American Journal of Obstetrics and Gynecology (2006) 194, 9616

www.ajog.org

Selective serotonin reuptake inhibitors and adverse pregnancy outcomes

Shi Wu Wen, MB, PhD,a,b,c,* Qiuying Yang, MD, PhD,a,b,d Peter Garner, MD,y William Fraser, MD, MSc,e Olufemi Olatunbosun, MD,f Carl Nimrod, MD,a,b Mark Walker, MSc, MDa,b
OMNI Research Group, Department of Obstetrics and Gynecology,a University of Ottawa Faculty of Medicine; Ottawa Health Research Institute, Clinical Epidemiology Programb; Department of Epidemiology and Community Medicine,c University of Ottawa Faculty of Medicine; McLauhlin Centre for Population Health Risk Assessment, Institute of Population Health,d University of Ottawa, Ottawa, Ontario, Canada; Department of Obstetrics and Gynecology, University of Montreal Faculty of Medicine,e Montreal, Quebec, Canada; Department of Obstetrics and Gynecology, University of Saskatchewan Faculty of Medicine,f Saskatoon, Saskatchewan, Canada
Received for publication December 2, 2005; revised January 16, 2006; accepted February 12, 2006

KEY WORDS
Depression Serotonin reuptake inhibitor Pregnancy Fetus Birth defect Low birth weight Preterm birth Fetal death Seizure

Objective: The purpose of this study was to assess the safety of the use of selective serotonin reuptake inhibitors in pregnancy. Study design: We carried out a retrospective cohort study of 972 pregnant women who had been given at least 1 selective serotonin reuptake inhibitor prescription in the year before delivery and 3878 pregnant women who did not receive selective serotonin reuptake inhibitors and who were matched by the year of the infants birth, the type of institute at birth, and the mothers postal code from 1990 to 2000 in the Canadian province of Saskatchewan. Results: The risks of low birth weight (adjusted odds ratio, 1.58; 95% CI, 1.19, 2.11), preterm birth (adjusted odds ratio, 1.57; 95% CI, 1.28, 1.92), fetal death (adjusted odds ratio, 2.23; 95% CI, 1.01, 4.93), and seizures (adjusted odds ratio, 3.87; 95% CI, 1.00, 14.99) were increased in infants who were born to mothers who had received selective serotonin reuptake inhibitor therapy. Conclusion: The use of selective serotonin reuptake inhibitors in pregnancy may increase the risks of low birth weight, preterm birth, fetal death, and seizures. 2006 Mosby, Inc. All rights reserved.

Supported by a grant from The Hospital for Sick Kids Foundation (grant #XG-02-098) and by a research and development Research Allowance from The Canadian Institutes for Health Research (S.W.W.). Based in part on nonidentiable data provided by the Saskatchewan Department of Health. The interpretation and conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Department of Health. Presented at the 26th Annual Meeting of the Society for Maternal Fetal Medicine, January 30-February 4, 2006, Miami, FL. y Deceased. * Reprint requests: Shi Wu Wen, MB, PhD, OMNI Research Group, Department of Obstetrics & Gynecology, University of Ottawa, Faculty of Medicine, 501 Smyth Rd, Box 241, Ottawa, Ontario, Canada, K1H 8L6. E-mail: swwen@ohri.ca 0002-9378/$ - see front matter 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2006.02.019

962 Depression is a common disorder among women of childbearing age.1 Selective serotonin reuptake inhibitors (SSRIs) generally are considered the rst-line drug therapy in most patients with depression.2 More recently, increased attention has been paid to the sideeects of SSRIs.3,4 The fetal risk of SSRIs cannot be excluded (SSRIs are labeled category C: studies in animals have shown fetal adverse eects, but there are no controlled studies in pregnant women, or studies in women and animals are not available, by the Food and Drug Administration for drug use in pregnancy).5 Previous studies have examined the safety of SSRIs in pregnancy.6-17 Most studies have reported relatively consistent ndings on the eects of SSRIs in pregnancy on neonatal withdrawal syndrome, low birth weight, and preterm birth,6-12 whereas a possible teratogenic eect of SSRIs in pregnancy has been reported inconsistently.7,13-17 There were possible selection bias and recall bias in these studies, however. The objective of the current study was to make a comprehensive assessment of the safety of prescription SSRIs in pregnancy (including periconception period), with the use of a large population database.

Wen et al digits of the mothers postal code were selected from the remainder of the database. These three variables are easy to be matched and potentially associated with adverse pregnancy outcomes. Because they are general determinants of adverse pregnancy outcomes, matching by these variables will be less likely to result in overmatching as compared with more specic determinants. Adverse pregnancy outcomes that were assessed in this study included preeclampsia, gestational diabetes mellitus, placenta previa, placental abruption, low birth weight (birth weight !2500 g), preterm birth (gestational age, !37 completed weeks), major and minor birth defects, fetal death, severe neonatal morbidity (that included sepsis, seizures, and the use of mechanical ventilation), and infant death. Fetal death is dened as a stillbirth with a birth weight of R500 g or a gestational age of R20 weeks. Birth defects were coded by the International Classication of Diseases 9th Revision (ICD-9)19 codes and were ascertained up to 1 year of age. We separated major birth defects (eg, neural tube defects, major cardiovascular defects, urinary tract defects, oral clefts, limb reduction, multiple anomalies, and other major structural defects [full list available on request]) from minor ones. Sepsis and seizures were coded by ICD-9 codes, and mechanical ventilation was coded by the Canadian Classication of Diagnostic, Therapeutic, and Surgical Procedures.20 Infant death was dened as deaths that occurred %1 year of age. We have hypothesized that differences in adverse maternal outcomes between SSRI users and none-users, if any, are attributable to the differences in maternal health status and demographic characteristics between the 2 groups, instead of the effect of SSRIs. Therefore, we included adverse maternal outcomes in our analysis to test this hypothesis.

Material and methods

Study population
We conducted a retrospective cohort study, using the linked maternal/infant/prescription records from the Canadian province of Saskatchewan. The Saskatchewan Health databases include prescription information on most residents (O90%) of the province of Saskatchewan.18 We rst identied all live births and stillbirths in Saskatchewan to Saskatchewan residents between January 1, 1990, and December 31, 2000 (SSRIs were introduced into the Saskatchewan Formulary in 1989). These data were then linked with physician and hospital data les to compile services for infants up to 1 year after birth and with the registry le to identify any deaths within that 1-year period. Mothers were identied for each birth. For each mother, physician services, hospital separation, and outpatient prescription drug information was compiled for the period beginning 1 year before the date of birth. Pregnant women with at least 1 SSRI prescription that was dispensed in the 1-year period before delivery were selected as the exposed group. According to Saskatchewan provincial law, Saskatchewan Health cannot release the health care information of an entire segment of population (eg, all pregnant women during a dened period of time), even if all personal identiers are removed. To respect the provincial law and to maximize the study power, a 4:1 nonexposed (ie, no SSRIs) per exposed subject, with individual matching by year of birth (within 2 years), by type of institute at birth (base, community, and tertiary centre), and by the rst 3

Statistical analysis
We rst described the distribution of baseline characteristics of the study subjects. We then presented the prescription of SSRIs, in individual category and in combination, and compared the occurrence of various adverse pregnancy outcomes between the 2 study groups. Multiple logistic regression analyses were performed to examine the independent associations between SSRIs and adverse pregnancy outcomes. Independent variables that were included in the regression models were of SSRIs in pregnancy, maternal age, receipt of provincial social assistance (an indication of poverty), drug dependence (ICD-9 codes: 291 [alcohol psychoses], 292 [drug psychoses], 303 [alcohol dependence syndrome], 304 [drug dependence], 305 [nondependent abuse of drugs], and 648.3 [drug dependence complicating pregnancy]), parity, and multigestation. For the use of mechanical ventilation and infant death, we further adjusted for gestational age.

Wen et al
Table I Comparison of baseline characteristics between exposed (n = 972) and nonexposed (n = 3878) groups, Saskatchewan, 1989-2000 Characteristic Maternal age (y)* !19 20-29 30C Social assistance* Drug dependence* Parity R1* Multigestationy Male sex
* P ! .01. y P ! .05.

963
Table II SSRIs Category of recorded dispensation of prescription Dispensation with SSRIs (n) Including dispensation Excluding dispensation with other categories with other categories of SSRIs of SSRIs 13 533 121 325 226 1 440 83 238 169

Exposed (n) 66 494 412 225 17 655 37 487 (6.8%) (50.8%) (42.4%) (23.2%) (1.8%) (67.39%) (3.81%) (50.1%)

Nonexposed (n) 303 2187 1388 482 16 2409 92 1977 (7.8%) (56.4%) (35.8%) (12.4%) (0.4%) (62.12%) (2.37%) (51.0%) Category Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline

Results
A total of 972 pregnant women with at least 1 SSRI prescription being dispensed in 1 year before delivery were identied from the 1990 to 2000 Saskatchewan linked mother/infant database. From the remainder of the maternal/infant database, 3878 pregnant women (10 subjects less than planned because not enough nonexposed women could be identied from the database according to the matching conditions) who had not received SSRIs in 1 year before delivery were selected. Exposed women were older, were more likely to receive social assistance, were more likely to have a diagnosis of drug dependence, had a higher parity, and had a higher rate of multigestation (Table I). Fluoxetine was the most frequently prescribed SSRI, with paroxetine, sertraline, uvoxamine, and citalopram, in declining order. Most of the patients used only 1 category of SSRI (Table II). The risks of low birth weight, preterm birth, fetal death, and seizures were increased in infants who were born to mothers with SSRI therapy (Table III). On the other hand, no increased risks of birth defects and maternal complications were observed (Table III).

Comment
Our population-based study found that the risks of low birth weight, preterm birth, fetal death, and seizures were increased in infants who were born to mothers who had received prescription SSRIs than in infants who were born to mothers without such exposure. On the other hand, no association between prenatal SSRIs and birth defects and adverse maternal outcomes was observed. Our data also described the patterns of SSRI use by categories of SSRIs in routine practice, which provide useful feedback information for clinicians.

Our study has several strengths. It is based on the population in Saskatchewan (O90% of the residents are eligible for provincial drug coverage), which reects the routine practice and reduces selection bias. Consistent data collection and coding procedures across dierent service sectors in the province and checks for eligibility of benets are built into claims processing systems, which contribute to the quality in a database that met the research requirement.18 The cohort study design allows an assessment of several outcomes simultaneously, which is not only more comprehensive in terms of safety but also helps to assess the validity of the study ndings. We have hypothesized that SSRIs should not be associated with increased risk of adverse maternal outcomes. The inability to nd an association between SSRIs and adverse maternal outcomes suggests that the observed association between SSRIs and infant outcomes may be true eects of the drug, instead of dierences in population prole of the 2 study groups. We have used a combination of matching and multiple regression analysis to reduce potential confounding by maternal demographic and socioeconomic factors. We have been able to follow the infants to 1 year of age, which can have a more complete ascertainment of birth defects. Drug exposure information in our data did not depend on the womans memory; hence, there was no possibility of recall bias.21 Limitations in our study should not be overlooked. Our study is an observational one in nature, which cannot guarantee comparability between the exposed and nonexposed groups. For example, drug dependence was more common among women with SSRI therapy, and drug dependence alone is a signicant risk factor for perinatal death. Also, it is dicult to separate the eect of maternal depression on perinatal death from the eect of prenatal SSRI use. Although we have tried to adjust for potential confounding by matching and regression analysis, the adjustment may be not sucient, and residual confounding may still exist. Our study relied on an existing database, and some important variables such as smoking and drinking are not available and cannot be considered in data analysis. Administrative data lack clinical details. For example, cause and

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Table III Outcome Preeclampsia Urinary infection Gestational diabetes mellitus Placental previa Placental abruption Birth weight !2500 g Gestational age !37 wk Major structural anomalies Minor structural anomalies Fetal death Infant death Sepsis Seizures Mechanical ventilation

Wen et al
Comparison of maternal, fetal and infant outcomes between exposed (n = 972) and nonexposed (n = 3878) groups Exposed group (n) 66 12 32 9 30 87 188 20 35 11 15 10 4 34 (6.8%) (1.2%) (3.3%) (0.9%) (3.1%) (9.0%) (19.3%) (2.1%) (3.6%) (1.1%) (1.5%) (1.0%) (0.4%) (3.5%) Nonexposed group (n) 223 31 83 27 69 206 465 76 133 17 22 23 5 87 (5.8%) (0.8%) (2.1%) (0.7%) (1.8%) (5.3%) (12.0%) (2.0%) (3.4%) (0.4%) (0.6%) (0.6%) (0.1%) (2.2%) Adjusted odds ratio (95% CI) 1.20 1.53 1.31 1.20 1.56 1.58 1.57 0.98 1.02 2.23 1.96 1.41 3.87 1.14 (0.90, (0.76, (0.86, (0.55, (0.99, (1.19, (1.28, (0.59, (0.69, (1.01, (0.97, (0.65, (1.00, (0.74, 1.61) 3.09) 2.01) 2.60) 2.46) 2.11) 1.92) 1.64) 1.51) 4.93) 3.94) 3.06) 14.99) 1.75)

timing of fetal death are essential for clinically relevant information, but these variables are not available in the data. Data on the drug doses, treatment regimens, and duration of treatment are unavailable. Reporting of neonatal deaths would be more reective of obstetric factors. However, infant death was recorded in the database instead, and no record on date of death was available. As a result, neonatal deaths cannot be separated from postneonatal deaths. Although our overall study sample was quite large, the numbers became smaller when stratied by specic SSRI. During data analysis, we tried to analyze the eects of specic SSRIs on adverse pregnancy outcomes. However, we chose not to report it because the numbers were too small to be clinically signicant. Administrative data are also prone to a certain degree of coding errors. Furthermore, there is no compliance information in Saskatchewans prescription drug le. Some patients who received the SSRIs from the pharmacy but who did not actually ingest them will be misclassied as exposure. We have not been able to deal with the problems that are caused by coding errors and noncompliance. However, a recent study of Saskatchewans database found high sensitivity, specicity, positive predictive, and negative predictive values for diagnosis of depression,22 which lends validity to this data set. Because information in Saskatchewans prescription drug le is taken from the pharmacists record instead of physicians prescription, the issue of noncompliance may be less severe. The only way to obtain data on actual drug consumption in pregnancy is by the mothers report. There is a trade-o between maternal self-reporting and the pharmacists record. A recent European study found that mothers were able to report only 76% of drug groups, and when data on the exact name of the drug was studied, this gure dropped to 52%.23 On the other hand, of the drugs that were dispensed by the pharmacy,

6% were not used (noncompliance). Misclassications caused by either coding error or noncompliance may have occurred randomly, which tends to attenuate the observed eects.21 Previous studies have assessed the safety of SSRIs in pregnancy, most of which were based on selective patient populations and relied on patient recall for drug information. Three Toronto studies did not nd an increased risk of adverse fetal and infant outcomes with prenatal SSRI exposure,13-15 although a California cohort study found an increased risk of preterm birth, admission to special care nursery, poor neonatal adaptation, and lower mean birth weight for infants with prenatal SSRI exposure.7 Hendrick et al16 found that maternal use of high doses of uoxetine (40-80 mg/d) throughout pregnancy may be associated with a risk for low birth weight. Several studies found increased risks of neonatal withdrawal syndrome,8,9 disruptions in a wide range of neurobehavioral outcomes,10 and lower Bayley psychomotor development indexes and Behavioral Rating Scale11 in infants with in utero SSRI exposure than unexposed children. A meta-analysis by Lattimore et al24 found that the summary odds ratios were 1.85 (95% CI, 0.79, 4.29), 3.64 (95% CI, 1.01, 13.08), 3.30 (95% CI, 1.45, 7.54), and 4.08 (95% CI, 1.20, 19.93), respectively, for prematurity, low birth weight, neonatal intensive care unit admission, and poor neonatal adaptation. Study results on the association between prenatal SSRIs use and birth defects were controversial. The California cohort study found a weak association between SSRIs and birth defects (an increased risk of presence of R3 minor anomalies [dened as no cosmetic or functional importance]).7 Hendrick et al16 examined the neonatal outcomes in infants who were born to 138 mothers who were treated by SSRIs during pregnancy and found that the rate of congenital anomalies

Wen et al was 1.4%, which is quite comparable to the general population rate. A recent review of the Swedish Medical Birth Registry that involved 4291 infants with prenatal SSRI exposure found no increased risk of birth defects,17 although a similar population-based cohort study in 4 Danish counties that involved 1054 SSRIexposed pregnancies found moderately increased risks for all birth defects (odds ratio, 1.4; 95% CI, 1.1-1.9) and congenital cardiac defects (odds ratio, 1.6; 95% CI, 1.0-2.6).25 On the other hand, a large case-control study from the United States that involved 5357 infants with birth defects and 3366 normal control infants found a substantially increased risk for prenatal SSRI therapy on omphalocele (n = 161 infants), with an odds ratio of 3.0 (95% CI, 1.4-6.1), particularly for paroxetine exposure (odds ratio, 6.3; 95% CI, 2.0-19.6).26 A postmarketing surveillance study by GlaxoSmithKline Inc found that rst-trimester exposure to paroxetine was associated with 2.2-fold increased risk of birth defects, which has prompted the company to change the labeling of their paroxetine (www.gsk.ca/en/health_info/). Unfortunately, no information on paroxetine was available in the 2 large European cohort studies, and the number of paroxetine in our data was too small to generate meaningful results. The mechanisms underlying the association between prenatal SSRI exposure and adverse fetal and infant outcomes remain unclear. SSRIs increase the brain serotonin levels, which is the suggested mode of therapeutic action.2 The increased serotonin level may impact the central nervous system of the developing fetus. In addition, laboratory investigations have shown that serotonin had a strong vasoconstriction eect on human umbilical arteries.27,28 The increased serotonin level that resulted from the maternal ingestion of SSRIs may increase the risk of adverse outcomes that are sensitive to the placental blood ow, such as intrauterine growth retardation and preterm births, which has been observed consistently in various studies, including the current one. The increased risk of perinatal death in infants with prenatal SSRI exposure, at least in part, may be the result of the eects of SSRIs on prematurity and growth retardation. It is unclear whether similar mechanisms exist for the association between prenatal SSRI exposure and birth defects. Given the possible fetal risk of prenatal SSRI exposure, the risks and benets of SSRIs for women of reproductive age with severe depression should be considered. A balanced approach to simultaneously weigh the need to control maternal depression against the potential risk of fetal exposure should be taken with the individual patient. A randomized controlled trial may be the ultimate tool to resolve this issue. However, it may not be ethical to conduct a randomized trial on potential side eects of SSRIs. Large-scale, population-based

965 cohort studies may be the only alternative. In the meantime, women whose condition requires treatment with SSRIs should be fully informed about the potential risk of these drugs; consultation with specialists who are experienced in treating depression may be needed. For those women who are exposed, increased fetal surveillance should be considered.

Acknowledgments
We thank Drs Sarah MacDonald and Dean Fergusson for critical appraisal of an earlier version of the manuscript.

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