamines | 30 (2.4%) | 17 (1.4%) | 1.79 (0.98–3.26) | .057 | 1.08 (0.55–2.12) | .824 |
| 16 (2.2%) mild | 1.63 (0.82–3.25) | .164 | 0.97 (0.46–2.06) | .937 | ||
| 14 (2.7%) severe | 2.01 (0.99–4.11) | .055 | 1.31 (0.58–2.95) | .515 | ||
| Antibiotics | 244 (19.5%) | 214 (17.0%) | 1.18 (0.96–1.44) | .112 | 1.10 (0.87–1.38) | .421 |
| 151 (20.7%) mild | 1.27 (1.01–1.60) | .045 | 1.24 (0.96–1.60) | .095 | ||
| 93 (17.9%) severe | 1.06 (0.81–1.38) | .680 | 0.91 (0.68–1.23) | .546 | ||
| Acid‐suppressive medication | 56 (4.5%) | 21 (1.7%) | 2.75 (1.66–4.58) | <.001 | 2.60 (1.48–4.53) | .001 |
| 36 (4.9%) mild | 3.05 (1.76–5.26) | <.001 | 3.06 (1.70–5.55) | <.001 | ||
| 20 (3.8%) severe | 2.35 (1.26–4.37) | .007 | 1.99 (1.01–3.94) | .048 | ||
| Antithrombotics | 98 (7.8%) | 80 (6.4%) | 1.25 (0.92–1.70) | .156 | 0.70 (0.49–1.00) | .052 |
| 34 (4.7%) mild | 0.72 (0.48–1.08) | .114 | 0.53 (0.34–0.84) | .007 | ||
| 64 (12.3%) severe | 2.06 (1.46–2.91) | <.001 | 0.86 (0.58–1.28) | .457 | ||
| Antihypertensives | 363 (29.0%) | 95 (7.6%) | 4.99 (3.92–6.36) | <.001 | 3.66 (2.78–4.83) | <.001 |
| 153 (20.9%) mild | 3.24 (2.46–4.26) | <.001 | 2.69 (1.97–3.69) | <.001 | ||
| 210 (40.3%) severe | 8.25 (6.28–10.84) | <.001 | 5.13 (3.75–7.02) | <.001 | ||
| Intestinal anti‐inflammatory agents | 16 (1.3%) | 10 (0.8%) | 1.61 (0.73–3.57) | .238 | 1.65 (0.66–4.09) | .284 |
| 9 (1.2%) mild | 1.55 (0.63–3.84) | .340 | 1.78 (0.66–4.77) | .254 | ||
| 7 (1.3%) severe | 1.70 (0.64–4.48) | .286 | 1.45 (0.47–4.45) | .513 | ||
| Total | 1252 (100) | 1256 (100) |
adjusted for maternal age, parity, type of delivery, body mass index (BMI), smoking, diagnosed hypertension and diabetes or gestational diabetes (GDM). CI, confidence interval; NSAID, nonsteroidal anti‐inflammatory drug; OR, odds ratio
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 32). 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.
4. DISCUSSION
We accessed the KUH Birth Register to analyse drug use in pregnant women suffering from preeclampsia to clarify the connection between the use of drugs and preeclampsia. This is the first study to evaluate as many as 16 groups of drugs during pregnancy and describe differences in drug use between women with preeclampsia and control women.
Our analysis revealed that approximately 50% of the women had used at least 1 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 were adjusted for many specific confounders such as maternal age, BMI and prepregnancy comorbidities such as diabetes and hypertension, the maternal use of 4 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 see26, but the role of paracetamol in the development of preeclampsia will need to be clarified in further studies. Rebordosa and coworkers25 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, attention deficit hyperactivity disorder and lower intelligence quotient in the developing foetus.27, 28, 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 study6 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 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 a known risk factor for preeclampsia35 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, 38, 39, 40, 41, 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 = 1252), which enabled us to evaluate the use of several different groups of drugs and to analyse their use according to the severity of disease. The KUH Birth Register included information on self‐reported use of drugs during pregnancy, which also covered 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 acetylsalicylic acid, which could be prescribed for the prophylaxis of preeclampsia.
In 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 there are other underlying factors that would reveal the potential role of drugs in the development of preeclampsia.
COMPETING INTERESTS
There are no competing interests to declare.
CONTRIBUTORS
All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data. All authors have been involved in drafting the manuscript or revising it critically for important intellectual content. All authors have given final approval of the version to be published. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Sahlman H, Koponen M, El‐Nezami H, Vähäkangas K, Keski‐Nisula L. Maternal use of drugs and preeclampsia. Br J Clin Pharmacol. 2019;85:2848–2855. 10.1111/bcp.14117
The authors confirm that the PI for this paper is Prof. Leea Keski‐Nisula and that she had direct clinical responsibility for the patients.
DATA AVAILABILITY STATEMENT
Research data are not shared.
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. [DOI] [PubMed] [Google Scholar]
- 2. Lahesmaa‐Korpinen A‐M. Raskaudenaikainen lääkkeiden käyttö Suomessa. SIC Lääketietoa Fimeasta. 2013;1:48‐52. [Google Scholar]
- 3. Berard A, Sheehy O. The Quebec pregnancy cohort‐‐prevalence of medication use during gestation and pregnancy outcomes. PLoS One. 2014;9(4):e93870. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 9. Hod T, Cerdeira AS, Karumanchi SA. Molecular mechanisms of preeclampsia. Cold Spring Harb Perspect Med. 2015;5(10). 10.1101/cshperspect.a023473 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. English FA, Kenny LC, McCarthy FP. Risk factors and effective management of preeclampsia. Integr Blood Press Control. 2015;8:7‐12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Avalos LA, Chen H, Li DK. Antidepressant medication use, depression, and the risk of preeclampsia. CNS Spectr. 2015;20(1):39‐47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Palmsten K, Huybrechts KF, Michels KB, et al. Antidepressant use and risk for preeclampsia. Epidemiology. 2013;24(5):682‐691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 18. Tooke L, Riemer L, Matjila M, Harrison M. Antiretrovirals causing severe pre‐eclampsia. Pregnancy Hypertens. 2016;6(4):266‐268. [DOI] [PubMed] [Google Scholar]
- 19. Wimalasundera RC, Larbalestier N, Smith JH, et al. Pre‐eclampsia, antiretroviral therapy, and immune reconstitution. Lancet. 2002;360(9340):1152‐1154. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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‐e314. [DOI] [PubMed] [Google Scholar]
- 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‐e154. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 32. Dagli U, Kalkan IH. Treatment of reflux disease during pregnancy and lactation. Turk J Gastroenterol. 2017;28(Suppl 1):S53‐S56. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 35. Weissgerber TL, Mudd LM. Preeclampsia and diabetes. Curr Diab Rep. 2015;15(3):9. ‐015‐0579‐4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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 [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 38. Krassas G, Karras SN, Pontikides N. Thyroid diseases during pregnancy: a number of important issues. Hormones (Athens). 2015;14(1):59‐69. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PubMed] [Google Scholar]
- 40. Negro R, Stagnaro‐Green A. Diagnosis and management of subclinical hypothyroidism in pregnancy. BMJ. 2014;349(oct06 4):g4929. [DOI] [PubMed] [Google Scholar]
- 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;32(17):2883‐2888. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Data Availability Statement
Research data are not shared.