Hypertension in Pregnancy, 26:179187, 2007

Copyright Informa Healthcare

ISSN: 1064-1955 print / 1525-6065 online
DOI: 10.1080/10641950701204554

Exposure to Amlodipine in the

1525-6065
1064-1955
LHIP
Hypertension in Pregnancy
Pregnancy, Vol. 26, No. 2, March 2007: pp. 121

First Trimester of Pregnancy

and During Breastfeeding
Amlodipine
Ahn et al. in Pregnancy

Hyun Kyong Ahn,1,2,3 Alejandro A. Nava-Ocampo,4,5

Jung Yeol Han,1,2,3 June Seek Choi,1,2,3 Jin Hoon Chung,2,3
Jae Hyug Yang,2,3 Mi Kyoung Koong,3 and Chong Taik Park3
1
The Korean Motherisk Program, Cheil Hospital & Womens Health-care Center,
Kwandong University School of Medicine, Seoul, Korea
2
Division of Maternal-Fetal Medicine, Cheil Hospital & Womens Health-care Center,
Kwandong University School of Medicine, Seoul, Korea
3
Department of Obstetrics and Gynecology, Cheil Hospital & Womens Health-care
Center, Kwandong University School of Medicine, Seoul, Korea
4
Division of Clinical Pharmacology & Toxicology, The Hospital for Sick Children
Toronto, Canada
5
PharmaReasons, Toronto, Canada
Objective: To assess the fetal outcome of three hypertensive women exposed to amlo-
dipine. 5 mg/day, in the first trimester of pregnancy. Case 1: The patient was treated
with amlodipine until 7 weeks of gestation. She was also exposed to levosulpiride, alumi-
num hydroxide gel, magnesium carbonate, and Ginkgo biloba. At 38+3 weeks of pregnancy,
she delivered a 3750 g healthy female baby, and restarted taking amlodipine, 5 mg/day,
while exclusively breastfeeding her daughter. At three months of age, the infant was
healthy. Case 2: The patient was treated with amlodipine from 2+2 to 3+4 weeks of preg-
nancy. Her treatment was modified to atenolol until the week 6+4 weeks, when she declined
any antihypertensive treatment. At 39+4 weeks of pregnancy, the patient delivered a 2600 g
baby. At 20 months old, the baby presented with intellectual delay and weakness in the
left arm and hand grasp. These neurological alterations were not attributed to her expo-
sure to amlodipine early in utero. Case 3: The patient was treated with amlodipine from
7+6 to 12 weeks of pregnancy. She was also taking sucralfate and lorazepam. At 12 weeks
of amenorrhea, ultrasound revealed a 15.3 mm, single fetal pole in the gestational sac
without cardiac activity. She underwent dilatation and evacuation of a dead
embryo. Conclusion: As reported with other calcium-channel blockers, amlodipine does
not appear to be teratogenic and it appears to be compatible with breastfeeding.

Keywords Antihypertensive agents, Calcium channel blockers, Maternal-fetal relations.

Address correspondence to Jung Yeol Han, M.D., The Korean Motherisk Program,
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Cheil
Hospital, Kwandong University School of Medicine, 119 Mookjung-Dong, ChoongGu,
Seoul 100380, Korea. E-mail: hanjungyeol@yahoo.com
180 Ahn et al.

INTRODUCTION
Cardiac and cerebrovascular diseases are the leading causes of death among
Asian women (1). Amlodipine is a calcium-channel antagonist with proven
efficacy for treating hypertension in adult and pediatric patients (24). Almost
a decade ago, a prospective, multicenter cohort study concluded that calcium
blockers did not represent a major teratogenic risk (5). A subsequent case-con-
trol study further supported that the exposure to calcium channel antagonists
in early pregnancy was not associated with an increased rate of major birth
defects (6). However, no cases of amlodipine exposure in pregnancy were
reported in either of these two studies. Although this reassuring information
may be extrapolated to any calcium channel antagonist, it would be desirable
to have information that may guide our counseling to women specifically
exposed to amlodipine during pregnancy.
As part of a department of obstetrics and gynecology, the Korean Mother-
isk Program is a unique service that provides teratogen information as well as
an obstetric follow-up and perinatal attention to any patient exposed to poten-
tial teratogens. We identified three hypertensive pregnant women who were
treated with amlodipine and who were prospectively followed. We aimed to
report their obstetric and fetal outcomes. One patient was also treated with
amlodipine while breastfeeding her infant.

CASES

Case 1
A 35-year-old hypertensive pregnant woman (gravida 4, para 1, spontane-
ous abortion 1, therapeutic abortion 1) had been treated with amlodipine, 5
mg/d for 36 months (Table 1). The patient was also taking levosulpiride (as a
prokinetic agent), amoxicillin, aluminum hydroxide gel, and magnesium car-
bonate for treatment of acute gastritis, and Ginkgo biloba as a peripheral
vasodilator. In addition, her husband, a renal transplant recipient, had been
taking cyclosporine as an immunosuppressant for five years.
At the time she was examined at the Korean Motherisk Program, she was
seven weeks into her pregnancy as calculated from the first day of her last
menstrual period and normotensive. She reported having gone to saunas
three times within the previous seven weeks. The patient decided not to con-
tinue with any of her medications, including her antihypertensive agent, but
agreed to close monitoring of her blood pressure and clinical and obstetric
health status. Throughout her pregnancy, her blood pressure was always
observed within normal ranges (e.g., 137/89 mmHg at 7 weeks, 129/87 mm Hg
at 12 weeks, 127/80 mm Hg at 17 weeks, 131/78 mm Hg at 23 weeks, 126/74
mm Hg at 26 weeks, and 136/87 mm Hg at 38 weeks of gestation). Because of
 Table 1: Demographic and maternal characteristics of women inadvertently exposed to amlodipine in the first trimester
of pregnancy.

Treatment during
Dose Duration of Pregnancy
Case Diagnosis Age (yr) G;P;A Medications (mg/day) Treatment (weeks + days) Other Exposures

1 Essential 35 4;1;3 Amlodipine 5 36 months Until week 7 Saunas

hypertension
Levosulpride 50 5 months Idem Husband taking
(intermittently) cyclosporine
after renal
transplantation
for 5 yr ago
Amoxicillin 500 5 months Idem
(intermittently)
Al(OH)3 gel 500 5 months Idem
(intermittently)
MgCO3 320 5 months Idem
(intermittently)
Ginkgo 80 5 months Idem
biloba (intermittently)
2 Essential 32 3;1;1 Amlodipine 5 1 week Until week 2+2 Brain CT scan
hypertension
+3
Atenolol 50 1 month From 2 to Chest X-ray
6+4 weeks
3 Polycystic 36 2;1;0 Amlodipine 5 1 month From 7+6 to
kidney 12 weeks
disease and
hypertension
Sucralfate 250 1 month Idem Alcohol
Imidapril 5 21 months Until week 7+5
Lorazepam 0.5 21 months Idem
Barnidipine 10 21 months Idem

G=gravida; P=para; L=living baby; A=abortions; Al(OH)3 gel=aluminum hydroxide gel; MgCO3=magnesium carbonate.

181
182 Ahn et al.

her age, we suggested that she undergo an amniocentesis, but she declined.
The triple marker screen was negative. Normal fetal growth and no evidence of
major congenital malformations were observed in a level II ultrasound per-
formed at 23 weeks of pregnancy (Table 2). Because of her history of a cesarean
section two years earlier, the patient underwent a second cesarean section at
38+3 weeks of pregnancy. The female baby weighing 3750 g (75th to 95th percen-
tile), with a head circumference of 34.6 cm (75th percentile), and an Apgar score
of 9 at 1 minutes and 10 at 5 minutes after birth, was born without any evi-
dence of gross malformations, as reported by a pediatrician. The percentile ref-
erence values of weight and head circumference for female newborns were
obtained from local reference tables (7).
On the day 5 postpartum, the patient was discharged from the hospital
without any medical or obstetric complications. At that time, her blood pres-
sure was 160/100 mm Hg. Because the patient had reported headache and her
diastolic blood pressure remained 100 mm Hg for 2 weeks of postpartum, the
patient restarted her treatment with amlodipine (5 mg/day) and decided to
exclusively breastfeed her baby, who was clinically monitored by a pediatri-
cian. The patients primary hypertension was reported to be under good con-
trol by a cardiologist. At 3 months of age, the baby weighed 6.3 kg (25th to
50th percentile), was healthy, and showed a normal neurodevelopment accord-
ing to that expected for her age, as judged by the careful clinical examination by
a pediatrician (Table 2). The mother (weight, 72.4 kg; height, 160 cm; BMI, 28.3
kg/m2) continued breastfeeding and taking amlodipine (5 mg/day) while under
continuing follow-up with her cardiologist.

Case 2
A 32-year-old hypertensive woman (gravida 3, para 1, therapeutic abor-
tion 1) underwent a brain CT scan and a chest X-ray at 2+2 weeks of preg-
nancy due to severe headache and vomiting; both results were reported as
normal. During clinical evaluation, her blood pressure was found to be 170/
110 mm Hg on average, and therefore she was treated with amlodipine, 5 mg/
day. The patient was treated with this antihypertensive agent from weeks 2+2
to 3+4 of gestation (Table 1). Since her blood pressure was repeatedly found at
170/110 mm Hg, the antihypertensive treatment was modified to atenolol
which she received until the week 6+4 of pregnancy when she started showing
signs of pregnancy. A positive urine test and identification of fetal heart beat
by ultrasound confirmed her pregnancy, and the patient declined to continue
her antihypertensive treatment. The time of exposure to amlodipine was
based on the first day of her last menstrual period.
The triple marker screen was negative and at 22 weeks of gestation, a
level II ultrasound examination showed a fetus with small gastric chamber
and mild ascites in the fetus lower abdomen. The patients blood pressure was
 Table 2: Fetal outcome and long term evaluation of babies exposed early in utero to amlodipine.

Duration of
Triple Test Pregnancy Mode of Birth 1- and 5-Min
Case Ultrasound Blood Screen (weeks + days) Delivery Sex Weight (g) Apgar Score Follow-up

1 At 23 weeks: normal At 17 weeks: 38+3 C-section Female 3,570 9, 10 At 3 months old:

(level-II ultrasound negative 6.3 kg, healthy
examination)
2 At 22 weeks: mild ascites, At 17 weeks: 39+4 Vaginal Female 2,600 9, 10 At 20 month old:
small gastric chamber negative weakness of
(level-II ultrasound left arm and
examination) intelectual
delay.
3 At 12 weeks: G-sac 12 Dilatation and
38.8mm (estimated GA: evacuation
9.2 weeks), a single
fetal pole of 15.3 mm
(estimated GA: 7.5
weeks) without cardiac
activity

Amniocentesis was not performed in any patient.

183
184 Ahn et al.

maintained under relatively good control throughout her pregnancy (e.g., 132/
89 mmHg at 9 weeks and 139/93 mm Hg at 25 weeks of pregnancy). At 39+4
weeks of pregnancy, the patient vaginally delivered a 2600 g female baby
[below the 10th percentile (7)], Apgar score of 8 at 1 minute and 9 at 5 minutes.
A careful physical examination detected no gross malformations or abnormal-
ities. However, at 20 months old, the infant weighed 10 kg [below the 10th per-
centile (7)] and had intellectual delay as well as weakness of her left arm and
hand grasp (Table 2). The motor activity and movement coordination of her
legs was found to be normal. The patient and her daughter were lost of follow-
up while trying to identify the etiology of the functional abnormalities
observed in her left upper extremity.

Case 3
A 36-year-old pregnant woman (gravida 2, para 1) with a polycystic kidney
disease and hypertension was being treated with an angiotensinconverting
enzyme inhibitor (imidapril, 5 mg/day) plus a calcium channel blocker
(barnidipine hydrochloride, 10 mg/day) (Table 1). However, her diastolic
blood pressure remained 100 mm Hg. Without signs of pregnancy, her
treatment was modified to amlodipine (5 mg/day) at 7+6 weeks of pregnancy
(gestational age was estimated from the first day of her last menstrual
period). At 8+2 weeks of amenorrhea, ultrasound revealed a single embryo
pole of 18 mm with normal cardiac activity. The patient was also taking
sucralfate and lorazepam for acute gastritis and anxiety. She reported that
occasionally drank approximately 1 ounce of alcohol. The patient continued
her treatment with amlodipine.
At 12 weeks of amenorrhea, an ultrasound examination showed the gesta-
tional sac containing a 15.3 mm single fetal pole without cardiac activity
(Table 2). The mean diameter of the sac was 38.8 mm, and the estimated ges-
tational age was 9+1 weeks. She underwent dilatation and evacuation of a
dead embryo.

DISCUSSION
This case series of three women appears to be the first reporting the exposure
to amlodipine in the first trimester of pregnancy. Two of the babies were born
without any evidence of gross malformations, although one showed a func-
tional alteration of the left arm at 20 months of age that would not be related
to the maternal exposure to amlodipine. We also report the first case of a
breastfeeding woman taking amlodipine.
A prospective, multicenter cohort study suggested that calcium blockers
(including nifedipine, verapamil, diltiazem, nimodipine, and felodipine) do not
represent a major teratogenic risk (5). In addition, a case-control study evaluating
 Amlodipine in Pregnancy 185

the exposure to calcium channel blockers (including verapamil, nifedipine,

and felodipine) in early pregnancy showed no increased risk for limb defects or
other major congenital abnormalities (6). None of these studies reported any
case on amlodipine. However, the observations reported by the two studies are
not in conflict with our case series. Therefore, despite the limitation of reports
or large studies including all the drugs belonging to this group of antihyper-
tensive drugs, we may reasonably reassure that there is no evidence of an
increased teratogen risk when counseling pregnant women exposed to these drugs.
Fetal growth is regulated by complex mechanisms in which hormonal and
vascular changes play a key role (810). Hypertension may adversely modify
the vascular supply to the placenta and favor adverse effects in the fetus. It
has been considered that teratogenicity of calcium channel blockers in experi-
mental animal models is mediated by a decreased uteroplacental blood flow
(11). However, administration of amlodipine did not increase the incidence of
congenital defects when administered throughout organogenesis in rats and
rabbits (12). In addition, administration of amlodipine to rats from day 17 of
gestation through parturition, the highest dose studied (10 mg/kg/day) was
lethal to some dams but none developmental defects were observed in the off-
spring (12). Similar findings were reported from a high dose study in pregnant
mice (13).
In patients with gestational hypertension, blood pressure reduction with
antihypertensive therapy was associated with no changes in umbilical artery or
maternal brachial artery Doppler systolic/diastolic ratios and a transient rise in
the uteroplacental systolic/diastolic ratio (14). It is probable that, at therapeutic
doses, calcium channel blockers do not appear to produce substantial alter-
ations in the uteroplacental flow of pregnant women. In addition, the adverse
effects of the beta-blocker atenolol on fetal growth appear to be explained by
complex mechanisms of blood control and pharmacological programming and
not simply by alterations in placental function reduction in uteroplacental blood
flow (15,16). The patient described in Case 2 was exposed early during preg-
nancy for a limited period of time to amlodipine and to atenolol, and it is, there-
fore, very unlikely that the low birth weight of her daughter can be explained by
treatment with either amlodipine or atenolol. Instead, we consider that the
hemodynamics of hypertensive pregnant women without treatment may alter
uteroplacental blood flow enough to alter fetal growth.
In addition, although implantation may occur as early as 6 to 8 days after
fertilization, in more than 80% of cases it occurs between days 8 and 10 (17).
The time from conception until implantation is considered as the all or none
period, as insults to the embryo result either in miscarriage or in intact sur-
vival. Exposure to amlodipine in the Case 2 would have occurred during this
period, which is unlikely to have adversely affected the embryo. Therefore, the
functional alterations observed in the baby at birth are unlikely to be
explained by her exposure to amlodipine early in utero.
186 Ahn et al.

Spontaneous abortions may be induced by multiples causes, and chromosome

abnormalities are responsible in 50% to 80% of cases (18). It is therefore difficult to
link amlodipine exposure and the embryonic death observed in the woman treated
with amlodipine between the weeks 7 and 12 of gestation. In addition, the patient
was also exposed to an angiotensin-converting enzyme inhibitor, a group of drugs
that were recently reported to increase the risk for major malformations (19).
However, we were not able to prove major malformations in the embryo by ultra-
sound. Therefore, we cannot further speculate whether the patients exposure to
imidapril resulted in life-threatening malformations in the embryo.
In our case series, one patient agreed to breastfeed her baby while being
treated with amlodipine. Although we did not quantify the amlodipine plasma
or milk levels in the mother or plasma drug levels in the baby, it was clinically
evident that no deleterious effects arose during the first three months of
extrauterine life.
In summary, as previously reported with other calcium channel antago-
nists, amlodipine does not appear to increase the risk for major congenital
malformations and appears to be compatible with breastfeeding.

ACKNOWLEDGMENTS
Alejandro A. Nava-Ocampo, M.D., was recipient of the 2006 Dr. Rafael Ramos
Galvn award from the Sociedad Mexicana de Pediatra, A.C., Mxico DF.

REFERENCES
1. He J, Gu D, Wu X, Reynolds K, Duan X, Yao C, Yao C, Wang J, Chen CS, Chen J,
Wildman RP, Klag MJ, Whelton PK. Major causes of death among men and women
in China. N Engl J Med 2005; 353:11241134.
2. Black HR. Calcium channel blockers in the treatment of hypertension and preven-
tion of cardiovascular disease: results from major clinical trials. Clin Cornerstone
2004; 6:5366.
3. Sever P. The VALUE trial: a commentary. J Renin Angiotensin Aldosterone Syst
2004; 5:99101.
4. Robinson RF, Nahata MC, Batisky DL, Mahan JD. Pharmacologic treatment of
chronic pediatric hypertension. Paediatr Drugs 2005; 7:2740.
5. Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B, Cook L, McElhatton PR,
Schmidt MA, Koren G. The safety of calcium channel blockers in human preg-
nancy: a prospective, multicenter cohort study. Am J Obstet Gynecol 1996;
174:823828.
6. Sorensen HT, Czeizel AE, Rockenbauer M, Steffensen FH, Olsen J. The risk of limb
deficiencies and other congenital abnormalities in children exposed in utero to cal-
cium channel blockers. Acta Obstet Gynecol Scand 2001; 80:397401.
7. Hong CU. Pediatrics. 4th ed., Korean Textbook Co., Seoul, Korea, 1989: 821822.
8. Gluckman PD, Pinal CS. Regulation of fetal growth by the somatotrophic axis. J
Nutr 2003; 133(Suppl 2):1741S1746S.
 Amlodipine in Pregnancy 187

9. Trujillo-Ortega ME, Mota-Rojas D, Hernandez-Gonzalez R, Velazquez-Armenta

EY, Nava-Ocampo AA, Ramirez-Necoechea R, Becerril-Herrera M, Alonso-Spils-
bury M. Obstetric and neonatal outcomes to recombinant porcine somatotropin
administered in the last third of pregnancy to primiparous sows. J Endocrinol
2006; 189:575582.
10. Lang U, Baker RS, Braems G, Zygmunt M, Kunzel W, Clark KE. Uterine blood
flow- a determinant of fetal growth. Eur J Obstet Gynecol Reprod Biol 2003;
110(Suppl 1):S55S61.
11. Danielsson BR, Reiland S, Rundqvist E, Danielson M. Digital defects induced by
vasodilatating agents: relationship to reduction in uteroplacental blood flow. Ter-
atology 1989; 40:351358.
12. Horimoto M, Takeuchi K, Iijima M, Tachibana M. Reproductive and developmen-
tal toxicity studies with amlodipine in rats and rabbits [in Japanese]. Oyo Yakuri
1991; 42:167176.
13. Orisakwe OE, Chilaka KC, Afonne OJ, Obi E, Ilondu N. Evaluation of the devel-
opmental toxicity of amlodipine besylate in mice. J Health Sci 2000; 46:4245.
14. Walker JJ, Mathers A, Bjornsson S, Cameron AD, Fairlie FM. The effect of acute
and chronic antihypertensive therapy on maternal and fetoplacental Doppler
velocimetry. Eur J Obstet Gynecol Reprod Biol 1992; 43:193199.
15. Bayliss H, Churchill D, Beevers M, Beevers DG. Anti-hypertensive drugs in preg-
nancy and fetal growth: evidence for pharmacological programming in the first
trimester? Hypertens Pregnancy 2002; 21:161174.
16. Easterling TR, Carr DB, Brateng D, Diederichs C, Schmucker B. Treatment of
hypertension in pregnancy: effect of atenolol on maternal disease, preterm deliv-
ery, and fetal growth. Obstet Gynecol 2001; 98:427433.
17. Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and
loss of pregnancy. N Engl J Med 1999; 340:17961799.
18. Hogge WA, Byrnes AL, Lanasa MC, Surti U. The clinical use of karyotyping spon-
taneous abortions. Am J Obstet Gynecol 2003; 189:397402.
19. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS,
Hall K, Ray WA. Major congenital malformations after first-trimester exposure to
ACE inhibitors. N Engl J Med 2006; 354(23):24432451.