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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

The aim of this prospective, observational study was to assess transplacental transmission of ketanserin, an antihypertensive drug used in pre-eclampsia, and to determine disposition and effects in the neonate after maternal ketanserin use. In 22 pregnant women with severe pre-eclampsia, admitted to the antenatal ward in the period 1999–2001, the ratio of drug levels in the umbilical cord to drug levels in maternal blood just before delivery was used as an indicator of placental transmission. Disposition of ketanserin was assessed using neonatal plasma concentrations of ketanserin in eight neonates after birth. A median placental transmission was found in the pre-eclamptic women of 0.95 (0.612–1.24) for ketanserin and for its metabolite, ketanserinol, of 0.60 (0.5–0.77). Pharmacologically relevant concentrations of ketanserin were found in the neonate after delivery. The elimination half-life of ketanserin in the neonate varied between 12.7 and 43.7 hours (median 19.3 hours) and of ketanserinol between 13.8 and 34.4 hours (median 18.7 hours). Despite the high placental transmission and disposition in the neonate, no apparent adverse effects in the neonates could be detected. In conclusion, a high placental transmission of ketanserin and its metabolite ketanserinol occurred after maternal treatment of pre-eclampsia with ketanserin and pharmacologically active concentrations of ketanserin are found in the neonate for a prolonged period after delivery.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

The mainstay of treatment of pre-eclampsia is lowering the maternal blood pressure by using (parenteral) antihypertensive drugs to help prevent the complications of high blood pressure in the mother and, in selected cases, to prolong the pregnancy.

Recently, the antihypertensive drug ketanserin has been marketed in the Netherlands for treatment of pre-eclampsia. Ketanserin is a 5-HT2a-receptor antagonist with weak alpha-1-agonistic properties.1 The drug has the advantage of causing few adverse effects in the mother and its use in the treatment of pre-eclampsia is increasing. Animal studies in the pregnant ewe have demonstrated placental transfer of ketanserin.2 However, in humans, no quantitative data on placental transfer of ketanserin and its effect on the fetus are yet available.

In our university hospital, patients with severe, early onset pre-eclampsia are treated with high doses of ketanserin for prolonged periods. To establish whether adverse effects of ketanserin in the fetus can be demonstrated, we determined the degree of placental transfer of ketanserin and its metabolite, ketanserinol, the extent of exposure in the neonate and the clinical outcome of the neonates.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Patients with severe pre-eclampsia were started on ketanserin infusion upon admission to the antenatal ward in the period 1999–2001. Severe pre-eclampsia was defined in our study as the occurrence after 20 weeks of gestation of a diastolic blood pressure ≥110 mmHg and proteinuria ≥0.3 g/L or a diastolic blood pressure >90 mmHg in combination with HELLP (haemolysis, elevated liver enzymes, low platelet count) syndrome. Ketanserin infusion was initiated at 4 mg/h and titrated, according to the blood pressure, in increments of 2 mg/h every 20 minutes to a maximum of 20 mg/h. Each increment was preceded by an intravenous loading bolus injection of 5 or 10 mg ketanserin. Treatment was targeted at an intra-arterial diastolic blood pressure of ≤90 mmHg (Korotkoff sound 5, sphygmomanometer). Patients who were already taking oral antihypertensive drugs on admission, such as methyldopa and/or nifedipine, continued using these medications.

Patients were treated with ketanserin until maternal or fetal conditions deteriorated and delivery was necessary.

The study received permission from the Institutional Review Board of the Erasmus MC and all patients gave informed consent.

To determine placental transmission of ketanserin, a maternal plasma sample was obtained just before delivery and an umbilical cord blood sample was obtained after delivery. The plasma levels of ketanserin and ketanserinol were assessed using a validated reversed-phase high performance liquid chromatographic assay with fluorescence detection, which was developed at the hospital pharmacy.3 The limit of quantification for both ketanserin and ketanserinol was 2.0 ng/mL.

The concentration ratios of ketanserin and ketanserinol levels of umbilical cord blood (F) versus maternal plasma (M) were used as a measure of placental transmission (F/M).

To determine the elimination of ketanserin in the neonate, two separate plasma samples were collected from the neonate within 36 hours of birth to measure the half-life of ketanserin. The elimination half-life (t½) of ketanserin was calculated using the formula t½= 0.693 (t2t1)/ln(conc1) − ln(conc2).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Twenty-two patients with 23 neonates were included (including one set of twins). The clinical characteristics of the patients and neonates are summarised in Table 1. One patient received ketanserin orally instead of intravenously. All babies were delivered by caesarean section.

Table 1.  Maternal (n= 22) and neonatal (n= 23) clinical characteristics. Values are expressed as n (%) or mean [range].
Maternal outcome
Maternal age (years)31.6 [20–40]
Gestational age at admission (weeks)28 [180–313]
Gestational age at delivery (weeks)303 [266–341]
Nulliparity14 (64)
Systolic blood pressure at admission (mm Hg)175 [140–240]
Diastolic blood pressure at admission (mm Hg)110 [95–120]
HELLP at admission18 (82)
Indication for delivery: 
 fetal ‘distress’13 (59)
 maternal ‘distress’6 (27)
 combination fetal/maternal distress2 (9)
 spontaneous onset of labour1 (4.5)
 
Neonatal outcome
pH umbilical cord7.25 [7.00–7.38]
Apgar <7 at 5 minutes4 (17)
Birthweight (g)1250 [520–2605]
Admission 
 intensive care unit21 (93)
 medium or transitional care1 (4)
 no hospital admission1 (4)
Mortality during admission3 (13)
ICU stay (days)6 [0–165]
Intraventricular hemorrhage grades III–IV2 (9)
Artificial ventilation12 (53)
Duration of ventilation (days)4 [1–165]

Ketanserin and ketanserinol (KT-ol) could be detected in each of 44 maternal (ketanserin concentration 32–489 mg/mL, ketanserinol concentration 33–933 mg/mL) and umbilical cord plasma samples (ketanserin concentration 26–373 mg/L, ketanserinol concentration 12–472 mg/mL).

The median transplacental transmission for ketanserin, calculated as ratio umbilical cord blood/maternal blood (F/M) was 0.95 (interquartiles 0.61–1.24, range 0.36–2.62). The mean placental transmission for ketanserinol was 0.60 (interquartiles 0.5–0.77, range 0.22–1.04).

Using the Spearman's correlation test, we (respectively) tested whether cumulative maternal dosage (median 1900 mg, range 39–10,240 mg), duration of therapy (median 71 hours, range 3–895 hours) or dose rate before delivery (median 10 mg/h, range 2–18 mg/h), had a significant correlation with the umbilical cord levels of ketanserin. We found a significant correlation between dosage rate before delivery and umbilical cord levels (correlation coefficient = 0.66, P < 0.05), between duration of therapy and umbilical cord levels (correlation coefficient = 0.69, P < 0.01) and between cumulative dosages and umbilical cord levels (correlation coefficient = 0.79, P < 0.01) for ketanserin.

We were able to obtain two separate plasma samples from eight neonates (gestational age 26 6/7 to 32 4/7 weeks, birthweight 670–1755 g) to determine the elimination half-life of ketanserin and ketanserinol. Maternal ketanserin use varied for these neonates between 2 and 12 mg/h during delivery and total antenatal maternal ketanserin dosage ranged between 49 and 3295 mg.The individual plasma levels in each neonate are graphically depicted in Fig. 1. The calculated half-life of ketanserin in these neonates varied between 12.7 and 43.7 hours (median 19.3 hours) and of ketanserinol between 13.8 and 34.4 hours (median 18.6 hours).

image

Figure 1. Neonatal plasma levels of ketanserin within 36 hours of birth, after maternal ketanserin use (n= 8).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Adequate information regarding exposure and possible effects of ketanserin on the human fetus and neonate in humans is lacking. Our study shows that maternal use of ketanserin results in high blood levels of ketanserin and its metabolite, ketanserinol, in the umbilical cord and in the neonate, indicating that ketanserin passes the placenta easily.

The transplacental passage of ketanserin is in accordance with our expectations, considering the drug's physicochemical properties (moderate lipophilic, molecular weight of 365 Da, pKa= 7.50).4 Being a weak base, ketanserin is highly un-ionised at the physiologic blood pH of the mother, which facilitates diffusion through the placenta. After passing the placenta, the slightly more acidic pH of the fetus might result in a shift of un-ionised ketanserin to a higher fraction of ionised ketanserin, which makes redistribution through the placenta back to the mother more difficult (ion trapping).

In the mothers, ketanserin is metabolised in the liver to ketanserinol.4 The affinity of the latter compound for the 5-HT2a receptor is about a thousand-fold less compared with the parent drug ketanserin. However, a reduction–oxidation equilibrium seems to exist between ketanserinol and ketanserin, resulting in an indirect pharmacological effect of ketanserinol. Ketanserinol is more hydrophilic than ketanserin, explaining the lesser degree of placental transmission for ketanserinol, compared with ketanserin that we found in this study. We made the assumption that the ketanserinol levels found in the umbilical cord were of maternal origin rather than that metabolised by the fetus because, although not specified in the protocol, usually venous umbilical cord blood was taken, reflecting the blood flow from the mother to the fetus. Also, the activity of most liver enzymes in the fetus is low, thus the fetal contribution to the formation of ketanserinol is likely to be marginal.

The F/M ratio, used as a measure of placental transmission, varied extensively in our study. This variation can probably be explained not only by differences in maternal exposure to ketanserin, but also by other individual factors, which will influence placental transfer, such as maternal plasma protein concentration and placental blood flow.

We found a correlation between ketanserin levels in the umbilical cord and cumulative maternal dosage, duration of therapy and dosage before delivery, respectively. This correlation was in accordance with our expectations, as diffusion of the drug, which is both concentration and time dependent, will play an important part in placental transfer.

The concentrations of ketanserin determined in the umbilical cord plasma samples and in the neonate are comparable to, and sometimes even higher than the therapeutic plasma concentrations in adult patients treated with ketanserin for chronic hypertension (15–140 mg/mL). This implies that pharmacological effects in the fetus and neonate are to be expected.

Bolte et al.5 reported placental transmission of ketanserin, but did not detect any apparent side effects in the neonate that could be attributed to the drug. Rossouw et al.6 confirmed the apparent safety of ketanserin for mother and fetus, but dosages were lower than used in our study. In our study, no apparent side effects were found in fetus or neonates, but because the study was non-comparative, no valid conclusions can be drawn.

In our study, the elimination half-life of ketanserin was prolonged in the neonate, compared with the elimination half-life of 14.3 hours (±4.4) found in adult volunteers.4 Neonates apparently clear ketanserin at a slower rate compared with adults, probably caused by immature metabolising systems in the liver of the neonate, especially in small for gestational age or premature neonates, as seen often in pre-eclamptic pregnancies.

For the assessment of the elimination rate, we have included in our study only neonates who stayed in our hospital for at least two days, for logistical purposes. This might have introduced a bias, as these babies probably are the most ill. However, the majority of the neonates 19 of 23 babies) stayed at the hospital for a longer period. The neonates studied spanned a wide range of gestational age, birthweight and amount of maternal drug use, and so this study population is representative of newborns from patients with early-onset pre-eclampsia patients.

Long term effects of fetal exposure to ketanserin were not studied but other workers7 have not found effects in infants up to six years after exposure.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

A high placental transmission of ketanserin and its metabolite ketanserinol occurred after maternal treatment of pre-eclampsia with ketanserin. Pharmacologically relevant concentrations of ketanserin are found in the neonate for a prolonged period after delivery.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

The authors would like to thank A. Yassen and D. Misieniumenie, pharmacy students, for their help in collecting the data and analysing the samples.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References
  • 1
    Bolte AC, van Geijn HP, Dekker GA. Pathophysiology of preeclampsia and the role of serotonin: a review. Eur J Obstet Gynaecol 2001;95(1):1221.
  • 2
    Schneider TJ, Struijk PC, Lotgering FK, Wallenburg HCS. Placental transfer and maternal and fetal hemodynamic effects of ketanserin in the pregnant ewe. Eur J Obstet Gynaecol Reprod Biol 1996;68: 179184.
  • 3
    Yassen A, Hanff LM, Vulto AG. Simultaneous quantitative analysis of ketanserin and ketanserinol in plasma by RP-HPLC with fluorescence detectionv. Biomed Chromatogr 2003;17: 517521.
  • 4
    Persson B, Heykants J, Hedner T. Clinical pharmacokinetics of ketanserin. Clin Pharmacokinet 1991;20(4):263279.
  • 5
    Bolte AC, van Geijn HP, Dekker GA. Pharmacological treatment of severe hypertension in pregnancy and the role of serotonine-2 receptor blockers. Eur J Obstet Gynaecol 2001;95(1):2226.
  • 6
    Rossouw HJ, Howarth G, Odendaal HJ. Ketanserin and hydralazine in hypertension in pregnancy—a randomised double-blind trial. S Afr Med J 1995;85(5):525528.
  • 7
    Steyn DW, Odendaal HJ, Kirsten GF. Mental development in children six years after in utero exposure to ketanserin—a follow-up study of a randomized controlled trial. Hypertens Pregnancy 2002;21(Suppl 1):131.

Accepted 12 February 2004