The use of phenothiazines during pregnancy and lactation.

Reproductive Toxicology, Vol. 6, pp. 475--490, 1992

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THE USE OF PHENOTHIAZINES DURING PREGNANCY LACTATION

AND

PATRICIA R. MCELHATTON Teratology Information Service, U.M.D.S. St. Thomas's Hospital, Lambeth Palace Road, London, SEI 7EH, U.K.

INTRODUCTION

in determining any possible cause-and-effect relationship between drug exposure and malformations. Unfortunately these individual case reports are often over-reported and in some instances the number of cases is exaggerated by pooling the results from several sources so that it becomes difficult to determine the actual number of infants involved and the prevalence and significance of the malformations reported. Therefore, the use of phenothiazines in pregnancy has posed an interesting problem. There are conflicting data in the literature regarding teratogenicity, and other forms of fetal and neonatal toxicity. Many of these discrepancies have arisen because the purpose for which the drugs were used and the dosage are not always clearly defined and there is some evidence that the outcome of pregnancy is much poorer in psychotic mothers irrespective of drug treatment. Furthermore, in a psychotic patient the doses used are likely to be higher and given for longer periods of time, when compared with those used over a period of a few weeks to treat the nausea and vomiting of pregnancy. The phenothiazines readily cross the placenta and elimination from the fetal and neonatal tissues is much slower than in the adult. Thus, toxicity can occur throughout the whole of pregnancy and into the neonatal period. Both structural malformations and neonatal extrapyramidal effects have been reported to occur following the use of phenothiazines. Phenothiazines are also secreted into breast milk, and opinions vary as to whether breast feeding should be contraindicated. In an attempt to evaluate the reported effects of the phenothiazines in pregnancy, the data are presented under the following headings: nausea and vomiting of pregnancy, nausea and vomiting during labour, studies where use was unclassified, individual case reports, pregnancy in the psychotic patient, drug therapy in the psychotic patient, and effects during lactation. The prototype for the phenothiazine group

The phenothiazines are a group of drugs that have been used effectively in the treatment of psychoses. However, these drugs have other clinically useful properties, including antiemetic, antinauseant, and antihistamine effects. In addition, they have the ability to potentiate the effects of analgesics, sedatives, and general anaesthetics, which has led to their use during labour and delivery. This makes the phenothiazines a complex group of drugs to review, because account has to be taken not only of the medical condition for which the particular drug is prescribed, but also the dose and duration of treatment together with the possible interactions with any concomitant medication. Although there are several published reviews, prospective and retrospective studies, and numerous individual case reports, the lack of a consistent approach to collection, assessment, and presentation of the results often means that the data are of limited value when trying to make a risk assessment for an individual. Some of the problems encountered when assessing the published data in pregnancy include the misuse of terms, the selection of certain drugs and the exclusion of others where multiple therapy is used, and different definitions of malformation rates, with postnatal problems often forgotten. The outcome of the pregnancies may not be described at all ifphenothiazines have been used to treat nausea and vomiting, because s u c c e s s is defined as cessation of symptoms, not effects on the fetus and delivery of a normal baby. Although the larger studies give an overall picture of the types of problems that may occur in hundreds of women who are exposed to the drug during their pregnancies, there are inherent difficulties in collecting the data and in determining the amount of detail in which that data can be presented. Whereas the individual case reports provide greater detail on a small number of exposures, these are of limited value 475

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is chlorpromazine, and much of the literature on pregnancy outcomes refers to the use of chlorpromazine. Data on other related drugs such as trifluoperazine, fluphenazine, and the butyrophenone, haloperidol will be given as available. NAUSEA AND V O M I T I N G OF PREGNANCY The phenothiazines, chlorpromazine often being the drug of choice, have commonly been used to treat nausea and vomiting of pregnancy, particularly hyperemesis gravidarium. Chlorpromazine has been used also as an antinauseant and analgesic during labour. Data on the use of prochlorperazine, trifluoperazine, fluphenazine, and haloperidol to treat nausea and vomiting will also be discussed.

Chlorpromazine (CPZ) There are two major studies during the 1950s on the use of CPZ to treat nausea and vomiting (N/V) of pregnancy, which give data on a total of 258 women (1,2). The vast majority of women were treated in the first trimester; some continued on into the second trimester as well. Precise figures cannot be quoted because of the way in which the data were presented. Although treatment was described as successful in over 90% of the women, that is, nausea and vomiting ceased or improved, the outcome of the pregnancies are not described in detail. Outcome of pregnancy is known for 10 (3.9%) of the women only, 7 (n = 158) full-term normal babies (1) and 3 (n = 100) spontaneous abortions (2). Data on the other 248 (96%) pregnancies were not recorded. The doses of CPZ used in both studies were similar, 30 to 200 mg daily in divided doses. No details are given on individual dose regimes or the duration of treatment.

Prochlorperazine The Californian Child Health and Development Project (CCHDP) 1959-1966 reports on the outcomes of 20,504 pregnancies (3). In this study there was a subgroup of 6305 women who suffered from nausea and vomiting of pregnancy; 4353 of these women had no drug treatment, whereas the other 1952 required treatment with antinauseants at some time during the first 84 days of pregnancy. The drugs used, often in combination with other nonspecified medication were: Bendectin 628 (32%); meclizine 613 (31%); phenothiazines 543 (28%), the drug of choice being prochlorperazine (433/543 = 81%); trimethobenzamine 193 (9%); and cyclizine 111 (6%). The ethnic origins of the mothers in the study popu-

Volume 6, Number 6, 1992

lation were described as 66% white, 23% black, and 11% oriental/Mexican/other. Severe congenital anomaly rates (SCA) per 100 live births were calculated at 1 month, 1 year, and 5 years of postnatal life. Overall the SCA for the N/V group were almost identical to those with no N/V. Furthermore, the SCA for those receiving medication for N/V was very similar to that for the mothers who took no medication for N/V. There were no significant differences in the incidence of malformations (P > 0.05) between any of the five groups of drugs and the group receiving no drugs. In the trimethobenzamine group, there was a suggestion of an increase in SCA at 5 years of age, nevertheless, the risk of teratogenicity, if any, was very low. The perinatal mortality rate (>_20 weeks) was lower in the N/V group (30.8 per 1000) than in the no N/V group (42.2 per 1000). Furthermore, in the N/V group, the perinatal mortality rates were similar for the drug groups (27.8 per 1000) and the no-drug group (32.1 per 1000). None of the mortality rates for the specific drug group differ from the no-drug group (P > 0.05). Following the concept that stillbirths, neonatal deaths, and SCA follow a continuous scale of fetal damage, the combined rates for the groups were compared. In the N/V drug group vs the no-drug group the rates were 60.1:60.2 per 1000, and for individual drugs, it was only the combined rate for trimethobenzamine that was significantly different from the no-drug cohort (P < 0.025). The authors conclude that the five groups of drugs used to treat nausea and vomiting in human pregnancy were not teratogenic with the possible but improbable exception oftrimethobenzamine. However, it was not possible from the data recorded to determine the dose of the drugs, the particular drug combinations used, or the duration of treatment. The analysis of these data and the methodologic limitations of this study have been severely criticised by Edlund and Craig (4) in a review of psychotropic drug use in pregnancy. Edlund and Craig reanalysed the data presented in the CCHDP report using a test based method of Miettinen which calculates a 90% confidence interval (CI) for the cumulative incidence difference between rates of congenital malformations in different populations. The results of this analysis suggest a possible increase in birth defects among children born to mothers first exposed to phenothiazines during the first 10 weeks of pregnancy. All of the increases occurred after 4 weeks with most marked changes from the 6th to 10th weeks with a rate of 5.4% compared with 3.2% in controls at 5 years of age. The 90% CI showed a possible effect of 2.6 times

Phenothiazines during pregnancy • P. R. MCELHATTON

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the congenital anomaly rate for controls for the group given phenothiazines during the 8th to 10th week. No explanation was given for this observation.

However, no details were given on the dose, time, and duration of treatment with trifluoperazine or data on any other drugs used.

Trifluoperazine

Fluphenazine

In 1962, the Canadian Food and Drug Directorate reported that there had been 8 cases of fetal toxicity (2 abortions, 3 with malformations, and 3 others in which the nature of the toxicity was not described) associated with the use of trifluoperazine, usually in combination with other drugs. This led to a warning not to use trifluoperazine in pregnancy being sent to Health Departments in the United Kingdom, Germany, France, and Italy. In the United Kingdom, there had been reports of 2 cases of diaphragmatic hernia and another report on twins with phocomelia (5). The report from the Canadian FDD has been heavily criticised because of the lack of details and critical evaluation of the data (6-10). Two other individual case reports were found: one infant had phocomelia of the upper limbs (11) and one infant had transposition of the great vessels (12), but both of the mothers had taken other drugs and in neither case could a cause-effect relationship be firmly established. Rawlings and colleagues (9) in reply to the warning published by Refshuage (5) stated that they had used trifluoperazine as a routine part of the treatment for repeated abortions, rather than to treat N/V. They report on 341 pregnancies in abortion prone patients which resulted in 5 congenital abnormalities, I l perinatal deaths (not due to malformations), 80 spontaneous abortions, and 245 normal outcomes. Thus, the incidence of malformations in this series is 1.46% compared with the population incidence of 1.5%. However, this figure is somewhat lower than expected, a more commonly quoted figure for the incidence of spontaneous malformations at birth in the United Kingdom is 2 to 3%. Some of the clinical trial data from 1958 to 1959 on the use oftrifluoperazine in pregnancy submitted to SKF were published in a series of papers in 1963 (6-8). These data on 480 pregnant women were reported by 74 clinicians taking part in the trials, 47 from Canada and 27 from the United States. Trifluoperazine either alone or in combination with other drugs was taken by 472 women (87%) for nausea and vomiting of pregnancy. The other 13% had mild psychiatric or emotional disturbances. There were 480 pregnancy outcomes in this group that were compared with 8472 control pregnancies. There was no increase in the incidence of spontaneous abortions, stillbirths, or malformations in the treated group.

King and colleagues (13) reported the results of a retrospective study in 468 women who took either fluphenazine alone, or as a combined preparation with pyridoxine or a placebo for nausea or vomiting during pregnancy. Outcome of pregnancy was reported on 394 of these women, 244 in the fluphenazine group (the number of women taking the single or combined preparation was not recorded) and 150 women in the control, placebo group. In the test group, 191 women (78%) were exposed in the first trimester and 53 women (22%) in the second trimester. The majority of these women, 196, were exposed for 1 to 2 weeks, to a daily dosage of 1 to 3 mg. There were no significant differences in the incidence of spontaneous abortions or perinatal mortality. Premature delivery of infants weighing less than 2.5 kg occurred in 8/220 (3.6%) live births in the test group compared with 8/140 (5.6%) in the controls. Malformations occurred in live-born infants only, in both groups. No data on malformations was available from the aborted fetuses. In the test group, 6 (2.7%) infants (n = 220) were malformed ( 1 spina bifida, 1 syndactyly, 2 talipes--lst trimester exposures, and 2 polydactyly--second trimester exposure) compared with 5 (3.6%) infants (n = 140) in the controls (1 talipes, 1 hypospadias, 1 inguinal hernia, 1 low-set ears, 1 undescended testis). The authors chose, without explanation, to exclude the three infants with cutaneous nevi (2 test group and I control) and one possible congenital heart defect in a control infant from these data. The incidence of malformations in either group was not significantly different from the spontaneous incidence for the general population. It is not possible in either group to determine from the data presented whether any of the malformed infants were premature, or the dose and duration of treatment with fluphenazine + pyridoxine in the test group. There have been occasional case reports (3 infants) of extrapyramidal effects in the neonate associated with prenatal exposure to fluphenazine (14-16).

Butyrophenones The butyrophenones, for example, haloperidol, are structurally related to the phenothiazines and are often used in situations where rapid control of hyperactive psychotic states is required. In a retrospective study of 100 patients treated for nausea and vomiting of pregnancy with haloperi-

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dol, treatment was described as successful in over 90% of women, less than 10% required additional medication. Ninety-two of the women were treated in the first trimester and eight in the second trimester. In this study, the outcome of pregnancy was known for 98 women, the other 2 were lost to follow-up. There were 92 full-term normal babies, 1 preterm normal baby, 4 spontaneous abortions, and 1 stillbirth. No congenital malformations were reported (17). There have been two case reports of limb reduction deformities associated with the first trimester use of haloperidol (18,19). But other studies have failed to confirm this association. Hanson and Oakley (20) reviewed the data on 86 infants with limb reduction deformities (LRD) taken from the Metropolitan Atlanta Congenital Defects Program from 1970 to 1973. When infants with minor deformities or abnormalities of genetic aetiology were excluded, the final study group consisted of 31 infants with severe LRD. None of the 31 mothers recalled taking haloperidol during their pregnancy. Whilst the authors appreciated the inherent difficulties of assessing data on a small number of subjects based on parental recall, they nevertheless concluded that there was no association between haloperidol and LRD in the Atlanta cases. No such malformations were observed in the data studied by van Waes and colleagues (17). Some of the discrepancies in these two studies may be partly explained in terms of the different doses used to treat nausea and vomiting and the other unspecified conditions, and the influence of maternal illness itself. At present, there is no good evidence to suggest that haloperidol is associated with either an overall increase in the incidence of malformations or with any specific types of malformation.

Summary Whilst there are numerous reports on the use of phenothiazines to treat nausea and vomiting of pregnancy, data on individual drugs and specific treatment regimes remain limited.


The published data on specific phenothiazine use are based on a total of approximately 1620 women. Although the outcome of a pregnancy is not always described in detail, the implication is that there were no significant differences when compared with control population data. The major studies reviewed are shown in Table 1.

NAUSEA AND VOMITING DURING LABOUR There are five large studies on the effects of CPZ + other drugs used as antinauseants and analgesics during labour (21-25). Three of these studies had control data; the remaining two were collective data obtained from a hospital series. Karp and colleagues (21) investigated the use of CPZ with or without other drugs to treat nausea and vomiting during labour. The study group consisted of 114 women: 11 had CPZ only, 106 had CPZ with various combinations of meperidine, atropine, and scopolamine, and 8 had CPZ combined with one or more drugs such as morphine, secobarbital, amobarbitol, meperidine, atropine, and scopolamine. The average dose of CPZ used was 25 mg, with a maximum dose of 100 mg in four divided doses. The number of patients who received the maximum dose was not stated. The control group of 100 mothers were described as untreated, but there is no indication in the data presented as to whether this means that they were not given CPZ or not given any drugs at all. The incidence of nausea and vomiting was reduced during all three stages of labour in the CPZ group, the total incidence ofemesis being 16% compared with 27% in the controls; furthermore, the symptoms were more severe in the controls with 7% vomiting more than three times. Chlorpromazine potentiated the effects of the analgesics used, thus enabling the dose of the analgesic drugs to be reduced by half. No comparable control data were given. Although individual patients showed variations in duration of labour, there was no

Table 1. Nausea and vomiting of pregnancy Main phenothiazine used Trifluoperazine Prochlorperazine Chlorpromazine Chlorpromazine Fluphenazine Haloperidol Not named Totals

No. women treated 472 433 158 100 244 100 110 1,617

Pregnancy (women) outcome reported 472 433 7 3 244 98 110 1,367

Authors Moriaty & Nance 1963 (8) Milkovich & van den Berg 1976" (3) Benaron et al. 1955 (1) Sullivan 1957 (2) King et al. 1963 (13) van Waes et al. 1969 (17) Milkovich & van den Berg 1976" (3)

*Part of a large prospective study in which other antinauseants were used and compared with phenothiazines.


overall significant difference between the two groups. The average drop in maternal blood pressure in the CPZ group was 10 points in systolic and diastolic readings that were observed mainly immediately after the induction of spinal anaesthesia, and in the toxaemic, hypertensive patients. As no numerical data are given for the CPZ group and no data at all on maternal blood pressure in the controls, the value of these observations in terms of management is difficult to assess. There were no other harmful effects on mother or baby in the CPZ group. The number of infants with delayed respiration was similar in the two groups; there were 10 (8.8%) infants, (3 [2.6%] of whom required resuscitation) in the CPZ group compared with 11 (11%) infants, (7 [7%] of whom required resuscitation) in the control group. There were no maternal or fetal deaths in either group. Harer and colleagues (22) reported the effects of CPZ during labour in 500 women compared with a group of 500 controls. All of these women were healthy, and had normal pregnancies. They were in spontaneous labour with no expected complications when they were admitted to hospital where they were alternatively assigned to either the study or control group. Whilst it is stated that an attempt was made to give equal relief for the discomforts of labour in both groups, the drug regime used is not described in any detail. Although the use of pethidine (Demerol) and morphine is mentioned, it is not adequately described. The patients in the study group received doses of CPZ of 50 to 200 mg; the majority (428) had 50 mg, whilst 33 mothers had 75 to 88 mg, 34 mothers had 100 to 125 mg, and only 5 mothers received the top dose range of 150 to 200 mg. This study does not record the effects of CPZ on the duration of labour, but attempts to evaluate the degree of pain relief as assessed by the obstetric care team and the mothers in the postpartum period. Unfortunately, these data are difficult to assess not only because of their subjective nature, but because the criteria for scoring pain relief in each group were also different. Overall, it would seem that 85% or more of mothers and obstetric personnel considered pain relief to be adequate to good. None of the patients developed jaundice, but some of the patients in both groups developed hypotension. These data were given in either numerical form or as a percentage and it is not always possible to marry the two sets of data. However, it would seem that 155 women (31%) in the CPZ group had hypotension compared with 16 (3.2%) in the controls. When women in whom the fall in blood pressure was negligible ( < 10 mm) were excluded, there remained 93 women (18.6%) in the CPZ group and 14 (2.8%) in the controls with a fall in blood pressure of 10 to 53

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mm. However, this large-range grouping is somewhat misleading. When these data are analysed further, it can be seen that the majority of women, 47 (9.4%) in the CPZ group had a fall in blood pressure 10 to 20 mm, another 33 (6.6%) women were in the 20 to 30 mm range, and only 13 (2.6%) women were in the severely hypotensive range, > 30 mm, compared with control figures of 12 (2.4%), nil, and 2 (0.4%), respectively. No data are given that would indicate whether the hypotension in the CPZ group was a dose related phenomenon. None of these mothers showed any other toxicity associated with the transient fall in blood pressure and there were no adverse effects observed on the tone of the fetal heart in term of either quality or rate during the hypotensive episode. The number of women who developed hypertension in each group was similar, 7 ( 1.4%) in the controls and 8 ( 1.6%) in the CPZ group. Nausea and vomiting in labour was reduced by 60% in the group receiving CPZ, but no numerical data or method of assessment are described for either group. The authors state that chlorpromazine required no modification of anaesthetic, but details for both groups that would allow critical evaluation are not recorded. There was no tendency to excessive blood loss in the CPZ group compared with the controls, in fact, the majority of the women taking CPZ bled less than the controls, as estimated by a blood loss of < 2 0 0 mL in 257 CPZ mothers (51.4%) vs. 172 control mothers (34.4%). Furthermore, no adverse effects attributable to CPZ were observed in the neonates. All of the infants in the CPZ group were live born, whereas in the controls there were nine stillbirths (1.8%) and one death at delivery (0.2%). Fewer infants in the CPZ group had problems at birth, 96.6% being described as being in good condition compared with 89.7% in the control group. Spontaneous respiration rates were 77.9% in the CPZ group and 73.3.% in the controls. No gross malformations were reported in either group. In a total of 1000 pregnancies, this is unusual as the incidence of spontaneous gross malformations is approximately 2 to 3% at birth. At 24 h postpartum the condition of most of the infants (98.6%) in the control group was described as good, but two infants (0.4%) had died and five (1%) were described as fair, whereas in the CPZ group, all the infants (100%) were in good condition. Lindley and colleagues (23) published data on the analgesic potentiating effects of CPZ during labour in normotensive women. Although there were 2093 women in this study, adequate data are available only in the 1881 charity patients. The other 212 private patients were added into the study at various

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times. The authors describe their treatment as successful, without giving details of the regimen used. In the main part of the study ( 1881 women) there were five treatment groups: (a) 79 women, CPZ 25 mg; (b) 187 women, CPZ 25 mg + meperidine 25 mg; (c) 520 women, CPZ 25 mg + meperidine 25 mg + scopolamine 0.4 mg; (d) 46 women, CPZ 12.5 mg + meperidine 50 mg ÷ scopolamine 0.4 mg; (e) 1049 women, CPZ 25 mg + meperidine 50 mg + scopolamine 0.4 mg. There was no control group. Good pain relief was defined as the patient being asleep, or nearly so, between contractions, and suffering a minimal amount of discomfort during contractions. Evaluation was made by both the mother and the obstetric staff. Meperidine and CPZ were administered every 2 to 3 hours as required, but only one dose of scopolamine was given. The most effective regime was in the group treated with CPZ 25 mg + meperidine 50 mg + scopolamine 0.4 mg, in which 84% of women described pain relief as good or fair (20%). Nausea and vomiting was said to be well controlled, but there were no data to support this statement. Side effects such as hypotension (6 mothers [0.32%]); and profound maternal sedation (9 mothers [0.48%]) were ascribed to CPZ by the authors. The disorientated and hyperactive behaviour in 19 mothers (1.01%) was ascribed to scopolamine because it was not observed in any of the 79 mothers on CPZ alone. No indication was given as to which treatment regime these mothers received, so it is difficult to assess how much of each drug (except scopolamine 0.4 mg) they actually took. Whilst it is valid to evaluate data within and between treatment groups, the lack of a control group without CPZ and the use of several drugs at different dosages makes the authors' conclusions that it was CPZ that caused sedation and hypotension difficult to accept. No maternal jaundice or blood dyscrasias were observed. The 1881 mothers gave birth to 1887 infants (3 sets of twins), most of whom (1582 [83.8%]) were in good condition at birth. The remainder were described as fair (225 [ 11.9%]) or poor (50 [2.6%]), poor being described as apnoeic and requiring active resuscitation. Thirty infants (1.6%) were stillborn; no other data on these infants was recorded. These data are difficult to evaluate because of the lack of control data and because the treatment groups to which these infants belong were not indicated. The pain relief obtained in the 212 private patients was described as almost 100% successful. The only variable between the charity patients and the private patients was the increased amount of drug used to obtain this degree of pain relief in the latter. No data were given to support


this statement, which makes critical evaluation impossible. Although this study provided data on a large number (2093) of patients, the majority of whom had good pain relief and successful outcomes for mother and infant, it is difficult to assess how much of each drug the mothers actually received. Furthermore, where problems arose, it was not possible to assess whether it was a dose-related phenomenon or which treatment group the mothers were in. Bryans and colleagues (24) reported the results of a study in which CPZ was used in obstetric analgesia. All of the infants in both the study and control group were delivered by the same two obstetricians. The study group consisted of 628 white women who received average doses of CPZ, 25 to 150 mg, meperidine 100 mg, and scopolamine 1.2 mg during labour. The control group consisted of 581 white women delivered in the previous year; although the controls did not receive CPZ, details of the specific medication used was not recorded. Concern had been expressed that CPZ would retard labour and cause a sudden and precipitous drop in maternal blood pressure. In this study, CPZ did not adversely affect the duration of labour (study group labour lasted an average of 8 h 12.5 min vs. controls 9 h 22 min). There was only one episode of severe maternal hypotension in the whole series (1/628 = 0.16%). Data on at least 1800 other women treated with CPZ who were delivered by other doctors in the same hospital during that period showed no overall adverse effects on blood pressure. The number of spontaneous vaginal deliveries in each group was similar, 431 (68.6%) in the study group, 410 (70.6%) in the controls. There was no increase in the incidence of adverse effects on the fetus or the neonate. In fact, the incidence of respiratory depression in the infants exposed to CPZ (3.6%) was less than half of that found in the control infants (7.6%). There were 14 stillborn infants in this study, nine (1.4%) in the CPZ group and five (0.8%) in the controls. However, 11/14 of these infants were already dead on admission to hospital, and of the remaining three, only one had been exposed to CPZ. Thus, no cause-effect relationship could be established. The number of neonatal deaths in each group was similar also, 8 (1.4%) in the controls, 11 (1.8%) in the study group (6 premature, 1 prolonged labour, 1 breech assisted, 1 abruptio placenta, 2 severe erythroblastosis), and could not be directly correlated with exposure to CPZ. The authors conclude that CPZ was safe for both mother and baby and it was possible to obtain a high degree of analgesia and


amnesia without psychomotor excitement. It is interesting that there were no infants with malformations or neonatal extrapyramidal effects reported in this study in which there were 1149 pregnancies. Christhilf and colleagues (25) investigated the use of CPZ as part of an analgesic-amnesic regime during labour. This 3-year study (1955-1958) involved 1019 women who were treated with CPZ 25 mg, scopolamine 0.3 to 0.6 mg, and meperidine 100 mg as soon as severe contractions started. At the beginning of the study it was thought that the routine use of secobarbita1200 mg could be eliminated. However, it was shown later that secobarbital was necessary, but at a reduced dosage of 100 mg. There was no control group in which the women did not take CPZ. Spontaneous delivery occurred in 540 women (53%); low forceps were required in another 412 women (40%). Estimates of analgesia and amnesia were made by both the patient and obstetrician at sometime during the first day postpartum. Supplementary evaluation of analgesia in 723 women (71%) was obtained by mail after they had returned home. The average duration of labour, compared with the national average, was shorter and pain relief was described as good by 74% of the mothers. No normotensive women showed a drop in systolic blood pressure of more than 20 mm Hg, and in no case did shock occur. None of these women required restorative measures. Twenty of these women (2%) were diagnosed as toxaemic, but no other data on these women were provided. The authors state that there was no excessive blood loss, nausea and vomiting was noticed only by its absence, and there were no maternal deaths. At delivery, the majority of babies (966 [94%]) were in good condition, 16 (1.6%) were described as poor, and there were four (0.4%) stillbirths. At 24 h postpartum, 13 (1.3%) of the babies, 8 of whom were born prematurely, had died, but the majority of the babies (1000 [97%]) were normal. Malformations were reported in only one infant who was born prematurely and subsequently died. It is not possible from the way in which the data were presented to determine to which treatment group the infants with neonatal problems belonged or whether the problems were due to a dose-related effect of the drugs. The authors concluded that 25 mg CPZ combined with lower doses of secobarbital, meperidine, and scopolamine provides good and safe analgesia during labour. No evidence of suppression of uterine contractions or any marked hypotensive effects were observed. There was no overall increase in the incidence of either fetal distress or neonatal deaths that

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could be attributable to CPZ. However, absence of control data and a lack of individual data in some instances make critical evaluation of these statements difficult.

Summary Despite the limitations of these early studies in the 1950s and 1960s, the results of the combined data of over 4000 pregnancies in which mothers were given chlorpromazine to control both nausea and vomiting during labour and as an adjunct to other analgesic and anaesthetic drugs indicate that (a) none of the five studies reviewed showed a significant difference in the onset and duration of labour compared with matched controls or population based data, and (b) one of the main worries with chlorpromazine was that it would cause a sudden and precipitous drop in maternal blood pressure and induce shock in the mother with concomitant effects on the neonate. Although a fall in blood pressure of varying severity was reported in some mothers in each of the studies, the overall conclusion was that there was no significant increase in either fetal or maternal toxicity associated with such hypotensive episodes. Unfortunately it is not possible to assess whether these hypotensive episodes were a dose related phenomenon or whether the mothers were normotensive or had problems with the pregnancy prior to receiving chlorpromazine. (c) Although any assessment of pain is highly subjective and shows wide individual variation, it would seem that the majority of these 4000 women and the obstetric staff caring for them thought pain control was adequate to good and the incidence of nausea and vomiting was considerably reduced; (d) there was no significant increase in the incidence of depressed fetal respiration or other forms of fetal toxicity, perinatal death, or maternal mortality; (e) reports on the number of malformed infants and of episodes of neonatal extrapyramidal effects were lacking. STUDIES W H E R E USE WAS UNCLASSIFIED There are two large prospective studies which report on the use of phenothiazines during pregnancy. However, neither the dose, duration of treatment, nor the indication for use were clearly stated for the majority of the cases, which makes interpretation difficult. Nevertheless, these studies provide useful background data on the outcome of a large number of pregnancies, the majority of which were normal. The difficulties arise with this type of general data when trying to assess the risks for individual patients requiting specific treatments.

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In a large prospective French Study of 12,764 women, there were 315 women who had taken phenothiazines at least once in the three months after the last menstrual period (26). Eleven infants (3.5%) had malformations, compared with 178/10,921 in the control group (1.6%), a significantly higher number than expected (P < 0.01). A variety of malformations were produced and these were significantly increased only for the three-carbon side-chain phenothiazines, a total of eight malformed infants, (chlorpromazine 4/57, methotrimeperazine 2/18, trimeperazine 1/49, and oxomemazine 1/14), but not for the two-carbon analogues (promethazine, propiomazine) or the piperazine (prochlorperazine, tritluoperazine) or piperidine (pimazine, thioridazine) side chains. Eight of the mothers were on monotherapy (5 = 3-carbon chain; 2 = 2-carbon chain; 1 = piperidine chain); the other three mothers took two phenothiazines, one of which was chlorpromazine. So, although chlorpromazine was taken by a total of four of the mothers whose infants had malformations, three of them had taken other phenothiazines also. When account was taken of the maternal medical and obstetric histories, the time of pregnancy at which these drugs were taken, and maternal recall bias, the authors concluded that their findings were not a chance phenomenon. The indication for use of the phenothiazines and the duration of treatment was given only for 10 of the 11 mothers who had malformed infants (4 depression, 3 insomnia, 2 vomiting, 1 allergy, 1 not specified), but, no information was given about the doses used. So it is not possible to assess whether there were any dose-related phenomenon. Although the increase in malformations is statistically significant for the 3-carbon side-chain group, the biologic significance, especially when dealing with such small numbers, remains unclear. There was no syndrome of effects. In the Boston prospective cohort study of 50,282 pregnancies, the malformation rates were similar in the 1309 offspring of mothers who had taken phenothiazines during the first 4 lunar months of pregnancy compared with those in 48,973 infants whose mothers had not taken these drugs (27). The mothers taking phenothiazines were divided into two groups, and the malformation rate in those heavily exposed was 6.2% (25/403) and in the intermediate exposure group 7.6% (69/906), compared with nonexposed controls 6.4% (3155/48973). Although there was a variety of malformations, there was no excess of any specific malformation, which is similar to the results reported by Rumeau-Rouquette and colleagues (26). Furthermore, there was no overall increase in the incidence of stillbirths or neonatal deaths and the


mean birth weights were similar for all groups. Postnatal follow-up was obtained in over half of these children. IQ was assessed at 4 years of age in 28,358 of these children and there were no differences between either those who had been exposed to phenothiazines and the controls, or between the groups; that is, heavily exposed ( 151 children), intermediate exposure (1990), and the controls (26,217).

Summary These two large prospective studies have provided background information on a large number of women (315 + 1309) who were taking phenothiazines in the first 4 months of pregnancy. However, these data are of limited value when trying to assess the risks for an individual woman who may require specific treatment. This is in part due to the following: (a) the lack of data on the particular drugs used, the dose, duration of treatment, and the indication for their use; (b) the two studies differ in that RumeauRouquette and colleagues (26) report a significant increase in malformations ( 11/315 = 3.5% vs. controls 178/10921 = 1.6%) for the 3-carbon side-chain phenothiazines whereas Slone and co-workers (27) do not. Slone and colleagues report the opposite in that there was no significant difference in the incidence of malformations, stillbirths, neonatal deaths, or postnatal development in the offspring of the 1309 mothers exposed to phenothiazines. Although a variety of malformations were reported in each study, there was no syndrome of effects. (c) The main value of these two studies lies in the fact that large numbers of women (1624) were exposed, the majority of whom gave birth to normal babies. INDIVIDUAL CASE REPORTS A number of reports have described various forms of fetal and neonatal toxicity in infants born to mothers who had taken phenothiazines. Eight reports were located describing the use of CPZ usually in combination with other drugs (14,16,28-33), and two reports in which trifluoperazine was implicated (11,12). The two cases of LRD allegedly associated with haloperidol exposure have been discussed previously (18-20). There were two infants with multiple malformations who were born to mothers taking CPZ and other drugs for nonpsychiatric conditions (28,32). In neither of these cases can a cause-effect relationship be established associating phenothiazines with the malformations. Eight mothers had psychiatric illnesses of varying severity. Two of these mothers, treated with chlorpromazine and other drugs, gave birth to babies with


no external malformations, but they developed abdominal distension in the early postpartum period which was diagnosed as small left colon syndrome (SLCS). Both infants made a good recovery and were developing normally by 5 weeks of age (33). The authors suggest that the effects of prenatal psychotropic drugs caused a decrease in intestinal motility resulting in SLCS. The other six mothers gave birth to seven infants all of whom were structurally normal but developed extrapyramidal effects and neurologic problems at various times during the neonatal period. In some infants these extrapyramidal effects lasted up to 6 months of postnatal life (14,16,29-31). There was no indication that this was associated with continued exposure to the drugs via the breast milk. There were two reports of different types of malformations involving trifluoperazine. Phocomelia of the upper limbs was reported in an infant who had been exposed in utero to both trifluoperazine and prochlorperazine during the first trimester (11). Vince (12) reported on an infant with transposition of the great vessels (TGV) who had been exposed to trifluoperazine and thioridazine at various times throughout the pregnancy. However, in neither case can a cause-effect relationship be established. These reports do not show either a significant increase in a particular type of malformation or a pattern of defects (2 multiple malformations, 2 SLCS, 1 TGV, 1 phocomelia) that can be attributed to the use of phenothiazines. However, seven of the infants did develop extrapyramidal effects that were thought to be due to the accumulation of the psychotropic drugs, particularly chlorpromazine, and their slow elimination in the neonate. However, this explanation is not entirely satisfactory for all the cases described, and it cannot be assumed that the effects seen in the infants were due entirely to the effects of chlorpromazine as all of these mothers were on multiple drug therapy. The mental and physical development of these infants was normal at 9 months of age, except in one infant (29) whose mother had fits during the pregnancy and required antiepileptic medication.

Summary Ten reports of individual infants with either malformations or postnatal toxicity were reviewed. However, no significant increase in a particular type of malformation or pattern of defects was observed. Although the mothers had been exposed to phenothiazines, usually as part of a multiple drug regime during early pregnancy, these adverse effects tend to be described as phenothiazine- or chlorpromazine-associated effects. However, there is no proven causeeffect relationship. Whilst it is important to report

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possible drug-associated malformation and neonatal toxicity, it is equally important not to over-interpret their significance. PREGNANCY IN T H E PSCYHOTIC PREGNANT PATIENT When reviewing the effects of phenothiazines in psychotic patients it is often difficult to separate the possible effects of the drugs from the effects of the disease per se. There is evidence to suggest that the outcome of pregnancy is much poorer in the psychotic patient, irrespective of the drugs or other types of therapy used (34,35). In a large prospective study, Rieder and colleagues (34) reported on the outcome of pregnancy from the Boston subgroup (9,280 subjects) of the Collaborative Perinatal Study of the National Institute of Neurological Diseases and Stroke (NINDS) (58,000 subjects). The pregnancies in the index group were chosen from those in which either the mother, the father, or both had been hospitalised in a psychiatric hospital. They were further subdivided according to the diagnosis of the psychiatric illness, for example, schizophrenia, other personality disorders, or other types of nonschizoid illness. The diagnosis and sex of the diagnosed parent in the index cases was as follows: In the schizophrenic group there were 71 sets of parents (38 mothers, 25 fathers, 8 both parents); in the group with personality disorders there were 46 sets of parents (24 mothers, 22 fathers); and in the nonschizoid group there were 37 sets of parents (16 mothers, 21 fathers). For each index case there were two control pregnancies in which there was no family history of psychiatric illness and the mother was not using tranquillisers. The controls were carefully matched for a range of obstetric, medical, and social factors. No data were given concerning drug use in the index group. Thus, the final index group consisted of 154 sets of parents (1 mother had two pregnancies) who gave birth to a total of 210 infants, who were compared with 420 infants from the control group. The outcome of pregnancy in the index group was as follows: 93 babies in the schizoid group, 60 babies in the group with personality disorders, and 57 babies in the nonschizoid illness group. The authors state that the use of routine medication (vitamins, iron, aspirin, polio vaccine) during pregnancy was excluded. Details of drug use by the mother are given only in pregnancies resulting in fetal or neonatal deaths. Fetal/neonatal deaths occurred in 7/93 (7.5%) of the schizoid group compared with 7/186 (3.8%) in the controls (P = 0.053). The combined data for the three index groups reports a total of I 1 fetal/neonatal

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deaths from 10 sets of parents. Psychiatric illness had been diagnosed in five mothers, three fathers, and in both parents in three cases. Furthermore, phenothiazines had been taken by four of five mothers who required additional medication during their pregnancies. The sample size was not large enough to separate out a possible association between the severity of the schizoid illness and the drugs used. It is interesting that the cause of death was described as unknown in all of the index cases compared with 2/7 in the controis. The abortion rate prior to 19 weeks of pregnancy was excluded because of difficulties in obtaining accurate data. However, the incidence of perinatal deaths (stillbirths and neonatal deaths) was higher in the schizoid group (n = 6, 4.3%) than in the controls (n = 9, 3.4%). The cause of death was different for each group. In the index group, four infants had severe CNS malformations (two in the schizoid group and one in each of the other groups) compared with one infant in the controls. The diagnosed parent in these cases was two mothers, one father, and one both parents. Two of these infants in the index group were stillborn and had other multiple malformations also. It is interesting that they were from twin pregnancies, in which the other twin was normal and alive. In only one of these cases did drug exposure occur (trifluoperazine and trihexyphenidyl). There were three stillborn infants with malformations in the controls. One of twin infants had gross neurologic malformations; the mother had been treated for pernicious anaemia with folic acid. The other two infants had a single malformation, neither of which was thought to contribute to the death of the infant; neither mother took medication. The overall analysis of the data from this part of the subgroup study (which was very similar to that observed in the larger study group from the entire study) has shown that there was no significant correlation between taking phenothiazines and the occurrence of fetal death. Furthermore there was less of a correlation between medication and fetal death than between such factors as severity of parental schizophrenia and fetal deaths. However, treatment regimes were not reported in this part of the study. The incidence of fetal deaths was higher in the offspring born to schizoid mothers, and more of these deaths were of unknown cause, compared with the controls. In the combined index groups, more of the fetal deaths were associated with neurologic malformations than in the combined control groups. The sex of the diagnosed parent in the index group is mentioned only in those pregnancies resulting in fetal/neonatal deaths. Thus, no overall assessment can be made from these data


concerning the maternal or paternal influence of the disease on the fetus. In a general review, Erlick-Robinson (35) discussed the evidence that infants of psychotic mothers have a much higher incidence of perinatal mortality and neonatal extrapyramidal effects. He emphasised that the doses used to reduce anxiety, nausea, and vomiting, and induce relaxation are much lower than those used to treat psychoses. As metabolism changes during pregnancy alterations in the dose given to the mother may be required. Elimination of these drugs in the fetus and neonate is much slower than in the adult. Although sedation and withdrawal symptoms lasting up to 6 months have been observed in some infants who had been chronically exposed in utero or exposed during the week prior to delivery, withdrawal symptoms in the neonate are not usually associated with acute treatment. However, Erlick-Robinson does not comment on the incidence of malformations per se.

Summary When assessing the effects of phenothiazines in the psychotic patient it is not always possible to separate the possible effects of the drugs from those of the disease per se. Over the years evidence has accumulated that suggests that the outcome of pregnancy is poorer in psychotic patients irrespective of the therapy used (34). However, the currently available data do not permit the effects of the maternal and or paternal influence of the disease to be distinguished. Nevertheless, although the data are very limited, they do show a stronger correlation between fetal death and severity of the schizoid illness than between medication and fetal death amongst the 210 infants studied. DRUG THERAPY IN THE PSYCHOTIC PREGNANT PATIENT There are several reports on the outcomes of pregnancy in women treated with antipsychotic drugs (10,36-43). In general, these studies indicate that drug treatment per se does not significantly increase the incidence of adverse affects on prenatal or postnatal growth and development. However, the methodology used in some of these studies is not always clearly described and the individual drug(s) used are not always named. Kris and colleagues have followed up 52 children born to mothers maintained on chlorpromazine, sometimes in combination with other psychotropic drugs, during pregnancy and the postpartum period (36-38). All of these women had psychiatric illnesses or had suffered a psychotic breakdown during a pre-

Phenothiazines during pregnancy • P. R. McELHATTON

vious pregnancy. Neither the treatment regime used nor the outcome of pregnancy and postnatal development was described in any detail for all 52 children, but was illustrated by a few selected case reports. The outcome of pregnancy and postnatal development was adequately described for five women who gave birth to six infants. There was also a brief statement on the outcome in another 10 pregnancies, but details were lacking in the remaining 27 women. Although the authors indicated that there was no increase in malformations and no impairment of physical and mental development in these children in the I 0-year follow-up period studied, no data were given to support this statement in the majority of the cases included in the study. Kxis concluded that drug treatment for the prevention of recurrent psychotic breakdown during pregnancy and the postpartum in the 52 cases she studied seems to have no adverse effects on either the mother, the fetus, or on the child during the early years of development (36), but the lack of published data does not permit critical evaluation. Similar findings were reported by Ayd (39), in a study of 27 pregnant women with psychiatric illness who were treated with chlorpromazine at various times during their pregnancies. Sixteen of these women had taken CPZ prior to and throughout their pregnancies, the dose range at around the time of conception was 150 to 900 mg per day. The pregnancy had no adverse effects on the course of the illness. All 16 women delivered full-term normal babies with birth weights within the normal range. Six of the infants were breast fed for 1 to 3 months with no apparent adverse effects. Postnatal follow up of these children aged 2 to 7 years has shown normal development. Although no intelligence test data were available, none showed any signs of retardation. Fifteen were described as having average and one above average intelligence, and no behavioural problems were reported. The other 11 women in whom psychiatric illness became overt after conception took an average dose of 200 mg per day CPZ at some time after the first trimester. Maintenance therapy was continued for periods of several months to years after delivery. All 11 women had full-term normal babies of average birth weight with no neonatal problems. Three of these infants were breast fed for a minimum period of 2 months. The subsequent growth and development of these infants (aged 1 to 6 years) had been normal. Sobel (40) reports the outcome of pregnancies from data obtained from medical records in eight New York State mental hospitals from 1949 to 1958. A group of 110 women who were treated with drugs and ECT during pregnancy was compared with a

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group of 200 untreated pregnant women from the same hospitals. Chlorpromazine with or without other treatments was given to 52 women at some time during their pregnancy. The doses used and the duration of treatment was not recorded, but it was stated that other drugs potentiating CPZ were used minimally if at all. Fetal toxicity was described in four pregnancies, namely one abortion, one stillbirth, one fetal damage (unspecified), and one live born infant with convulsions and developmental retardation (CPZ 8% vs. control 7%). There were no significant differences in abortion rate, incidence of premature births, or perinatal deaths in the CPZ group compared with the controls. However, numerical values were not given to support this statement. The condition of the other 48 babies was not clearly described, apart from the 3 infants (1 threatened abortion, 1 premature) who had severe respiratory distress syndrome (RDS). One of these (unspecified) subsequently died. Although there were five other premature babies of similar birth weights, born about the same time, who did not have RDS, the mothers of these infants were on lower doses of CPZ. Sobel concluded that daily doses of CPZ >__500 mg in the latter part of the pregnancy may depress the reticular activating system with secondary effects (depression) of the respiration centres. There were no instances of respiratory distress in the infants of mothers who took less than 500 mg per day. Follow up data at 1 to 4 months of age showed no increases in mortality or morbidity associated with CPZ. One of the most striking features of this study is that 8% of the treated and 7% of the controls had perinatal deaths compared with a general population rate at that time of 3.6%. This is very similar to the finding of the NINDS study in which the neonatal mortality (stillbirths and neonatal deaths) rate was 7.5% compared with 3.8% for a much better matched series of controls (34). This increase in neonatal deaths seems to contradict the data reported by other workers (44,45). However, the discrepancy may be due to the fact that these authors have studied childhood deaths rather than perinatal deaths, often completely omitting fetal deaths from their overall evaluations. Furthermore, most of these studies use general population rather than matched controls when comparing the data from different populations. In France, Favre-Tissot and colleagues (41) reported on the outcome of pregnancy in women who had taken different types of CNS drugs such as major analgesics, major and minor tranquillisers, antidepressants, and antinauseants. The actual number of women who were taking each type of drug was not stated. The data reported referred to pregnancy out-

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come in 395 women who took psychotropic drugs, including phenothiazines, at various times during their pregnancy. Three groups of women were studied: (a) psychotropic drugs prior to pregnancy (n = 17); (b) psychotropic drugs up to 3 months of pregnancy (n = 316); and (c) psychotropic drugs after the third month of pregnancy (n = 62). There were 369 full-term normal babies, 5 of whom were premature. Abortion occurred in eight women and there were 2 neonatal deaths associated with prolonged gestation. Malformations occurred in 12 infants (3 systolic murmur, 1 mitral valve insufficiency and other cardiac problems, 1 hydronephrosis, 1 craniostenosis, 3 club foot, 2 multiple malformations including palatal and digital abnormalities, and 1 was not described). Ten of the malformations occurred in the mothers treated during the first 3 months of pregnancy and there was one malformation in each of the other groups. Nevertheless, the authors conclude that there was no appreciable difference in pregnancy outcome amongst the three groups of women. However, as no indications for psychotropic drug use were described and neither were the individual drugs used, nor the dose and duration of treatment specified, it is not possible to concur with the authors' opinion. Spielvogel and Wile (43) briefly reviewed the outcome of 13 pregnancies in women with a variety of psychiatric disorders. The authors examined psychodynamic issues, legal and medical aspects of treatment, and medical management. Although the use of drugs is referred to, these are not specified apart from lithium carbonate. Four mothers took no drugs during pregnancy and gave birth to four normal babies and one stillborn infant. The other nine mothers had medication of whom three had lithium. They gave birth to six normal babies, one premature infant who died neonatally from meningitis, one stillborn infant with dwarfism, and one infant with Ebstein's anomaly (exposed in utero to lithium). Whilst these case reports highlight some of the management problems encountered in treating psychotic patients, the lack of specific data on the drug regime used makes them of limited value.

Summary The treatment of the psychotic pregnant patient is somewhat different from that of the nonpregnant patient. The critical questions of whether or not to continue treament in psychotic patients or to start treating a pregnant woman who has become psychotic have been the subject of much debate. Studies in which psychotic pregnant women have been treated with phenothiazines with or without other


medication have produced conflicting data on both fetal and neonatal effects. Such data show considerable variations in the incidence of abortions, malformations, perinatal mortality, neonatal extrapyramidal effects, and on postnatal growth and development (36-43). These differences may be due in part to the wide range of doses of phenothiazines used, which tends to be related to the severity of the maternal illness; the doses are certainly much higher (3- to 5-fold) than the doses used to treat nausea and vomiting. Although the combined data from these studies refers to pregnancies in some 600 psychotic women treated with various drug regimes, the actual outcome of these pregnancies is illustrated by selected cases only, approximately eighty (13%) in all. The other outcomes tend to be described in general terms, with the implication that the majority of infants were normal. Moreover, in those studies that provide postnatal follow-up data for periods varying from l month to l0 years, there seems to be no overall increase in adverse effects, for example, increased mortality or low IQ scores, directly attributable to phenothiazine exposure. This includes infants who suffered respiratory distress, or extrapyramidal effects for several months (36-40). It is interesting that none of the larger studies where phenothiazines have been used at various times during pregnancy and the puerperium to treat a wide range of conditions have reported a significant increase in the incidence of neonatal extrapyramidal effects. However, amongst the individual case reports, there were seven infants with extrapyramidal symptoms and neurologic sequelae. All six of their mothers had been treated for psychiatric illnesses with several CNS drugs throughout pregnancy, particularly around the time of delivery. The doses of the phenothiazines used, usually CPZ (400 to 1800 mg per day) were high. There was no evidence to suggest that these infants obtained additional phenothiazines via breast milk. No reports were located that indicated that extrapyramidal effects or neonatal respiratory depression were associated with chronic or acute treatment with low doses. Furthermore, from the data presented by Kris and co-workers (36-38) and Ayd (39) it would seem that the risks to the fetus from a psychotic episode that is untreated are much greater than those associated with maternal drug treatment. BREAST FEEDING

There are very few published data on the neonatal effects of psychotropic drugs via breast milk. Furthermore, the data that do exist present conflict-

Phenothiazines during pregnancy • P. R. McELHATTON

ing views and are based on a few selected cases (4652). This lack of consistent opinion combined with a fear of adverse neonatal effects, many of which are theoretical, often has led to breast feeding being discouraged if the mother is taking psychotropic drugs. In general, the neonate is more sensitive to drugs, and the elimination of psychotropic drugs is much slower than in the adult. The major concerns related to these factors are that there will be an accumulation of drug in the neonate resulting in lethargy, extrapyramidal effects, or adverse effects on CNS maturation and subsequent development. Furthermore, phenothiazines have been shown also to release bilirubin from its binding sites, which may cause neonatal jaundice. However, published data to support these adverse effects are somewhat lacking. The data in the literature comes from two main sources; drug measurements in breast milk (46,49,53,54) and retrospective case reports of infants who have been breast fed by mothers taking psychotropic drugs (36,38,39,48). Occasionally, a third source of information is quoted, namely lactation studies in animals (52), which because of inherent difficulties in their design are of very limited value in assessing human risk. Blacker and colleagues (46) reported that oral doses of 600 mg CPZ did not produce detectable levels in breast milk based on milk samples that were taken from one psychotic mother taken at intervals of 60, 120, and 180 rain following a maintenance dose of 1200 mg CPZ daily. The highest concentration of CPZ in the milk was 0.29 #g/mL at 120 min. Thus, if the infant consumed 124 mL milk it would receive 10 #g CPZ. The baby's growth and development was described as normal, but the duration of breastfeeding was not described. These authors concluded that the microgram quantities of CPZ excreted in breast milk were physiologically insignificant and that breastfeeding was safe. Wiles and colleagues (49) measured CPZ and some of its metabolites in samples of breast milk from four mothers, two of whom breastfed their infants. One of these infants with a plasma concentration of 95 #g/L was reported to be drowsy and lethargic, whilst the other infant with a plasma concentration of 7 #g/L showed no adverse effects. This suggests that CPZ can be higher in milk than in maternal plasma. It was not possible to evaluate whether placental transfer contributed to the drug concentrations measured. The range of drug concentration in the milk was 7 to 98 #g/L with a maximum fetal dose of 15 #g/kg per day. Thus, there are a total of 5 individual cases reported in the literature where CPZ concentration in breast milk and or

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infant plasma have been measured. Unfortunately these data have often been misinterpreted, the implication being that the results were obtained from groups or studies, rather than from five infants. Conflicting data exist for haloperidol also. One report indicates that it is secreted into breast milk in appreciable amounts, based on measurements in one woman taking l0 mg daily without causing adverse effects on the infant (53) whilst another report again based on one woman states that it is present in negligible amounts (54). The animal data indicate that neuroleptics can cause adverse effects on the developing nervous system, which led Bennett and coworkers to question the prudence of further neonatal exposure via the breast milk (52). Pharmacologically, it is not surprising that there is such a wide variation in the drug concentrations measured in the milk because of the different maternal doses used and the wide intersubject variation in the way that these drugs are metabolised. So even on the assumption that infants ingest 150 mL/kg/day of breast milk, and the milk plasma ratio of the drug is known, the way in which the individual mother metabolises the drug plays an important part in assessing the dose received by the infant. Although there are numerous reviews describing both the reported effects and possible theoretical adverse effects of the psychotropic drugs in what seems to be several hundred breastfed infants; there were only two studies found that contained original data (36,38,39,48), and even these were in summary form. Kris and colleagues in three reports from 1957 to 1961 stated that there had been no adverse effects observed in seven infants who had been breastfed whilst their mothers were taking CPZ. Five of the mothers breastfed for up to 3 months and one other breastfed for 4 months. These infants when aged between 5 and 16 months showed no abnormal behaviour or development. Ayd (39,48) followed up 27 women who had been treated with CPZ at various times during pregnancy and the puerperium. But only six of these mothers, all of whom were maintained on CPZ, breast fed their infants. Four infants were nursed for 3 months, one infant for 7 weeks, and one infant for 4 weeks. None of the infants showed any adverse effects. All of these mothers had previously nursed infants whilst not taking CPZ and reported no differences in infant behaviour. Thus, the data on the effect of CPZ via breast milk on postnatal development are based on 13 documented cases. Although references to several women nursing their infants were cited, no details

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were given. No drug concentration in either breast milk or infants' plasma are recorded. The two major reviews on this subject offer different opinions as regards breastfeeding whilst taking psychotropic medication. The American Academy of Pediatrics conclude that as the concentrations of these drugs in breast milk are low, there is little likelihood of adverse effects on the infant. Thus, they do not contraindicate breast feeding in this group of women (51). Bennett (52) on behalf of the W H O Working Group on Drugs and Human Lactation adopts a much more cautious approach to this problem in that he thinks that the limited data available on the secretion of chlorpromazine into breast milk do not permit the concentration of the drug ingested by the infant to be accurately estimated. Nevertheless, he questions the prudence of exposing infants to drugs that allegedly affect the developing CNS. The Working Group is of the opinion that until the situation has been clarified, it seems advisable to avoid the administration of psychotropic drugs to breastfeeding women unless there are compelling clinical indications. No cases of neonatal jaundice associated specifically with psychotropic drug use were found. Neonatal jaundice is common in premature infants, and if women on antipsychotic drugs require preterm delivery, this may contribute to the occurrence or severity of the neonatal problems, which may be enhanced if the infant is breastfed. Thus, careful observation of the neonate in such circumstances would be required.

Summary The two acknowledged world authorities who have reviewed the available data have published conflicting views on whether breast feeding should be contraindicated in women taking phenothiazines (51,52). Thus, for the individual woman and her physician the assessment of risk is complex, and statements such as avoid breastfeeding unless these are compelling reasons are less than helpful. In fact, most of the warning labels concerning the use of phenothiazines in pregnancy and lactation consist of such general statements but give little indication as to why the drugs are being contraindicated. Although some of the phenothiazines have been marketed for 40 years, only five individual published cases were found in which measurements of chlorpromazine in milk or infant plasma were reported (46,49), and another two cases in which haloperidol was measured (53,54). There was lack of uniformity in these data, which is not too surprising in that there was a wide range of doses used and there is consider-


able intersubject variation in the rate of metabolism of these drugs. Despite numerous anecdotal reports of phenothiazine exposure via the breast milk, follow-up data of a reasonably well-documented nature were found for 13 children only. These data showed no increase in neonatal jaundice or adverse effects on behaviour or development. These data were obtained during routine postnatal assessments, not from actual drug measurements (36,38,39,48). The possibility of adverse CNS effects associated with pre- and postnatal exposure to psychotropic drugs has also raised concerns. Although animal studies have shown that biochemical alterations in the CNS can cause interference in receptor transmission (55) and sensitivity (56), there are no equivalent data for the human fetus/neonate. The inherent difficulties of extrapolating animal data to humans tend to cause more problems than the data solve for the majority of clinicians. Even when human data are available, difficulties still exist in interpreting what are often conflicting data in terms of risk assessment for an individual patient. Although brain development in the human subject continues throughout pregnancy and well into postnatal life, none of the follow-up studies (some up to 10 years of age) on infants exposed to psychotropic drugs in utero or via the breast milk have reported significant deficits in either physical or mental development. C O N C L U S I O N S AND R E C O M M E N D A T I O N S The incidence of spontaneous gross malformations at birth is 2 to 3%, so any increase in risk must be set against these background data. There is no clear evidence that the phenothiazines cause a significant increase in malformations, and no particular phenothiazine is more fetotoxic than any of the others. Other forms of fetal and neonatal toxicity are usually related to the doses used and the severity of the maternal illness and are difficult to separate in most circumstances. Thus, when faced with the decision of whether or not to treat a pregnant woman with a phenothiazine, we have found the following scheme useful. Whenever possible use a single drug, in the lowest possible effective dose for an appropriate period of time, determined by the condition requiring treatment.

Acute treatment Nausea and vomiting (usually first trimester). Where dietary and other non-drug-related measures have failed, there is no reason to withhold phenothi-


azines merely because of the pregnancy. It is preferable to use a phenothiazine about which possible adverse effects in pregnancy are known rather than a new drug about which little is known in human pregnancy.

Nausea and vomiting during labour (third trimester use). Although there is evidence of hypotension in a small number of mothers, there was no overall increase in fetal-neonatal or maternal toxicity. Overall, the use of phenothiazines during labour has been described as beneficial to both mother and baby, thus there is no reason to withhold them if they are required. As phenothiazines are being used in combination with other anaesthetic-analgesic drugs at this time, mother and neonate should be monitored carefully for possible toxicity due to drug interactions. Slow elimination of phenothiazine in the neonate occasionally causes lethargy or extrapyramidal effects. Other uses (any trimester). Phenothiazines are sometimes required to treat allergy and related conditions. There is no clear reason to withhold this treatment if it is required. Chronic treatment (treatment at any time) As the outcome of pregnancy in psychotic women is known to be poorer, and because psycotic episodes during pregnancy can be deleterious to both the mother and baby, it is important that the mother receives appropriate treatment with whichever drugs are necessary to control her symptoms. There is no clear evidence that treatment with high doses of phenothiazines throughout pregnancy is associated with a significant increase in malformations. However, the possibility of spontaneous abortion and perinatal mortality does exist. In such cases it is not always possible to say whether it is the drugs used or the severity of the maternal illness that is the causative factor. Some infants exhibit signs of drug-related neonatal toxicity such as sedation, lethargy, or extrapyramidal effects. The evidence of drug-induced neonatal jaundice is much weaker; it may be more likely if the infant is premature. An awareness of these problems coupled with careful observation and good paediatric care to reduce toxicity would seem essential. No evidence was found to indicate that postnatal development of these infants was seriously impaired. Furthermore, it is recommended that the psychotic woman receives counselling about the possible adverse effects on the fetus, preferably before she becomes pregnant. Provided that the illness is well managed, and good pre- and postnatal care is avail-

489

able, the majority of such pregnancies have a normal outcome.

Breastfeeding Current information is based on inadequate and conflicting data from about 20 published cases. Anecdotal evidence on phenothiazines accumulated over 40 years or more indicates that there are no major problems specifically related to breastfeeding. If the mother wishes to breastfeed it may be useful to consider the following criteria: 1. The benefits of breastfeeding and the maternalinfant bonding are considerable and may play an important role in the mother's motivation to care for the baby. There is no evidence to suggest that phenothiazines via the breast milk are associated with permanent damage to the infant. 2. Where toxicity is suspected, careful observation of the infant for signs of sedation, lethargy, irritability, or changes in feeding or sleeping patterns would be appropriate. 3. If these symptoms occur, consideration should be given to the possible cause, such as any residual phenothiazines in the infant's tissue, which were obtained prenatally, or whether the phenothiazincs in the infant are obtained entirely via the breast milk. Similarly, if other medication is being used by the mother, toxicity and drug interactions may be related to this. 4. Whilst formulae exist by which the approximate dose of a given phenothiazine in breast milk can be estimated, these measurements alone are of limited value. Measurements ofphenothiazines in the infant's plasma and urine may be required also in order to determine whether the major source of toxicity is related to the residual levels of phenothiazines in fetal tissues or to the drug obtained via the breast milk. If the toxic symptoms are considered to be due entirely to the drug transferred via the breast milk, then cessation of breast feeding should be considered. REFERENCES 1. Benaron HBW, Dorr EM, Roddick W J, Johnson RP, Gossack L, Tucker BE. The use of chlorpromazine in the obstetric patient: a preliminary report. 1. In the treatment of nausea and vomiting of pregnancy. Am J Obstet Gynecol. 1955;69:776779. 2. Sullivan CL. Treatment of nausea and vomiting of pregnancy with chlorpromazine. Postgrad Med. 1957;22:429-432. 3. Milkovich L, van den Berg BJ. An evaluation of the teratogenicity of certain antinauseant drugs. Am J Obstet Gynecol. 1976; 125:244-248. 4. Edlund M J, Craig TJ. Antipsychotic drug use and birth defects: an epidemiologic reassessment. Comprehensive Psychiatry. 1984;25:32-37.

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5. Refshauge WD. Phenmetrazine and trifluoperazine. Med J Aust. 1963;1:58. 6. Schrire I. Trifluoperazine and foetal abnormalities. Lancet. 1963;1:174. 7. Moriarity AJ. Trifluoperazine and congenital malformations. Can Med Assoc J. 1963;88:97. 8. Moriarity AJ, Nance MR. Trifluoperazine and pregnancy. Can Med Assoc. 1963;88:375-376. 9. Rawlings W J, Ferguson R, Maddison TG. Phenmetrazine and trifluoperazine. Med J Aust. 1963;1:370. 10. Ananth J. Congenital malformations with psychopharmacologic agents. Comprehensive Psychiatry. 1975;16:437-445. 11. Hall G. A case of phocomelia of the upper limbs. Med J Aust. 1963;1:449-450. 12. Vince DJ. Congenital malformations followingphenothiazine administration during pregnancy. Can Med Assoc J. 1969;100:223. 13. King JT, Barry MC, Neary ER. Perinatal findings in women treated during pregnancy with oral fluphenazine. J New Drugs. 1963;Jan/Feb:21-25. 14. Hill RM, Desmond MM, Kay J L. Extrapyramidal dysfunction in an infant of a schizophrenic mother. J Pediatr. 1966;69:589-595. 15. Cleary MF. Fluphenazine decanoate during pregnancy. Am J Psychiatr. 1977;134:815-816. 16. O'Connor M, Johnson GH, James DI. Intrauterine effect of phenothiazines. Med J Aust. 1981 ;1:416-417. 17. Van Waes A, Van de Velde E. Safety evaluation ofhaloperidol in the treatment of hyperemesis gravidarum. J Clin Pharm. 1969;9:224-227. 18. Dieulangard P, Coignet J, Vidal JC. Sur un cas d'ectro-phocomelie, puet-rtre d'origine medicamenteuse. Bull Fed Soc Gynecol Obstet. 1966;18:85-87. 19. Kopelman AE, McCullar FW, Heggeness L. Limb malformations following maternal use of haloperidol. JAMA. 1975;231:63-64. 20. Hanson JW, Oakley GP. Haloperidol and limb deformity. JAMA. 1975;231:26. 21. Karp M, Lamb VE, Benaron HBW. The use of chlorpromazine in the obstetric patient: a preliminary report. II. The treatment of nausea and vomiting of labor and delivery with special reference to the effects on analgesia and anesthesia and on the newborn. Am J Obstet Gynecol. 1955;69:780-785. 22. Harer WB. Chlorpromazine in normal labor. Obstet Gynecol. 1956;8:1-9. 23. Lindley JE, Rogers SF, Moyer JH. Analgesic-potentiating effect of ehlorpromazine during labor. Obstet Gynecol. 1957;10:582-586. 24. Bryans CI, Mulherin CMcL. The use of chlorpromazine in obstetrical analgesia. Am J Obstet Gynecol. 1959;77:406-411. 25. Christhilf SM, Monias MB, Riley RA, Sheehan JC. Chlorpromazine in obstetric analgesia. Obstet Gynecol. 1960;15:625-629. 26. Rumeau-Rouquette C, Goujard J, Huel G. Possible teratogenic effect of phenothiazines in human beings. Teratology. 1977;15:57-64. 27. Slone D, Siskind V, Heinonen O, Monson RR, Kaufman DW, Shapiro S. Antenatal exposure to the phenothiazines in relation to congenital malformations, perinatal mortality rate, birth weight and intelligence quotient score. Am J Obstet Gynecol. 1977;128:486-488. 28. O'Leary JL, O'Leary JA. Nonthalidomide ectromelia: report of a case. Obstet Gynecol. 1964;23:17-20. 29. Tamer A, McKey R, Arias D, Worley L, Fogel BJ. Phenothiazine-induced extrapyramidal dysfunction in the neonate. J Pediatr. 1969;75:479-480. 30. Hammond JE, Toseland PA. Placentaltransfer ofchlorpromazine. Arch Dis Child. 1970;45:139-140. 31. Levy W, Wisniewski K. Chlorpromazine causing extrapyramidal dysfunction: in newborn infant of psychotic mother. New York State J Med. 1974;74:684-685.

Volume 6, Number 6, 1992 32. Ho C-K, Kaufman RL, McAlister WH. Congenital malformations: cleft palate, congenital heart disease, absent tibiae and polydactyly. Am J Dis Child. 1975; 129:714-716. 33. Falterman CG, Richardson CJ. Small left colon syndrome associated with maternal ingestion of psychotropic drugs. J Pediatr. 1980;97:308-310. 34. Rieder RO, Rosenthal D, Wender P, Blumenthal H. The offspring of schizophrenics: fetal and neonatal deaths. Arch Gen Psychiatry. 1975;32:200-211. 35. Erlick-Robinson G, Stewart DE, Flak E. The rational use of psychotropic drugs in pregnancy and postpartum. Can J Psychiatry. 1986;31:183-190. 36. Kris EB. Children born to mothers maintained on pharmacotherapy during pregnancy and postpartum. Recent Adv Biol Psych. 1961;4:180-187. 37. Kris EB. Children of mothers maintained on pharrnacotherapy during pregnancy and postpartum. Curt Ther Res. 1965;7:785-789. 38. Kris EB, Carmichael DM. Chlorpromazine maintenance therapy during pregnancy and confinement. Psychiatr Q. 1957;31:690-695. 39. Ayd FJ. Children born of mothers treated with chlorpromazine during pregnancy. J Clin Med. 1964;71:1758-1763. 40. Sobel DE. Fetal damage due to ECT, insulin coma, chlorpromazine or reserpine. Arch Gen Psychiatry. 1960;2:606611. 41. Favre-Tissot M., BroussolleP. Du pouvoirtrratog~nerventual des produits psychopharmacologiques in Brill A (ed): Neuropsychopharmacology. Proceedings of the Fifth International Congress of the Collegium lnternationale Neuro-psychopharmacologium. Amsterdam, Excerpta Medica Foundation. 1967:583-696. Excerpta Medica Foundation. 1967;583-691. 42. Shader RI. Pregnancy and psychotropic drugs. In: Shader R1 and DiMascio A. (eds.), Psychotropic drug side effects: clinical and theoretical perspectives. Baltimore: Williams and Wilkins Co.; 1970:206-213. 43. Spielvogel A, Wile J. Treatment of the psychotic pregnant patient. Psychosomatics. 1986;27:487-492. 44. Erlenmeyer-Kimling L. Mortality rates in the offspring of schizophrenic parents and a physiological advantage hypothesis. Nature. 1968;220:798-800. 45. Lindelius R. A study of schizophrenia: a clinical, prognostic and family investigation. Acta Psych Scand. 1970;Suppl. 216. 46. Blacker KH, Weinstein BJ, Ellman GL. Mother's milk and chlorpromazine. Am J Psychiat. 1962; 119:178-179. 47. Knowles JA. Effects on the infant of drug therapy in nursing mothers. Drug Ther. 1973;3:57-65. 48. Ayd FJ. Excretion of psychotropic drugs in human breast milk. Int Drug Ther Newslet. 1973;8:33-40. 49. Wiles, DH, Orr MW, Kilakowska T. Chlorpromazine levels in plasma and milk of nursing mothers. Br J Clin Pharm. 1978;5:272-273. 50. Ananth J. Side effects in the neonate from psychotropic agents excreted through breast-feeding. Am J Psychiatry. 1978;135:801-805. 5 I. American Academy of Pediatrics. Psychotropic drugs in pregnancy and lactation. Pediatrics. 1982;69:241-244. 52. Bennett PN, WHO Working Group. Drugs and human lactation. Amsterdam, New York, Oxford: Elsevier; 1988. 53. Whalley LJ, Blain PG, Prime JK. Haloperidol secreted in breast milk. Br Med J. 1981;282:1746-1747. 54. Stewart RB, Karas B, Spring PK. Haloperidol excretion in human milk. Am J Psycbiat. 1980;137:849-850. 55. LundbergP. EngetJ. Neurochemicalbrain changes associated with behavioural disturbances after early treatment with psychotropic drugs. In: Vernadikis A, Giacobini E, Filogamo G. (eds.) Maturation of neurotransmission. Basel: S. Karger; 1978:226-235. 56. Rosengarten H, Friedhoff A. Enduring changes in dopamine receptor cells of pups from drug administered to pregnant and nursing rats. Science. 1979;203:1133-1135.

Committee Opinion No. 637: Marijuana Use During Pregnancy and Lactation.

Pharmacokinetics of metoprolol during pregnancy and lactation.

Maternal cardiac arrhythmias during pregnancy and lactation.

[Antiepileptics during pregnancy and lactation. Pharmacokinetic data].

Breast diseases during pregnancy and lactation.

Breast cancer during pregnancy and lactation.

Letter: Propranolol therapy during pregnancy and lactation.

The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation.

Medication use during pregnancy and lactation: the new FDA drug labeling.

Vitamin D metabolism during pregnancy and lactation in the rat.

The use of flaxseed flour during pregnancy and lactation reverses lower birth weight in offspring from diabetic mothers but averts the development during lactation.

Cognitive-behavioural treatment of panic disorder during pregnancy and lactation.

[Treatment of Chronic Functional Constipation during Pregnancy and Lactation].

Health Effects of Carotenoids during Pregnancy and Lactation.

Multiple sclerosis and vitamin D during pregnancy and lactation.

Use of sodium aurothiomalate during lactation.

[Psychotropic drugs during pregnancy and lactation: development practice].

Lead in bone: implications for toxicology during pregnancy and lactation.

AAP recommendations on iodine nutrition during pregnancy and lactation.

Prolactin binding in rat mammary gland during pregnancy and lactation.

Breast infarction during pregnancy and lactation: A case report.

Use of DMARDs and biologics during pregnancy and lactation in rheumatoid arthritis: what the rheumatologist needs to know.

Pregnancy and lactation--migraine management.

Migraine in pregnancy and lactation.